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  • WCLC 2018

    19th World Conference on Lung Cancer

    Access to all presentations that occur during the 19th World Conference on Lung Cancer in Toronto, ON

    Presentation Date(s):
    • Sept 23 - 26, 2018
    • Total Presentations: 2384

    To review abstracts of the presentations below, narrow down your search by using the Filter options below, and then select the session listing of your choice. Click the "+" for a presentation to expand & view the corresponding Abstract details.

    Presentations will be available 24 hours after their live presentation time

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    MS11 - Stigma and Lung Cancer: Unintended Translational Consequences of Effective Tobacco Control (ID 790)

    • Type: Mini Symposium
    • Track: Prevention and Tobacco Control
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 206 AC
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      MS11.01 - Identifying Consequences of Stigma on Lung Cancer Care Delivery and Patient Outcomes (Now Available) (ID 11445)

      15:15 - 15:35  |  Presenting Author(s): Heidi Hamann

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      MS11.02 - Stigma of Tobacco and Lung Cancer: A South American Perspective (Now Available) (ID 11446)

      15:35 - 15:55  |  Presenting Author(s): Clarissa Baldotto

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      MS11.03 - Prevalence of Perceived Lung Cancer Stigma Among Medical and Nursing Students (Now Available) (ID 11447)

      15:55 - 16:15  |  Presenting Author(s): Jamie L Studts

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      MS11.04 - Taking a Smoking History in the Context of Lung Cancer Treatment: Missed Opportunities for Stigma-Reducing Empathic Encounters with Throacic Oncologists (Now Available) (ID 11448)

      16:15 - 16:35  |  Presenting Author(s): Peter G Harper

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    MS12 - Immunotherapy and RT (ID 791)

    • Type: Mini Symposium
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 105
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    OA07 - Oligometastasis: What Should Be the State-Of-The-Art? (ID 905)

    • Type: Oral Abstract Session
    • Track: Oligometastatic NSCLC
    • Presentations: 8
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 107
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      OA07.01 - Phase II Study of Pembrolizumab for Oligometastatic Non-Small Cell Lung Cancer (NSCLC) Following Completion of Locally Ablative Therapy (LAT) (Now Available) (ID 12590)

      15:15 - 15:25  |  Presenting Author(s): Joshua Michael Bauml  |  Author(s): Rosemarie Mick, Christine Ciunci, Charu Aggarwal, Christiana Davis, Tracey Evans, Charuhas Deshpande, Linda Miller, Pooja Patel, Evan Alley, Christina Knepley, Faith Mutale, Roger B Cohen, Corey J Langer

      • Abstract
      • Presentation
      • Slides

      Background

      Patients (pts) with oligometastatic NSCLC may benefit from LAT (e.g., surgery, stereotactic radiation (SRT)). It is unclear if systemic therapy can provide benefit after LAT. We completed a Phase II study evaluating the efficacy of pembrolizumab after LAT, hypothesizing that immunotherapy would be effective in the setting of a minimal disease burden.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligibility stipulated oligometastatic NSCLC (up to 4 sites) with completion of LAT to all known sites of disease. Within 4-12 weeks of completing LAT, pts began pembrolizumab 200 mg every 21 days for 6 mos, with a provision to continue for up to a year in the absence of progression (PD) or toxicity. Progression-free survival (PFS) and overall survival (OS) were measured from the start of LAT. A sample size of 42 pts would provide 80% power for a test at 5% 1-sided type I error to increase PFS to >=10 mos compared to a historical control PFS of 6.6 mo.

      4c3880bb027f159e801041b1021e88e8 Result

      Since January 2015, 45 pts have been enrolled. Median age is 64 years; 53% male; 89% Caucasian; 89% current and former smokers. Most common metastatic sites are lung (16 pts), brain (18), liver (9), and bone (9). LAT included surgery (30 pts), SRT (30), and chemoradiotherapy (23). Adverse events have been mostly mild. There were two episodes of Grade 3 pneumonitis, two episodes of Grade 3 colitis, and one episode of Grade 3 adrenal insufficiency. Median follow-up from start of LAT is 20.1 mos. To date, 19 pts have had PD or died. Median PFS was 25 mos. PFS rates (+ SE) at 12, 18 and 24 mos are 72%+7%, 54%+9% and 50%+9%, with 10 free of PD/death beyond 24 mos. To date, 10 pts have died. Median OS has not yet been reached. OS rates (+ SE) at 12, 18 and 24 mos are 91%+4%, 82%+7% and 73%+8%, with 14 pts alive beyond 24 mos. Median PFS was 16.9 mos for pts with metachronous disease (n=33), not yet reached for pts with synchronous disease (n=12). Median OS has not yet been reached in either group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pembrolizumab after LAT for oligometastatic NSCLC is feasible and well tolerated. PFS appears quite favorable, preliminarily Final analysis will be performed September 2018. Updated survival estimates and biomarker data will be presented.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA07.02 - ATOM: A Phase II Study to Assess Efficacy of Preemptive Local Ablative Therapy to Residual Oligometastases After EGFR TKI (Now Available) (ID 12977)

      15:25 - 15:35  |  Presenting Author(s): Oscar S.H. Chan  |  Author(s): Kwok Chi Lam, Jacky Yu Chung Li, Frankie Choi, Catherine Wong, Amy Chang, Frankie Mo, Ki Wang, Rebecca Yeung, Tony S. Mok

      • Abstract
      • Presentation
      • Slides

      Background

      NSCLC patients (Pts) harboring EGFR mutation invariably develop resistance to EGFR TKI at a median time of 9-13 months. Prior studies have showed that local ablative therapy (LAT) upon oligoprogression (OP) can extend the duration of TKI therapy effectively. We postulate that residual positron emission tomography (PET) avid lesions after initial treatment of EGFR TKI may harbor resistant clones and preemptive LAT may improve progression free survival (PFS).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This single-arm phase II study aims to determine the efficacy of preemptive LAT to residual metabolic active oligo-metastases after initial TKI. Pts with stage IIIB/ IV EGFR M+ NSCLC who possessed oligoresidual (OR) disease (≤ 4 PET-avid lesions with SUV ≥2.5) after a 3-mth TKI therapy were enrolled. Those with initial PR underwent screening PET-CT. PET avid ORs would be treated by LAT, either by stereotactic ablative radiotherapy (SABR) or surgery per clinicians’ discretion. TKI was continued after LAT until it was considered ineffective. PET-CT was done on the 3rd and 12th month post-LAT (or at progression), apart from regular imaging. Further LAT was allowed if OP was detected. Primary endpoint was PFS rate at 1 year from enrollment. Overall survival (OS), treatment safety and comparison with screen failure cohorts were secondary endpoints.

      4c3880bb027f159e801041b1021e88e8 Result

      18 Pts were enrolled from 2014-17. Recruitment was stopped before the planned number (n = 34) due to slow accrual. Two were not analyzed due to consent withdrawal and significant protocol violation. Median follow up was 28.7 mth. Among the 16 analyzed Pts, the 1 year PFS rate (i.e. 15 mth post TKI) was 62.5%. OS data was not yet mature. All LAT were done by SABR, and none experienced ≥grade 3 SABR related toxicities. Compared with screen failure cohort (n = 43, metabolic CR or PR with residual disease not fulfilling LAT criteria), the 1 year and 2 year PFS favored treatment arm, though statistically not significant (62.5% vs 47.1%, 30.0% vs 7.9%; p = 0.15).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The 1-yr PFS rate is encouraging. A trend of improved long term PFS is noted in Pts receiving preemptive LAT to residual PET-avid OM after initial TKI compared with Pts without LAT. Further studies are warranted.

      Clinical Trial information: NCT01941654

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA07.03 - Addition of Local Therapy to EGFR TKI Showed Survival Benefit in EGFR-Mutant NSCLC pts with Oligometastatic or Oligoprogressive Liver Metastases (Now Available) (ID 12263)

      15:35 - 15:45  |  Presenting Author(s): Tao Jiang  |  Author(s): Caicun Zhou, Huijuan Wang, Qian Chu

      • Abstract
      • Presentation
      • Slides

      Background

      Our previous study demonstrated that EGFR-mutant NSCLC patients (Pts) with liver metastases (LM) showed poor response to EGFR-TKIs than those without LM, suggesting that additional treatment is warranted. Recently, several clinical studies indicated that local therapy (e.g. surgery and radiotherapy) could significantly improve progression-free survival (PFS) in NSCLC Pts with oligometastatic or oligoprogressive disease. This study aimed to investigate whether addition of local therapy to EGFR-TKIs could provide a better survival benefit than TKIs alone in EGFR-mutant NSCLC Pts with oligometastatic or oligoprogressive LM.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Pts with EGFR-mutant NSCLC and LM were enrolled. Oligometastatic LM was defined as < 5 sites in liver without extrahepatic metastases at initial diagnosis. Oligoprogressive LM was defined as < 5 sites in liver without extrahepatic metastases during TKIs therapy. For oligoprogressive cohort, PFS1 was calculated from time of initiation of TKI therapy to first RECIST 1.1 defined progress disease (PD) or death. PFS2 was calculated from time of initiation of TKI therapy to off-TKI PD.

      4c3880bb027f159e801041b1021e88e8 Result

      Totally, 135 cases with EGFR-mutant NSCLC and LM were eligible (64 with oligometastatic LM and 71 with oligoprogressive LM). In oligometastatic cohort, 20 Pts received EGFR-TKIs (E) and 23 Pts received EGFR-TKIs plus local therapy (E+LT) as first-line treatment. The addition of local therapy showed a significantly longer PFS (12.9 vs. 7.9 m, P = 0.041) and OS (36.8 vs. 21.3 m, P = 0.034) than EGFR-TKIs alone. In oligoprogressive cohort, 24 Pts received continuation of EGFR-TKIs plus local therapy (cE+LT) and 25 Pts received switch therapy (ST). Median PFS1 was similar. Median PFS2 (13.9 vs. 9.2 m, P = 0.007) and OS (28.3 vs. 17.1 m, P = 0.011) was significantly longer in cE+LT group than in ST group. Multivariate analysis revealed that addition of local therapy was independently associated with prolonged PFS (HR = 0.435, P = 0.028) and OS (HR = 0.434, P = 0.071) in Pts with oligometastatic LM. Distant metastatic sites were the major pattern of failure in EGFR-TKI plus local therapy group while locoregional recurrence including primary lesions and LM was the major reason in TKI alone group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The current study suggested that EGFR-TKIs plus local therapy demonstrated the prolonged survival benefit than EGFR-TKIs alone in EGFR-mutant NSCLC Pts with oligometastatic or oligoprogressive LM. These findings suggest that local therapy should be further explored in large-scale, strictly designed clinical trials as a standard treatment option in this clinical scenario.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA07.04 - Discussant - OA 07.01, OA 07.02, OA 07.03 (Now Available) (ID 14558)

      15:45 - 16:00  |  Presenting Author(s): Gregory M.M. Videtic

      • Abstract
      • Presentation
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      Abstract not provided

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      OA07.05 - Local Ablative Therapy Improves Survival in Patients with Synchronous Oligometastatic NSCLC Harboring EGFR Mutation Treated with EGFR-TKIs (Now Available) (ID 11141)

      16:00 - 16:10  |  Presenting Author(s): Yaping Xu  |  Author(s): Qinghua Xu, Fei Zhou, Hui Liu, Caicun Zhou

      • Abstract
      • Presentation
      • Slides

      Background

      Non-small-cell lung cancer (NSCLC) is the most common cause of cancer deaths worldwide. Patients with oligometastatic disease can represent an indolent phenotype that could benefit from local ablative therapy(LAT). Howerver, whether first-line continual EGFR-TKIplus LAT could have potential benefit in EGFR-mutant NSCLC patients with oligometastatic disease remains undetermined.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with stage IV EGFR-mutant NSCLC and no more than five metastases at diagnosis in 2 months were enrolled. All patients were treated with first-line EGFR-TKIs. Consolidation LAT included radiotherapy or surgery. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier curves.

      4c3880bb027f159e801041b1021e88e8 Result

      From October 2010 to May 2016, 145 patients were enrolled, including 51 (35.2%) who received consolidation LAT to all oligometastatic sites (All-LAT group), 55 (37.9%) who received consolidation LAT to either primary tumor or oligometastatic sites (Part-LAT group), and 39 (26.9%) who did not receive any consolidation LAT (Non-LAT group). The median PFS in All-LAT, Part-LAT, and None-LAT group were 20.6 months, 15.6 months, and 13.9 months, respectively (P<0.001). The median OS in All-LAT, Part-LAT, and None-LAT group were 40.9 months, 34.1 months, and 30.8 months, respectively (P<0.001). The difference was significant between All-LAT group and Part-LAT or Non-LAT group but was not significant between Part-LAT and Non-LAT group. The median OS was significantly improved with consolidation LAT for primary tumor (40.5 versus 31.5 months, P<0.001), brain metastases (38.2 versus 29.2 months, P=0.002), adrenal metastases (37.1 versus 29.2 months, P =0.032). Adverse events (Grade≥3) due to radiotherapy included pneumonitis (7.7%) and esophagitis (16.9%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The current study demonstrated that consolidation LAT to all sites was a feasible option among patients with EGFR-mutant oligometastatic NSCLC during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with consolidation LAT to partial sites or observation alone.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA07.06 - Efficacy of Local Consolidative Therapy for Oligometastatic Lung Adenocarcinoma Patients Harboring EGFR Mutations. (Now Available) (ID 12523)

      16:10 - 16:20  |  Presenting Author(s): Fang Hu  |  Author(s): Jianlin Xu, Bo Zhang, Changhui Li, Wei Nie, Ping Gu, Ping Hu, Huimin Wang, Yujun Zhang, Yinchen Shen, Shuyuan Wang, Baohui Han, Xueyan Zhang

      • Abstract
      • Presentation
      • Slides

      Background

      For oligometastatic lung adenocarcinoma patients with sensitive EGFR mutations, the role of local consolidative therapy (LCT) remains debatable. The purpose of this study was to investigate the efficacy of LCT in these patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Advanced stage patients with oligometastatic lung adenocarcinoma who harboring EGFR mutation were identified at the Shanghai Chest Hospital from 2010 to 2016.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 253 patients (149 patients who received LCT plus EGFR-TKIs [combination group] and 104 patients who received EGFR-TKIs [TKI monotherapy group] were included. The median PFS time in the combination group was 14 months versus 9 months in the TKI monotherapy group (HR=0.57, 95% [CI] 0.44, 0.79, p<0.01, Figure 1 A). The median OS time in the combination group was 33 months versus 20 months in the TKI monotherapy group (HR=0.56, 95% [CI] 0.41, 0.75, p<0.01, Figure 1D). Survival benefit was independent of EGFR mutation type (PFS: 19del, p=0.02, Figure 1B; 21L858R, p<0.01, Figure 1C; OS: 19del, p=0.0189, Figure 1E; 21L858R, p<0.01, Figure 1F) and metastatic sites .figure 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      LCT combined with TKI therapy was feasible and significantly improved PFS and OS among oligometastatic lung adenocarcinoma patients with sensitive EGFR mutations, and thus, should be considered as an important medical treatment during clinical management.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA07.07 - PFS and OS Beyond 5 years of NSCLC Patients with Synchronous Oligometastases Treated in a Prospective Phase II Trial (NCT 01282450) (Now Available) (ID 13389)

      16:20 - 16:30  |  Presenting Author(s): Dirk De Ruysscher  |  Author(s): Rinus Wanders, Lizza Hendriks, Angela Van Baardwijk, Bart Reymen, Ruud Houben, Gerben Bootsma, Cordula Pitz, Anne-Marie C. Dingemans

      • Abstract
      • Presentation
      • Slides

      Background

      There is increasing interest in the treatment of synchronous oligometastases of NSCLC. Two randomized studies demonstrated an increased PFS by adding a radical local treatment to systemic therapy in responding patients, but long-term data are lacking. We previously reported a median PFS of 12 months and a median OS of 13.5 months in 39 radically treated patients with synchronous oligometastases in a prospective study (De Ruysscher J Thorac Oncol 2012). As the minimal follow-up is now exceeding 6 years, we here report the long-term PFS and OS.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Prospective single-arm phase II trial. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). No previous response to systemic treatment was required.

      4c3880bb027f159e801041b1021e88e8 Result

      Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44-81). Twenty-nine (74%) had local stage III; 17 (44%) brain, seven (18%) bone, and four (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment.

      Median overall survival (OS) was 13.5 months (95% CI 7.6-19.4); 1-, 2-, 3-, 4-, 5, 6-year OS was 56.4%, 23.3%, 12.8 %, 10.3 %, 7.7 %, 5.1 % (2 patients), respectively.

      Median progression-free survival (PFS) was 12.1 months (95% CI 9.6-14.3); 1-, 2-, 3-, 4-, 5, 6-year PFS was 51.3%, 13.6 %,12.8 %, 7.7 %, 7.7 %, 2,5 % (1 patient), respectively.

      Of the 3 patients with a PFS after 5 years, 1 had a squamous cell cancer T2N2 with a single pathologically proven bone metastasis in the sternum, 1 had a NSCLC-NOS T4N0 with a single adrenal metastasis, and 1 a T1N2 adenocarcinoma with a pathologically proven contralateral lung metastasis. The latter patient is still free of disease.

      Two patients developed a second primary cancer: 1 tongue carcinoma after 70 months and 1 an adenocarcinoma in the contralateral lung after 71 months. Both patients died of their second cancer.

      Three patients (7.7 %) had a local recurrence, all in the PTV of their primary tumor.

      Only one patient was treated with a TKI (gefitinib) at progression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      After radical treatment of oligometastases, approximately 8 % of the patients achieve a PFS after 5 years. Entering patients in trials combining local therapy with novel systemic agents (e.g. chemo-immunotherapy) remains mandatory.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA07.08 - Discussant - OA 07.05, OA 07.06, OA 07.07 (Now Available) (ID 14559)

      16:30 - 16:45  |  Presenting Author(s): Sue S Yom

      • Abstract
      • Presentation
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      Abstract not provided

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    OA08 - Mesothelioma: Immunotherapy and microRNA for Diagnosis and Treatment (ID 907)

    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 8
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 201 BD
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      OA08.01 - Long-Term Efficacy and Safety of Nivolumab in Second- or Third-Line Japanese Malignant Pleural Mesothelioma Patients (Phase II: MERIT Study) (Now Available) (ID 11833)

      15:15 - 15:25  |  Presenting Author(s): Takashi Nakano  |  Author(s): Morihito Okada, Takashi Kijima, Keisuke Aoe, Tatsuya Kato, Nobukazu Fujimoto, Kazuhiko Nakagawa, Yuichiro Takeda, Toyoaki Hida, Kuninobu Kanai, Fumio Imamura, Satoshi Oizumi, Toshiaki Takahashi, Mitsuhiro Takenoyama, Hiroshi Tanaka, Yuichiro Ohe

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is a rare and highly aggressive malignancy with poor prognosis and no treatment is approved for patients (pts) progressing after 1st line pemetrexed-platinum doublet. Here, we report latest analysis of MERIT study in previously treated Japanese MPM pts to update the previous report (WCLC 2017, Goto Y, et al).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This open-label study enrolled advanced or metastatic MPM pts previously treated with up to two regimens of chemotherapy including pemetrexed-platinum doublet. Enrollment criteria also included histologically-confirmed, unresectable MPM without prior surgery, measurable lesion and ECOG performance status 0-1. There was no restriction of PD-L1 status. Pts received Nivolumab 240 mg flat dose Q2W until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) (modified RECIST by independent review committee, expected response rate was 19.2%); secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety.

      4c3880bb027f159e801041b1021e88e8 Result

      Thirty-four pts received Nivolumab in this study. Males: 85.2%, median age: 68.0 years (range 43-78), PS 1: 61.8%, epithelial/sarcomatoid/biphasic: 79.4%/8.8%/11.8%, 1 prior regimen: 70.6% and PD-L1 (≧1%)/PD-L1 (<1%)/not evaluable: 58.8%/35.3%/5.9%. At a median follow-up of 16.8 months (range: 1.8-20.2), ORR was 29.4 % (n=10, 95%CI: 16.8-46.2). DCR was 67.6% (n=23, 95%CI: 50.8-80.9). Median DOR was 11.1 months (95%CI: 3.5-16.2). Median PFS was 6.1 months (95%CI: 2.9-9.9) in all pts, 7.2 months (2.8-15.0) in PD-L1 (≧1%) and 2.9 months (1.4-9.3) in PD-L1 (<1%). Median OS was 17.3 months (95%CI: 11.5-NR) in all pts, 17.3 months (8.2-NR) in PD-L1 (≧1%), 11.6 months (5.8-NR) in PD-L1 (<1%), across tissue types, 15.7 months (95%CI: 8.0-NR) in epithelioid and not reached in sarcomatoid/biphasic pts. Six- and 12-month survival rates were 85.3% (95%CI: 68.2-93.6) and 58.8% (95%CI: 40.6-73.2). Twenty-six (76.5%) pts experienced treatment-related adverse event (TRAE), and 11 (32.4%) experienced grade 3/4 TRAEs. Most commonly reported TRAEs were skin disorder (n=6, 17.6%), elevated lipase (n=5, 14.7%), elevated amylase and diarrhea (n=4, 11.8%). Four pts required dose discontinuation because of interstitial pneumonia (n=2, grade2 and 3) and pneumonitis (n=2, grade3).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab shows durable long term efficacy and manageable safety profile in Japanese 2nd/3rd line MPM pts.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA08.02 - DREAM - A Phase 2 Trial of Durvalumab with First Line Chemotherapy in Mesothelioma: Final Result (Now Available) (ID 12022)

      15:25 - 15:35  |  Presenting Author(s): Anna K. Nowak  |  Author(s): Peey-Sei Kok, Willem Joost Lesterhuis, Brett G.M Hughes, Chris Brown, Steven Chuan-Hao Kao, Deme Karikios, Thomas John, Nick Pavlakis, Kenneth O’byrne, Sonia Yip, Wei-Sen Lam, Karen Briscoe, Chris S. Karapetis, Martin R Stockler

      • Abstract
      • Presentation
      • Slides

      Background

      We report here the final results of a single-arm, phase 2 trial designed to determine the activity, safety and tolerability of durvalumab, cisplatin and pemetrexed as first line therapy in MPM. ANZ Clinical trial registry number: ACTRN12616001170415

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Participants were considering first line chemotherapy for MPM, were unsuitable for radical surgery, had an un-irradiated target lesion, and had good performance status (ECOG PS 0-1). Objective tumour response (OTR) and progression free survival (PFS) were assessed primarily according to the modified Response Evaluation Criteria in Solid Tumors for MPM (mRECIST) and as secondary endpoints according to RECIST modified for immunotherapy (iRECIST). Study treatment was durvalumab 1125mg, cisplatin 75mg/m2, and pemetrexed 500mg/m2 all given intravenously on day 1, and repeated every 3 weeks for a maximum of 6 cycles, followed by durvalumab 1125 mg every 3 weeks until progression, unacceptable toxicity, or a maximum total of 12 months. The primary endpoint was PFS at 6 months (PFS6). The sample size of 54 provided 90% power to distinguish the observed proportion PFS6 from a null hypothesis of 45% versus an alternative of 65% with a 1-sided alpha of 5%. Tissue and blood samples were required and collected for translational correlative studies.

      4c3880bb027f159e801041b1021e88e8 Result

      We recruited 54 participants from Dec 2016 to Sep 2017. Median age was 68 (range 42-82), 82% were male, 60 had ECOG PS 0, and 82% had epithelioid histology. Dose intensities were 97% for cisplatin and 94% for durvalumab. The proportion PFS6 was 57% (31/54, 90% CI 45-68%); median PFS was 6.9 months (95% CI 5.5-9.0). The OTR rate was 48% (95% CI 35-61%) according to mRECIST and 50% (95% CI 37-63) according to iRECIST. The median duration of response was 6.5 months. Grade 3-5 adverse events occurred in 36 participants, including neutropenia in 13%, nausea in 11%, anaemia in 7%, fatigue in 6% and any grade peripheral neuropathy in 35%. There were 4 deaths on study, none attributed to durvalumab. Immune-related adverse events occurred in 17 participants, and were of grade 3 or worse in 8, including increased lipase (1), pancreatitis (1), and renal impairment (1).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The combination of durvalumab, cisplatin, and pemetrexed has demonstrated sufficient activity, safety, and tolerability as first line therapy in MPM to warrant further evaluation in a large-scale, randomised phase 3 trial.

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      OA08.03 - Phase II Trial of Pembrolizumab (NCT02399371) In Previously-Treated Malignant Mesothelioma (MM): Final Analysis (Now Available) (ID 12045)

      15:35 - 15:45  |  Presenting Author(s): Arpita Desai  |  Author(s): Theodore Karrison, Pamela Rose, Yi-Hung Carol Tan, Bianca Hill, Erika Pemberton, Christopher Straus, Tanguy Seiwert, Hedy Lee Kindler

      • Abstract
      • Presentation
      • Slides

      Background

      We conducted a phase II trial to assess the activity of pembrolizumab in a non-selected population of mesothelioma patients and determine a PD-L1 expression threshold.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients had histologically-confirmed pleural or peritoneal MM, PS 0-1, prior pemetrexed/platin, disease progression on ≤2 prior regimens. Pembrolizumab 200 mg was administered Q21 days; CT scans were obtained Q9 weeks. The primary endpoints determined: 1) the objective response rate (ORR) in an unselected and a PD-L1 positive population; 2) the optimal threshold for PD-L1 expression using the 22C3 IHC tumor cell/tumor proportion score (TPS) assay. Proceeding to a second stage required ≥3 responses in 35 PD-L1 unselected patients in Part A. Part B would PD-L1 preselect only if a threshold was determined in Part A. At WCLC 2016, we reported 7 responses in Part A, and no PD-L1 threshold was identified (ROC 0.62). Thus, Part B enrolled 30 additional patients without biomarker enrichment.

      4c3880bb027f159e801041b1021e88e8 Result

      65 patients enrolled 5/15-2/18; 1 withdrew. PS 0: 53%; male: 77%; median age: 68 (range 26-85); 1 prior chemotherapy 61%; pleural 87.5%; epithelioid 76.6%, biphasic 15.6%, sarcomatoid 7.8%. Mean cycles: 9 (range 1-34). Partial response: 19%, stable disease: 47%, disease control rate: 66%. ORR by histology: epithelioid 16%, biphasic 10%, sarcomatoid 40%. ORR by disease site: pleural 20%, peritoneal 12.5%. Median progression-free survival: 4.5 months (95% CI: 2.3, 6.2). Median overall survival: 11.5 months (95% CI: 7.6, 14). Grade ¾ toxicity: adrenal insufficiency 3%, pneumonitis 3%, rash 3%, colitis 1.6%, confusion 1.6%, hepatitis 1.6%, hyperglycemia 1.6%. Grade 5: hepatitis 1.6%, unknown 1.6%. PD-L1 expression by TPS (N = 62): none (< 1%) 45%; low (1-49%) 32%; high (≥50%) 23%. ORR by TPS: none 7%, low 26%, high 31%. PD-L1 did not correlate with RR as a continuous metric (ROC area 0.65; 95% CI: 0.48, 0.82), though there was a trend towards a higher ORR in PD-L1 ≥1% (28%) compared with PD-L1 <1% (7%). Median PFS by TPS: none 3.1 months, low 6.2 months, high 6.1 months; 1-year PFS by TPS: none 7%; low 7%; high 31%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Single-agent pembrolizumab has robust activity in PD-L1 unselected, previously-treated mesothelioma. There were no unexpected toxicities. Responses were more frequent in pleural and sarcomatoid MM. Although an optimal PD-L1 threshold could not be identified, a trend towards a higher response rate and more durable PFS with increasing PD-L1 expression was observed. Funded in part by a Mesothelioma Foundation grant.

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      OA08.04 - Discussant - OA 08.01, OA 08.02, OA 08.03 (Now Available) (ID 14560)

      15:45 - 16:00  |  Presenting Author(s): Thomas John

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA08.05 - Quantifying Tumour Infiltrating Lymphocytes (TILs) in Malignant Pleural Mesothelioma (MPM) -Defining the Hot, the Warm and the Cold Tumours. (Now Available) (ID 13326)

      16:00 - 16:10  |  Presenting Author(s): Thomas John  |  Author(s): Bibhusal Thapa, Marzena Walkeiwicz, Gareth Rivalland, Carmel Murone, Khashayar Asadi, Stephen Arthur Barnett, Simon Knight, Shona Hendry, Prudence Russell

      • Abstract
      • Presentation
      • Slides

      Background

      Immunological infiltrates into tumor tissues have been associated with improved prognosis in many cancers including breast, colorectal, cervical, melanoma and lung. While most studies evaluating TILs have been based on evaluation of individual types of T lymphocytes, more recently, a morphological assessment of the TILs based on a simple hematoxylin & eosin (H&E) slide examination has been shown to be an independent positive prognostic factor in HER2 positive early stage breast cancer and lung cancer. We used similar methods to explore the immune microenvironment in a large mesothelioma cohort.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using full face sections of MPM tumour samples, we assessed lymphocytes infiltrating tumour stroma.TILs score was calculated as a % of stromal area assessed to be covered by TILs by an experienced pathologist. Tissue microarrays (TMA) were constructed and stained with PD-L2, LAG3 and TIM3 antibodies. These data were combined with PD-L1 expression, CD4+ and CD8+ infiltration in the same cohort reported previously. We explored the clinical and pathological correlates of the level of TILs.

      4c3880bb027f159e801041b1021e88e8 Result

      Amongst 329 patients evaluated, 308 samples were evaluable for TILs characterisation. The scores ranged from 0-90 (median 30). Stratified using tertiles, 142 patients had low TILs, 68 had medium and 98 had high TILs. High TILs were seen in patients who were PD-L1 (Chi square test p = 0.002) and PD-L2 positive (Chi square test p <0.0001) and of non-epithelioid histological subtype (Fischer’s exact test p = 0.01). On univariate analysis, PD-L2 positivity (HR = 3.2; CI = 2.2-4.6; Log rank P < 0.0001), high TILs (HR = 2.03; CI = 1.5-2.6; Log rank P < 0.0001), and high TIM3+ lymphocytes (HR = 1.3; CI = 1.0-1.7; Log rank P < 0.04) were found to be related to poorer overall survival (OS). On multivariate analysis, higher TILS was found to remain significantly associated with poorer OS along with non-epithelioid histology and poor physiological status.

      8eea62084ca7e541d918e823422bd82e Conclusion

      High TILs correlated with non-epithelioid histology and greater expression of PD-L1 and PD-L2. In contrast to other tumor types, a high TIL infiltrate was negatively prognostic.

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      OA08.06 - Tumour Suppressor MicroRNAs Modulate Drug Resistance by Targeting Anti-Apoptotic Pathways in Malignant Pleural Mesothelioma (MPM) (Now Available) (ID 13539)

      16:10 - 16:20  |  Presenting Author(s): Yuen Yee Cheng  |  Author(s): Marissa Williams, Monica Phimmachanh, Patrick Winata, Glen Reid

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural mesothelioma (MPM) is an aggressive thoracic malignancy with limited treatment options. MPM has a poor prognosis, predominately due to its inherent drug resistance and its limited response to current therapies. Aberrant microRNA expression is a common event in neoplasms with many implicated in chemo-resistance, however their role in MPM drug resistance is largely unexplored.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To investigate the role of microRNAs in MPM drug resistance, we generated MPM cell lines with acquired drug resistance to cisplatin, gemcitabine and vinorelbine by periodic treatment with the IC50 of each chemotherapeutic agent. Expression levels of mature microRNAs were compared between parental MPM cell lines and cell lines with acquired drug resistance using RT-qPCR. BCL2 is an anti-apoptotic gene and a known target of miR-15a/16-1 and miR-34a. To determine if microRNAs potentiate drug sensitization via a Bcl-2 mediated anti-apoptotic pathway, drug sensitivity assays were carried out following reverse-transfection with microRNA mimics and Bcl-2 siRNAs combined with cisplatin, gemcitabine and vinorelbine treatment. Following microRNA mimic transfection in 6-well plates, levels of apoptosis and necrosis were determined by PI and annexin V staining while Bcl-2 mRNA and protein expression was determined by RT-qPCR and Western blotting respectively.

      4c3880bb027f159e801041b1021e88e8 Result

      Expression of miR-15a/16-1 and miR-34a was downregulated in MPM cells with acquired resistance to cisplatin, gemcitabine and vinorelbine, compared to the parental counterpart. Transfection with mimics corresponding to miR-15a/16-1 were most effective in improving sensitivity to all chemotherapeutics tested in drug resistant cell lines. In parental cell lines, miR-15a/16-1 mimic induced sensitization was also observed but restoration of miR-34a and miR-34b was also capable of improving response to cisplatin and vinorelbine. Forced miR-15/16 and miR-34a expression also sensitized both parental and resistant cell lines to cisplatin, gemcitabine and vinorelbine via induction of apoptosis; their ability to increase levels of drug-induced apoptosis suggest they may sensitize cells to chemotherapeutics via an anti-apoptotic mechanism involving Bcl-2. miR-15a/16-1 and miR-34a transfection caused Bcl-2 mRNA and protein reduction, confirming their regulation of Bcl-2 in MPM. Furthermore, siRNA induced knockdown of Bcl-2 also induced a modest improvement in drug sensitivity.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Restoration of microRNA expression sensitized both drug resistant and parental cell lines to chemotherapeutic agents and increased levels of drug-induced apoptosis. Taken together, this data suggests that miR-15a/16-1 and miR-34a are involved in the acquired and intrinsic drug resistance phenotype of MPM cells in part by modulation of apoptotic mechanisms via targeting Bcl-2.

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      OA08.07 - In Silico Discovery of Unannotated miRNAs in Malignant Pleural Mesothelioma Reveals Novel Tissue-of-Origin Markers (Now Available) (ID 14155)

      16:20 - 16:30  |  Presenting Author(s): Brenda C. Minatel  |  Author(s): Erin A Marshall, Christine Anderson, Kevin W. Ng, Katey S.S. Enfield, Adam P Sage, Zhaolin Xu, Wan Lam, Victor D Martinez

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is an aggressive disease. One of the major clinical challenges associated with MPM is the lack of biomarkers capable of distinguishing primary MPM from cancers that have metastasized to the pleura. The current gold standard consists of a panel of positive and negative protein markers to confirm tissue-of-origin; however, many cases remain undistinguishable from other thoracic cancers. Recent studies have suggested that the human genome encodes more microRNAs (miRNAs) than currently annotated. These undescribed sequences have been shown to display enhanced tissue and lineage specificity. Therefore, we hypothesize that MPM tumors express a specific set of previously unannotated miRNA sequences with tissue-specific expression capable of distinguishing MPM from other thoracic diseases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Novel miRNA candidates were detected from small RNA-sequencing data generated by The Cancer Genome Atlas (TCGA) (n=87 MPM) using the miRDeep2 algorithm, a well-established novel-miRNA prediction algorithm. The possible biological roles of these miRNA candidates were investigated by performing a genome-wide 3’UTR target prediction analysis. Additionally, their tissue-specificity was assessed using expression profiles of 1,093 lung tumors from four independent cohorts of adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). Finally, we developed a miRNA-based classifier model using the weighted voting class prediction method to distinguish MPM from other thoracic cancers.

      4c3880bb027f159e801041b1021e88e8 Result

      Our initial analysis revealed 424 miRNA candidates, which were subsequently filtered by RNA structure, abundance of sequencing reads, and genomic location, resulting in 154 previously unannotated miRNA sequences. Interestingly, the novel miRNAs were predicted to target protein-coding genes involved in MPM biology, including the Ataxia Telangiectasia Mutated (ATM) gene, a tumour-supressor gene frequently mutated in MPM. Likewise BRCA1 Associated Protein 1 (BAP1), involved in the DNA damage response pathway, was also a predicted target. Principal component analyses revealed that novel-miRNA expression was able to distinguish MPM from LUAD and LUSC. Furthermore, our miRNA-based classifier model revealed 10 novel miRNAs capable of successfully identifying 86 out of the 87 MPM cases (98.80%) and 100% of LUAD cases (true positive rate = 98.85%, false positive rate = 1.150%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Here, we provide evidence for the presence of 154 previously unannotated miRNA species relevant to MPM. These miRNAs not only significantly expand the miRNA repertoire but also unveil specific roles in MPM biology. Most importantly, the strikingly high sensitivity and specificity of the novel miRNA-based classifier in distinguishing MPM from LUAD illustrates the potential of using these novel miRNAs to supplement current clinical markers to define MPM.

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      OA08.08 - Discussant - OA 08.05, OA 08.06, OA 08.07 (Now Available) (ID 14561)

      16:30 - 16:45  |  Presenting Author(s): Emanuela Felley-Bosco

      • Abstract
      • Presentation
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      Abstract not provided

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    OA09 - Prevention and Cessation (ID 909)

    • Type: Oral Abstract Session
    • Track: Prevention and Tobacco Control
    • Presentations: 8
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 205 BD
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      OA09.01 - 5As to 3As: Evolution of the Systematic Approach to Smoking Cessation in Ontario’s Regional Cancer Centres (Now Available) (ID 14066)

      15:15 - 15:25  |  Presenting Author(s): William Kenneth Evans  |  Author(s): Erin Cameron, Mohammad Haque, Naomi Schwartz, Sahara Khan, Rebecca Truscott

      • Abstract
      • Presentation

      Background

      Smoking is responsible for approximately 30% of all cancer deaths in Canada, and more than 85% of lung cancer cases. Cancer patients who continue to smoke experience decreased treatment efficacy and safety, increased toxicities, greater risk of cancer recurrence and second primaries, poorer quality of life, and decreased survival. Evidence suggests that quitting smoking after diagnosis can significantly reduce these adverse effects. In 2012, Cancer Care Ontario (CCO) introduced a Framework for Smoking Cessation to be implemented across the province’s 14 Regional Cancer Centres (RCCs). In 2017, the Framework was revised from a 5As (Ask, Advise, Assess, Assist, Arrange) to a 3As (Ask, Advise, Act) brief intervention model.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The transition to a 3As model was based on emerging evidence, feedback from CCO’s Smoking Cessation Advisory Committee and Regional Smoking Cessation Champions, as well as learnings from a preliminary program evaluation. The revised Framework recommended an “opt-out” approach to referring smokers to cessation services. Following an environmental scan and site visit with each RCC to assess the current state, site-specific action plans were developed to promote alignment with the revised Framework. Action steps were given priority ratings in the areas of data capture, referrals, and resources. Two phone calls were held with each RCC to monitor progress on action plan implementation. Knowledge translation resources were created to support healthcare providers’ uptake of the 3As model.

      4c3880bb027f159e801041b1021e88e8 Result

      Smoking cessation interventions are often perceived by health care providers as time-consuming; the 3As model made the intervention briefer but no less effective. Over 3,000 knowledge translation resources were distributed to support healthcare providers working directly with cancer patients, including pocket cards and posters with suggested scripts. While the revised Framework officially launched in April 2018, early adopters of the 3As model and opt-out approach have seen improved performance on the Accepted a Referral indicator (proportion of smokers who accepted a referral to cessation services). In 2017, one RCC’s rate tripled from 10.1% to 30.9% in 6 months, while another improved from 13.2% to 36.9% in the same period.

      8eea62084ca7e541d918e823422bd82e Conclusion

      To improve program effectiveness, CCO’s smoking cessation initiative transitioned from a 5As to a 3As model and an opt-out referral process. Frontline staff have indicated a willingness to adopt the simplified approach, and early results show a promising increase in the number of smokers who are connected to smoking cessation services.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA09.02 - Acceptance of Smoking Cessation Services in Cancer Care Ontario’s Lung Cancer Screening Pilot for People at High Risk (Now Available) (ID 13032)

      15:25 - 15:35  |  Presenting Author(s): William Kenneth Evans  |  Author(s): Gail Elizabeth Darling, Beth Miller, Erin Cameron, Monica Yu, Martin Tammemägi

      • Abstract
      • Presentation

      Background

      Participation in lung cancer screening can be a teachable moment for smoking cessation. Current smokers who attend for lung screening may also be motivated to quit. In June 2017, Cancer Care Ontario launched organized lung cancer screening at 3 pilot sites in Ontario with smoking cessation embedded in the screening pathway. Participants are recruited through primary care providers and public-facing messaging.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Smoking cessation services (SCS) are offered to all current smokers (anyone who smoked a cigarette in the past 30 days) interacting with the pilot. Individuals found ineligible for screening are offered a direct referral to the Canadian Cancer Society’s Smokers’ Helpline. Screen-eligible individuals are scheduled for smoking cessation counselling during their baseline low-dose computed tomography (CT) appointment, using an opt-out approach. Hospital-based SCS are provided by trained counsellors and consist of 10 minutes (minimum) of behavioural counselling, a recommendation or prescription for pharmacotherapy, and arrangements for proactive follow-up. The proportions of current smokers who accept referral to SCS and who attend hospital-based smoking cessation counselling are being monitored throughout the pilot. A participant satisfaction survey is completed after the screening appointment (if applicable). Data on quit rates, quit attempts, heaviness of smoking and relapse among screening participants is being captured.

      4c3880bb027f159e801041b1021e88e8 Result

      Between June and October 2017, 50% of the 1241 individuals who underwent risk assessment to determine eligibility for screening were current smokers. Of the 808 individuals eligible for screening, 63% were current smokers: 52% were male, (age 55-64, 61%; 65-74, 39%), 55% had a high school education or less. 27% of ineligible individuals were current smokers. 83% of all current smokers (regardless of screen-eligibility) accepted a referral to SCS. Of screen-eligible current smokers, 89% accepted hospital-based cessation counselling; 88% of those who had a baseline low-dose CT in the reporting period attended a hospital-based counselling session. 93% of survey respondents (response rate 56%) reported being satisfied with the smoking cessation counselling they received.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Acceptance of SCS by current smokers in Cancer Care Ontario’s lung cancer screening pilot is very high. A large majority of screened current smokers have attended a hospital-based counselling session, and satisfaction with this service was high. These findings suggest that an opt-out approach is acceptable to individuals motivated to attend a lung screening program. The final pilot evaluation in spring 2020 will evaluate the success of the smoking cessation initiative by assessing quit attempts, quit rates and relapse among screening participants.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA09.03 - Discussions Between Health Professionals and Smokers About E-Cigarettes: Results from the ITC Policy Evaluation Project (Now Available) (ID 13257)

      15:35 - 15:45  |  Presenting Author(s): Shannon Gravely  |  Author(s): James F Thrasher, K. Michael Cummings, Janine Ouimet, Ann McNeill, Gang Meng, Eric N. Lindblom, Ruth Loewen, Richard O’connor, Mary E. Thompson, Sara C. Hitchman, David Hammond, Bryan W. Heckman, Ron Borland, Hua Hie Yong, Tara Elton-Marshall, Maansi Bansal Travers, Coral Gartner, Geoffrey T. Fong

      • Abstract
      • Presentation

      Background

      The current scientific evidence on the effectiveness of e-cigarettes for smoking cessation is limited, but shows e-cigarettes may be at least as effective as nicotine replacement therapy (NRT), which is a standard treatment for cessation and broadly recommended by health professionals (HPs). E-cigarettes are now more popular for cessation than licensed NRT and prescription medications in countries such as England, the United States (US), and Canada; however, debate exists on whether HPs should advise smokers to use e-cigarettes, particularly for those who have medical comorbidities (e.g., chronic lung disease). The present study included smokers from four countries to examine: (1) the prevalence of: (i) HP advice to quit smoking, (ii) discussions about e-cigarettes, and (iii) recommendations to use e-cigarettes; and (2) smoker’s characteristics associated with discussing e-cigarettes and receiving advice to use them.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data come from the 2016 International Tobacco Control (ITC) Policy Evaluation Project Four-Country Tobacco and E-cigarette Survey, which includes nationally representative samples of adult (≥18 years) smokers from Canada (n=1,922), the US (n=1,501), England (n=2,105), and Australia (n=1,038). Participants eligible for analysis had visited a HP in the last year.

      4c3880bb027f159e801041b1021e88e8 Result

      Among all smokers who visited a HP in the last year, 47.5% received advice to quit smoking, 6.8% reported discussing e-cigarettes, and 2.1% of smokers were recommended to use an e-cigarette (36.1% of those who had a discussion). Discussions and e-cigarette recommendation were more common among smokers who were: younger, highly educated, advised to quit smoking, more frequent e-cigarette users, positive about e-cigarettes, and believed that the public approved of vaping. While smokers with diabetes (p=0.026) or cancer (p=0.018) were more likely to discuss e-cigarettes with a HP, they were not more likely to be recommended to use them. Smokers with chronic lung disease were more likely to be recommended to use an e-cigarette than smokers without lung disease (p=0.026).

      8eea62084ca7e541d918e823422bd82e Conclusion

      These findings suggest that HPs are not taking advantage of discussions with smoking patients to encourage cessation, to provide information about different smoking cessation methods (e.g., suggest e-cigarettes as a cessation aid for smokers who are not willing or able to quit with other strategies), and to encourage smokers who are not inclined to quit to use e-cigarettes as a less-harmful alternative to smoking. More research is urgently needed to assess whether e-cigarettes are a viable alternative to cigarettes for people with lung disease to help them stop smoking and prevent further lung deterioration.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

    • +

      OA09.04 - Discussant - OA 09.01, OA 09.02, OA 09.03 (Now Available) (ID 14562)

      15:45 - 16:00  |  Presenting Author(s): Betty Tong

      • Abstract
      • Presentation

      Abstract not provided

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

    • +

      OA09.05 - Potential Reduction in Lung Cancer Mortality in the US from 2015-2065: A Comparative Modeling Approach (Now Available) (ID 11662)

      16:00 - 16:10  |  Presenting Author(s): Jihyoun Jeon  |  Author(s): Theodore R. Holford, David T. Levy, Eric J. Feuer, Pianpian Cao, Jamie Tam, Lauren Clarke, John Clarke, Chung Yin Kong, Rafael Meza

      • Abstract
      • Presentation

      Background

      Tobacco control efforts implemented since the 1960s in the US have led to considerable reductions in smoking and smoking-related diseases including lung cancer. It is, however, unclear to what extent tobacco use and lung cancer mortality will be further reduced during the next half century due to control efforts that have already been implemented until 2015. To address this question, we developed simulation models that explicitly relate smoking temporal patterns to future lung cancer rates.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Four independent lung cancer natural history models were developed using US smoking (1964-2015) and lung cancer mortality (1969-2010) data. Each model projected lung cancer mortality by smoking status (ages 30-84) from 2015 to 2065 under a status quo scenario, in which current smoking patterns are assumed to continue into the future. Sensitivity analyses were conducted comparing optimistic and pessimistic assumptions relative to the status quo.

      4c3880bb027f159e801041b1021e88e8 Result

      Models validated well to observed lung cancer mortality. Under the status quo scenario, age-adjusted lung cancer mortality is projected to drop 79% from 2015 to 2065. Concomitantly, the annual number of lung cancer deaths is projected to decrease from 135,000 to 50,000 (63% reduction). Despite these decreases, 4.4 millions deaths from lung cancer are projected to occur in the US from 2015-2065.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Tobacco control efforts since the 1960’s will continue to lead to reductions in lung cancer rates well into the next half century. Nonetheless, additional prevention efforts are required to sustain and expand these gains, and further reduce the lung cancer burden in the US.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

    • +

      OA09.06 - Molecular Alterations and Estimated Indoor Radon in NSCLC Patients from the French National Cancer Institute Registry: Radon France Study (Now Available) (ID 14168)

      16:10 - 16:20  |  Presenting Author(s): Laura Mezquita  |  Author(s): Fabrice Barlesi, Edouard Auclin, David Planchard, Angela Botticella, Anas Gazzah, Pernelle Lavaud, Frank Aboubakar Nana, Cecile Lepéchoux, Benjamin Besse

      • Abstract
      • Presentation

      Background

      Radon is a radioactive gas, considered the leading cause of lung cancer in non-smokers. We assessed the correlation between the radon exposure areas in France and the molecular alterations nationally registered in non-small cell lung cancer (NSCLC) patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively collected all NSCLC tested for EGFR, BRAF, HER2 and KRAS mutations (m) and ALK and ROS1 rearrangements (r) on the 28 French Plateform led by INCa (French National Cancer Institute). The prevalence of molecular alterations by region was correlated to the indoor radon risk area based on the official French (Institut de Radioprotection et de Sûreté Nucléaire, INSN, France). Paris and its region Ile-de-France were not included in this analysis due to its high rate of patients that are native from other regions.

      4c3880bb027f159e801041b1021e88e8 Result

      116.424 NSCLC were included. Overall, KRAS was positive in 27,7% (27.314/98.522), EGFR in 11,27% (13.125/116.424), ALK in 3,2% (2.928/91.291), BRAF in 2,3% (2.419/105.919), ROS1 in 1,12% (373/33.222) and HER2 in 0,8% (816/97.749) of all cases.

      We stratified the French regions in 3 areas based on their exposure to radon: high (Auvergne-Rhône-Alpes, Bretagne, Normandie, Pays de la Loire), intermediate (Bourgogne-Franche-Comté, Nouvelle Aquitaine, Occitanie, Provence-Alpes-Cote-d'Azur) and low explosure (Centre Val-de-Loire, Grand Est, Hauts de France). The prevalence of driver alterations (EGFR, BRAF, HER2 and ROS1 were significantly higher in high exposure area. The prevalence of KRAS mutations was significantly higher in low exposure area.

      Low risk

      Intermediate

      High

      P

      EGFR mutation

      1962 (10%)

      4338 (11%)

      4176 (11.4%)

      <0.0001

      ALK rearrangement

      577 (3.3%)

      1019 (3%)

      896 (3%)

      0.35

      BRAF mutation

      327 (1.8%)

      830 (2.4%)

      692 (2.4%)

      0.0001

      HER2 mutation

      109 (0.6%)

      266 (0.9%)

      252 (0.8%)

      0.01

      ROS1 rearrangement

      61 (0.9%)

      133 (0.9%)

      126 (1.3%)

      0.005

      KRAS mutation

      4717 (29.8%)

      9215 (28.2%)

      7895 (27%)

      <0.0001

      Molecular drivers*

      3037 (3.9%)

      6587 (4.4%)

      6142 (4.4%)

      <0.0001

      * EGFR, BRAF & HER2 mutations, ALK & ROS1 rearrangements; KRAS mutation excluded.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NSCLC molecular alterations that are linked to low tobacco consumption were higher in the French region with high radon exposure. Role of the radon in lung cancer carcinogenesis of specific molecular subtypes should be further explored.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

    • +

      OA09.07 - Association Between Outdoor Air Pollution And Lung Cancer in Female Never Smokers (Now Available) (ID 14485)

      16:20 - 16:30  |  Presenting Author(s): Renelle L Myers  |  Author(s): Michael Brauer, Sim Ladhar, Sukhinder Atkar-Khattra, John Yee, Cheryl Ho, Anna McGuire, Kyle Grant, Alex Lee, Barbara Melosky, Sophie Sun, Martin Tammemägi, Stephen Lam

      • Abstract
      • Presentation

      Background

      Long term exposure to ambient particulate matter (PM2.5) has been associated with an increased risk of developing lung cancer, and is estimated to be responsible for ~23% of global lung cancer deaths. No current lung cancer screening risk prediction model uses air pollution as an individual risk factor in its risk calculation. As smoking rates decrease globally, and air pollution increases, it is important to assess the effect of long term outdoor air pollution exposure on lung cancer risk especially in never smokers.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We enrolled 421 patients with newly diagnosed lung cancer presenting to BC Cancer and conducted a detailed residential history from birth to estimate their air pollution exposure since 1996 when accurate high-resolution concentration estimates of PM2.5 particulate matter derived from satellite observations and ground measurements became available. The average PM2.5 exposure was quantified by combining residential histories with exposure data.

      4c3880bb027f159e801041b1021e88e8 Result

      The demographics of the 262(62%) ever smokers, and 159(38%) never smokers with lung cancer are shown in Table 1. Median exposure of all cancer patients was 7.1 PM2.5 ug/m3 (IQR 6.8-7.3; Range 4.3-65.8). Of the ever smokers, 6.1% had a PM2.5 >10 ug/m3 whereas 15.1% of the never smokers had a PM2.5 >10 ug/m3. Among never smokers with lung cancer with high PM2.5 exposure >10 ug/m3, 74% were female and 83% were of Asian descent. Using a logistic regression model, we demonstrated a significant association between air pollution exposure and never smokers compared to ever smokers in women: Odds Ratioper_1_LN-transformed unit = 12.05 (p<0.001). This association was absent in males (interaction p=0.006).

      8eea62084ca7e541d918e823422bd82e Conclusion

      table1.jpgIn women with lung cancer, outdoor air pollution exposure was significantly higher in never smokers than in ever smokers. This association was not observed in men with lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

    • +

      OA09.08 - Discussant - OA 09.05, OA 09.06, OA 09.07 (Now Available) (ID 14563)

      16:30 - 16:45  |  Presenting Author(s): Douglas Arenberg

      • Abstract
      • Presentation

      Abstract not provided

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

  • +

    PC03 - Controversies in Management of Resectable Thymoma (ID 842)

    • Type: Pro-Con Session
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 6
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 205 AC
  • +

    PC04 - Targeted Therapy for NSCLC (ID 843)

    • Type: Pro-Con Session
    • Track: Targeted Therapy
    • Presentations: 6
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 106
    • +

      PC04.01 - Optimal Sequencing of EGFR TKI Therapy (Gefitinib/Erlotinib/Afatinib First versus Osimertinib First) (Now Available) (ID 11614)

      15:15 - 15:27  |  Presenting Author(s): James Chih-Hsin Yang

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PC04.02 - Optimal Sequencing of EGFR TKI Therapy - 3rd Generation First (Now Available) (ID 11615)

      15:27 - 15:39  |  Presenting Author(s): Karen L. Reckamp

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PC04.03 - Adjuvant Targeted Therapy for pts with Genomic Alterations - Yes (Now Available) (ID 11616)

      15:39 - 15:51  |  Presenting Author(s): Shun Lu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PC04.04 - Adjuvant Targeted Therapy for pts with Genomic Alterations - No (Now Available) (ID 11617)

      15:51 - 16:03  |  Presenting Author(s): Lecia Sequist

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PC04.05 - NGS/Whole Exome Sequencing for Routine Use (Now Available) (ID 11618)

      16:03 - 16:15  |  Presenting Author(s): Daniel S.W. Tan

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PC04.06 - Focused Panels for Molecular Profiling for Routine Use (Now Available) (ID 11619)

      16:15 - 16:27  |  Presenting Author(s): Fernando Lopez-Rios

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 37
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
    • +

      P1.01-01 - ROS1-Positive Non-Small Cell Lung Cancer: Real-World Data in Korea (Now Available) (ID 11799)

      16:45 - 18:00  |  Presenting Author(s): Beung Chul Ahn  |  Author(s): Sehhoon Park, Sung Won Lim, Hye Ryun Kim, Min Hee Hong, Byoung Chul Cho, Myung-Ju Ahn

      • Abstract
      • Slides

      Background

      ROS1 rearranged non-small cell lung cancer (NSCLC) is classified as a distinct molecular subset with a therapeutically druggable target. ROS1 rearrangement is most often identified in never-smoker with adenocarcinoma and EGFR and ALK wild type patients. Treatment with tyrosine kinase inhibitors (TKIs) which target the ROS1 kinase domain is considered standard of care for the ROS1-positve NSCLC, by showing a robust and durable response. However, information regarding the clinical characteristics and the outcomes of TKI treatment in the real world remains limited.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We have identified 103 consecutive cases of ROS1-positive NSCLC from January 2001 to February 2018 by break apart fluorescence in situ hybridization (FISH) (n=84), next-generation sequencing (n=23) or both (n=3). Information on fusion breakpoints was available for 8 patients. Clinical data including patient characteristics, incidence of brain metastasis, and response to chemotherapy or TKI were retrospectively analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      The median age was 56 years, 58.9% of patients were female, and 75.7% were never smokers. Adenocarcinoma was predominant (98.1%), and 2 cases with pleomorphic carcinoma were identified. Sixty percent of patients had an extra-thorax metastatic lesion, and 22% had intracranial lesion at the initial presentation or at the time of recurrence. Median time to brain metastases was 12.0 months (range 2.1 to 84.1). Majority of the patients received palliative chemotherapy (93.2%), and 7.8% of patients received definite concurrent chemoradiotherapy. Most common fusion partner was CD74 followed by SDC4, EZR, TPM3, TFG, ZCCHC8, SLMAP, and MYO5C, all of which had preserved tyrosine kinase domain of ROS1. There were no clinical correlations between different fusion partners and TKI treatment outcomes. The median overall survival for the study population was 52.1 months (95% confidential interval [CI] 23.6 – not reached). For 90 patients treated with pemetrexed-based chemotherapy, the overall response rate (ORR) and progression-free survival (PFS) was 53.3% and 8.0 months (95% CI 6.4 – 11.7), respectively. The ORR and PFS was 70.7% and 12.7 months (95% CI 8.1 – 21.8) for 50 patients treated with TKI. Brain metastasis was more commonly observed during the TKI treatment (15.5%) than pemetrexed-based chemotherapy (6.7%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      ROS1-positive NSCLC has distinct clinical characteristics with high and durable response to both TKI and pemetrexed-based chemotherapy. Given its novel characteristics and distinct clinical responses to conventional chemotherapies and TKIs, the treatment strategy for ROS1-positive NSCLC remains to be further developed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-02 - Long-Term Outcomes with First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 3-Year Follow-Up from CheckMate 012 (ID 12380)

      16:45 - 18:00  |  Presenting Author(s): Scott J Antonia  |  Author(s): Scott N. Gettinger, Hossein Borghaei, Jonathan W. Goldman, Julie R. Brahmer, Neal E. Ready, David E Gerber, Laura Q Chow, Rosalyn Juergens, Scott A. Laurie, Frances A Shepherd, Xuemei Li, Ang Li, William J. Geese, Matthew D. Hellmann

      • Abstract

      Background

      CheckMate 012 (NCT01454102) is a phase 1 study evaluating several nivolumab monotherapy/combination regimens as first-line treatment for advanced non-small cell lung cancer (NSCLC). CheckMate 012 was the first study to suggest the benefit of nivolumab plus ipilimumab in NSCLC. In the phase 3 study CheckMate 227, nivolumab plus ipilimumab recently demonstrated significantly improved progression-free survival (PFS) as well as more frequent, deeper, and more durable responses versus chemotherapy in patients with chemotherapy-naive advanced NSCLC and high tumor mutational burden (TMB). Here, we provide 2-year follow-up results for nivolumab plus ipilimumab from CheckMate 012. Three-year results, the longest follow-up to date for an immuno-oncology combination in NSCLC, will be presented.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients had recurrent stage IIIb or stage IV chemotherapy-naive NSCLC and Eastern Cooperative Oncology Group performance status 0–1. Patients received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks (n=38) or every 6 weeks (n=39) until disease progression, unacceptable toxicity, or consent withdrawal; pooled results of these two cohorts are presented. Endpoints included safety/tolerability (primary); objective response rate and PFS (secondary); and overall survival (OS), chemotherapy-free survival (CFS), and efficacy by TMB status (exploratory).

      4c3880bb027f159e801041b1021e88e8 Result

      With 2 years of follow-up, no new safety signals were observed. Thirty-three of 77 patients (43%) achieved objective responses, including six investigator-assessed complete responses (8%), three of which were complete pathological responses. Responses were durable (median duration of response, not reached; range, 1.4+ to 27.9+ months). The 2-year PFS rate was 29%. At the time of database lock, 32 of 34 patients (94%) with OS ≥2 years were alive, with four (12%) remaining on treatment and progression-free; 14 (41%) were off treatment and progression-free without subsequent therapy. Three-year follow-up results to be presented include OS, PFS, and select data on CFS, efficacy by TMB status, and characteristics of long-term survivors.

      8eea62084ca7e541d918e823422bd82e Conclusion

      With long-term follow-up, nivolumab plus ipilimumab continued to demonstrate durable clinical benefit and a consistent safety profile as first-line treatment for patients with advanced NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      P1.01-03 - Effect of Prophylactic Cranial Irradiation on Cognitive Function and QoL in NSCLC Patients at High Risk of Brain Metastases (ID 14166)

      16:45 - 18:00  |  Presenting Author(s): Oscar Arrieta  |  Author(s): Ana Gonzalez-Ling, Federico Maldonado, Miguel Angel Salinas Padilla, Manuel Arguelles, Laura-Alejandra Ramírez-Tirado, Zyanya Lucia Zatarain-Barrón, Feliciano Barron, Luis Antonio Cabrera-Miranda, Diana Flores, Andrés F. Cardona

      • Abstract
      • Slides

      Background

      Up to 50% of NSCLC patients develop brain metastases (BM). Prophylactic Cranial Irradiation (PCI) is a potentially useful strategy to prevent this event, although its use remains controversial due to inherent risks. Therefore, actions such as dose adjustment for Whole Brain Radiotherapy (WBRT), or hippocampal-sparing techniques have been explored. We evaluated the impact of PCI on cognitive function and Quality of Life (QoL).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Within the clinical trial NCT01603849 we evaluated a total of 84 histologically-confirmed NSCLC patients with high risk of developing BM (adenocarcinomas harboring oncodrivers (EGFR or ALK) and/or carcinoembryonic antigen (CAE) level at diagnosis ≥20 pg/mL). Patients were randomized 1:1, 41 to receive PCI and 43 to observation. Cognitive function (CF) was evaluated before and after treatment and at 6, 9 and 12 months with Mini Mental State Examination (MMSE). Reliable Change Index was used to evaluate the effect on CF. QoL was assessed through the European Organization for Research and Treatment of Cancer (EORTC-QLQ-30). Differences between groups were compared with Mann Whitney U and Friedman test. OS was estimated from the first MRI assessing the absence of BM until death/last follow-up with Kaplan-Meier and compared with Log-Rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      83.3% of patients presented an EGFR-mutation (n=60) or ALK-rearrangement (n=6). Median OS was 42.8 vs. 25.9 months among patients with or without PCI (p=0.031). MMSE scores and median score values for global QoL, fatigue and cognitive functioning did not differ among groups or at baseline and follow-up. There were also no differences in percentual change at 1-yr (Table).

      Clinical changes (MMSE)

      3 months

      6 months

      9 months

      1 yr

      n/N (%)

      n/N (%)

      n/N (%)

      n/N (%)

      Without PCI

      Without Changes

      38/43 (88.4)

      34/42 (81)

      34/42 (81.0)

      29/37 (78.4)

      Cognitive Deterioration

      0/43 (0)

      2/42 (4.8)

      0/42 (0)

      0/37(0)

      Cognitive Improvement

      5/43 (11.6)

      6/42 (14.2)

      8/42 (19.0)

      8/37 (21.6)

      With PCI

      Without Changes

      39/41 (95.1)

      31/34 (91.2)

      31/34 (91.2)

      27/31(87.1)

      Cognitive Deterioration

      1/41 (2.4)

      0/34 (0)

      0/34 (0)

      1/31(3.2)

      Cognitive Improvement

      1/41 (2.4)

      3/34 (8.8)

      3/34 (8.8)

      3/31 (9.7)

      Baseline

      3 months

      6 months

      9 months

      1 yr

      p-Value (*)

      Diff. at 1 yr

      Median (IQR)

      Median (IQR)

      Median (IQR)

      Median (IQR)

      Median (IQR)

      Median (IQR)

      Global QoL

      Without PCI

      66.7 (50.0 - 83.3)

      66.7 (50.0 - 83.3)

      66.7 (64.6 - 83.3)

      83.3 (66.7 - 85.4)

      83.3 (75.0 - 87.5)

      <0.001

      8.3 (0.0 - 29-2)

      With PCI

      66.7 (50.0 - 83.3)

      66.7 (50.0 - 83.3)

      66.6 (66.7 - 83.3)

      83.3 (66.7 - 83.3)

      83.3 (75.0 - 83.3)

      <0.001

      0.0 (0 - 25.0)

      p-Value (diff between groups)

      0.956

      0.786

      0.903

      0.172

      0.595

      0.791

      Fatigue

      Without PCI

      22.2 (11.1 - 44.4)

      33.3 (22.2 - 44.4)

      22.2 (11.1 - 44.4)

      22.2 (11.1 - 44.4)

      22.2 (11.1 - 33.3)

      <0.001

      0.0 (-22.2 - 0.0)

      With PCI

      22.2 (5.6 -33.3)

      33.3 (11.1 - 33.3)

      22.2 (8.3 - 33.3)

      22.2 (8.3 - 33.3)

      22.2 (0.0 - 33.3)

      <0.001

      0 (0 - 0)

      p-Value (diff between groups)

      0.493

      0.132

      0.942

      0.931

      0.93

      0.553

      Cognitive

      Without PCI

      83.3 (66.7 - 100.0)

      83.3 (66.7 - 100.0)

      83.3 (66.7 - 100.0)

      73.3 (83.3 - 100.0)

      73.3 (83.3 - 100.0)

      0.004

      0 (0 - 0)

      With PCI

      83.3 (66.7 - 100.0)

      83.3 (66.7 - 100.0)

      83.3 (66.7 - 100.0)

      91.7 (70.8 - 100.0)

      83.3 (83.3 - 100.0)

      0.017

      0.0 (0.0 - 0.0)

      p-Value (diff between groups)

      0.854

      0.983

      0.521

      0.411

      0.757

      0.734

      8eea62084ca7e541d918e823422bd82e Conclusion

      PCI was not associated with significant differences in MMSE and QoL scores, furthermore there were no differences when assessing specific subscales (e.g. fatigue and cognitive functioning). These results along with the clinical benefit in OS highlight the benefit of this approach particularly among patients at high risk of developing BM.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-04 - Treatment Patterns and Overall Survival Following Biomarker Testing in Real-World Advanced NSCLC Patients (ID 12743)

      16:45 - 18:00  |  Presenting Author(s): Fabrice Barlesi  |  Author(s): Luis Paz-Ares, Damian R. Page, Ashwini Shewade, Peter Lambert, Tariq I. Mughal, Laurie M. Gay, Mohsen Khorshid, Brandon Arnieri, William Capra, Stefan Foser, Céline Mascaux, Lukas Bubendorf, Lisa I. Wang

      • Abstract

      Background

      Foundation Medicine (FMI) comprehensive genomic profiling and other next-generation sequencing (NGS) tests are gaining importance in routine clinical management of non-small cell lung cancer (NSCLC). They assess multiple genetic alterations that drive sensitivity or resistance to treatment, enabling optimal therapeutic decisions. We evaluated the effect of biomarker testing on treatment patterns and overall survival (OS) in real-world advanced NSCLC (aNSCLC) patients receiving different test types, and in non-tested patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The Flatiron Health (FH) Database comprises patient-level electronic health records from a large network of US cancer clinics. Patients had aNSCLC diagnoses between 01/2013 and 05/2017, ≥2 clinic visits in the FH network, first treatment starting ≤90 days after aNSCLC diagnosis, and biomarker tests before first treatment. Testing data were abstracted for five biomarkers (EGFR, ALK, KRAS, ROS1, and PD-L1). Patients were hierarchically categorized into three testing groups: FMI, other NGS, and single-biomarker non-NGS. Biomarker status and patterns in first treatment were described. Cox proportional hazards models were used to compare OS among testing groups and non-tested patients.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 11/30/2017, 355 patients had ≥1 FMI test, 780 had ≥1 other NGS test, and 6,363 had ≥1 non-NGS test prior to first treatment; 5,148 patients were never tested. Table 1 summarizes biomarker status, treatment patterns, and results of multivariate survival models adjusted for baseline demographic and clinical differences among testing groups. Patients with FMI tests were more likely to receive NCCN-recommended targeted treatments. Better OS was observed for FMI, other NGS, and non-NGS compared with non-tested patients.

      FMI

      Other NGS

      Non-NGS

      Non-tested

      (n = 355)

      (n = 780)

      (n = 6,363)

      (n = 5,148)

      n

      %

      n

      %

      n

      %

      n

      %

      Biomarker status1

      EGFR mutation

      51

      14.4

      121

      15.5

      853

      13.4

      -

      -

      ALK rearrangement

      8

      2.3

      23

      2.9

      187

      2.9

      -

      -

      ROS1 rearrangement

      0

      0

      3

      0.4

      33

      0.5

      -

      -

      KRAS mutation

      94

      26.5

      189

      24.2

      415

      6.5

      -

      -

      PD-L1-positive

      21

      5.9

      112

      14.4

      234

      3.7

      -

      -

      Patterns in first treatment

      NCCN-recommended
      targeted therapy2,3

      77

      21.7

      129

      16.5

      1,037

      16.3

      112

      2.2

      Non NCCN-recommended targeted therapy2,4

      2

      0.6

      3

      0.4

      11

      0.2

      40

      0.8

      NCCN-recommended ICI2,5

      36

      10.1

      102

      13.1

      381

      6.0

      229

      4.4

      Non NCCN-recommended ICI2,6

      2

      0.6

      0

      0

      8

      0.1

      3

      0.1

      Multivariate Cox proportional hazards model to compare OS, hazard ratio (95% CI)

      All aNSCLC7

      0.72*

      (0.61, 0.85)

      0.74*

      (0.66, 0.83)

      0.78*

      (0.74, 0.83)

      1.00

      (ref)

      aNSCLC, non-squamous
      cell histology8

      0.69*

      (0.61, 0.79)

      0.76*

      (0.70, 0.80)

      0.69*

      (0.57, 0.83)

      1.00

      (ref)

      All aNSCLC9

      0.93

      (0.77, 1.13)

      1.05

      (0.92, 1.21)

      1.00

      (ref)

      -

      -

      aNSCLC, non-squamous
      cell histology10

      0.91

      (0.74, 1.13)

      1.01

      (0.87, 1.17)

      1.00

      (ref)

      -

      -

      aNSCLC, non-EGFR-mutated, non-ALK-rearranged, non-squamous cell histology11

      0.9

      (0.74, 1.10)

      0.94

      (0.82, 1.08)

      1.00

      (ref)

      -

      -


      ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; NCCN, National Comprehensive Cancer Network.

      1 Denotes biomarker status overall prior to starting first treatment and represents overall status from all test-types. In case of multiple tests, the following hierarchy is used: positive>negative>pending/unsuccessful/indeterminate/unknown.

      2 Based on the NSCLC NCCN Guidelines, Version 3. 2018; 02/21/2018.

      3 NCCN-recommended targeted therapy implies treatment regimens containing at least one of the following: erlotinib, afatinib, gefitinib, osimertinib, crizotinib, ceritinib, alectinib, brigatinib, dabrafenib+trametinib, cabozantinib, vandetanib, ado-trastuzumab emtansine.

      4 Non NCCN-recommended targeted therapy implies treatment regimens containing at least one of the following: necitumumab, cetuximab, panitumumab, vemurafenib, dabrafenib, trametinib, trastuzumab, pertuzumab+trastuzumab, venetoclax.

      5 NCCN-recommended ICI implies treatment regimens containing at least one of the following: pembrolizumab, nivolumab, atezolizumab.

      6 Non NCCN-recommended ICI implies treatment regimens containing at least one of the following: ipilimumab, avelumab.

      7 Adjusted for age, sex, race, clinic type, payer type, smoking history, stage at initial diagnosis, ECOG performance status, histology, and year of advanced diagnosis.

      8 Adjusted for age, sex, race, clinic type, payer type, smoking history, stage at initial diagnosis, ECOG performance status, and year of advanced diagnosis.

      9 Adjusted for age, sex, race, clinic type, payer type, smoking history, stage at initial diagnosis, ECOG performance status, histology, year of advanced diagnosis, sample type used for the test, and biomarker status.

      10 Adjusted for age, sex, race, clinic type, payer type, smoking history, stage at initial diagnosis, ECOG performance status, year of advanced diagnosis, sample type used for test, and biomarker status.

      11 Adjusted for age, sex, race, clinic type, smoking history, stage at initial diagnosis, ECOG performance status, and year of advanced diagnosis.

      * Indicates a statistically significant estimate (p<0.05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Complexity of real-world aNSCLC biomarker testing and associated treatments creates challenges when comparing OS among testing groups. In the future, as more treatments targeting a wider array of genomic alterations become available and accessible, the utility of NGS-based assays to guide NCCN-recommended treatments with actionable targets and differences in OS may become more apparent.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-05 - Metformin in Combination with Crizotinib for The Treatment of EML4-ALK+ Lung Cancer. (ID 12801)

      16:45 - 18:00  |  Presenting Author(s): Abigail Bland  |  Author(s): Mhairi Nimick, John Ashton

      • Abstract
      • Slides

      Background

      Lung cancer accounts for the highest incidence of cancer mortality worldwide, equating to around 2 million deaths each year. Oncogenic receptor tyrosine kinases (RTK) have been discovered to play a role in cancer progression, and can be the target of novel therapeutics. The anaplastic lymphoma kinase receptor (ALK) is an RTK, and as a result of a chromosomal 2 rearrangement, fuses with echinoderm microtubule associated protein like-4 (EML4) forming the oncogenic EML4-ALK receptor. EML4-ALK contributes to 2-7% of all lung cancer cases and currently the first-line treatment is crizotinib, a tyrosine kinase inhibitor. Although crizotinib produces tumor regression, most patients will develop resistance, constituting a major research problem. Novel strategies are being explored and one such treatment is the anti-hyperglycemic, metformin. Epidemiological studies have shown that metformin reduces the risk of cancer and pre-clinical studies are examining this cytotoxic effect. This work aimed to determine the cytotoxicity and mechanism of a crizotinib/metformin combination in vitro in EML4-ALK+ lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Crizotinib, metformin and the combination were examined using EML4-ALK+ human lung adenocarcinoma cells (H3122), ALK-/KRAF+ human lung adenocarcinoma cells (A549) and crizotinib-resistant (CR-H3122) cells maintained in crizotinib (0.8 µM). Cytotoxicity was tested using the sulforhodmaine B assay and to assess the validity of this assay the MTT assay was used as a comparison. Western blotting examined changes in ALK, p-ALK, mTOR, p-mTOR. Propidium iodine staining and flow cytometry examined changes in the cell cycle in H3122 cells.

      4c3880bb027f159e801041b1021e88e8 Result

      Crizotinib exhibits greater potency in H3122 cells compared to the ALK- A549 (IC50’s of 0.16 µM vs. 1 µM). Interestingly, the addition of metformin (5 mM) to both cell lines did not change the IC50, however, reduced cell viability by ~30% at lower doses of crizotinib. The MTT assay found the same effect. The IC50 of metformin in H3122 cells was 22 mM, whereas this potency was lost in CR-H3122 cells (only a 50% reduction in cell viability with 50 mM). Mechanistically it was discovered that metformin decreases mTOR phosphorylation, a downstream protein of ALK, but has no effect on p-ALK. Both crizotinib and metformin produced a G1 phase arrest, with the effect being enhanced with the combination.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Metformin enhances the effect of low dose crizotinib. It appears that metformin acts by targeting the downstream protein, mTOR, and produces a G1 phase arrest, instead of directly inhibiting ALK. The addition of metformin to chemotherapeutics provides a potential treatment for EML4-ALK+ and other lung cancers.

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      P1.01-06 - Plinabulin, a Novel Immuno-Oncology Agent Mitigates Docetaxel Chemotherapy -Induced-Neutropenia and -Thrombocytopenia in NSCLC Patients. (Now Available) (ID 13016)

      16:45 - 18:00  |  Presenting Author(s): Douglas W. Blayney  |  Author(s): Stephan Ogenstad, Yuankai Shi, Qingyuan Zhang, Lihua Du, Lan Huang, Ramon Mohanlal

      • Abstract
      • Slides

      Background

      Plinabulin (Plin) is a novel non-GCSF small molecule with anti-cancer activity, in development for prevention of Chemotherapy (Chemo)-Induced-Neutropenia (CIN) and under evaluation with induced by Docetaxel (Doc), Adriamycin, Cyclophosphamide, Irinotecan, Gemcitabine, Carboplatin, Abraxane). Plin is administered as a single IV infusion per cycle, and on the same day of Chemo, 30 minutes after Chemo. In contrast to G-CSF, Plin has anti-cancer, immune-enhancing activity due to dendritic cell activation and related T-cell proliferation, and Plin does not cause bone pain. Our randomized phase (Ph) 2 study 101 (NCT00630110) in lung cancer (NSCLC) with Docetaxel (Doc) 75 mg/M2 +/- Plin established the baseline for Grade 4 neutropenia without Plin. We recently completed the Ph2 portion of the Ph2/3 Study 105 (NCT03102606), comparing Plin with Pegfilgrastim (Peg) for Doc CIN prevention in NSCLC. The 20 mg/m2 Plin dose was equally effective as Peg for CIN, and this dose will be taken into Ph3. The CIN nadir was earlier with Peg, and occurrence of bone pain was higher with Peg vs Plin (33% vs 11%, resp), suggesting a different mechanism of action (MoA). To further understand Plin’s MoA, we analyzed hematology results with Plin and Peg treated subjects.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Ph2 Study 105: NSCLC Pts were randomized to Doc 75 mg/ m2 day (D)1, and either Peg 6 mg D2 (n=14), or Plin at 5 (n=14),10 (n=13), 20 (n=14) mg/ m2 D1 (30 minutes after Doc). Blood for central hematology analysis was collected through Cycle 1. Grade (Gr) 4 neutropenia data without Plin (that is Plin 0 mg/ m2) data was taken from study 101.

      4c3880bb027f159e801041b1021e88e8 Result

      Docetaxel-induced Gr 4 Neutropenia was 14%, 23%, 14%, 33% when Doc was combined with Plin at a dose of 20, 10, 5, 0 mg/ m2 . At the highest Plin dose of 20 mg/ m2, Gr 4 Neutropenia frequency (14% for Plin or Peg) and Duration of Grade 4/Severe Neutropenia (DSN; 0.5 days for Plin or Peg) were similar for Plin and Peg, however Gr 4 thrombocytopenia frequency was 50% with Peg and 36% with Plin. All Grade thrombocytopenia was significantly higher (p=0.036) with Peg vs Plin.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Plin appears to be equally effective as Peg against Doc CIN, however Plin, but not Peg, reduced Doc-induced thrombocytopenia. This is further indication of a difference in MoA for Plin vs Peg.

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      P1.01-07 - Immune-Related Pneumonitis in NSCLC Patients Treated with Immune Checkpoint Inhibitors (ICI): Impact of Previous Thoracic Radiotherapy (ID 12805)

      16:45 - 18:00  |  Presenting Author(s): Angela Botticella  |  Author(s): Tony Ibrahim, Laura Mezquita, Lizza Hendriks, Jerome Le Pavec, Roberto Ferrara, Caroline Caramella, Jordi Remon, Stephane Champiat, Jean-Marie Michot, Pernelle Lavaud, Frank Aboubakar Nana, Pierre Gustin, David Planchard, Anas Gazzah, Aurélien Marabelle, Deutsch Eric, Benjamin Besse, Cecile Le Pechoux

      • Abstract

      Background

      Pneumonitis is a potentially lethal side effect of immune checkpoint inhibitors (ICI), occurring in 1–5% of patients enrolled in clinical trials. Little is known about the interactions between ICI and previous thoracic radiation. This is the aim of the present study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between December 2012 and November 2017, 318 consecutive non-small cell lung cancer (NSCLC) patients received ICI in our Institution and their charts were retrospectively analyzed. Primary endpoint was to determine whether previous radiotherapy had an effect on pulmonary toxicity. Pulmonary toxicity was retrospectively assessed by Common Terminology Criteria for Adverse Events version 4.0.

      4c3880bb027f159e801041b1021e88e8 Result

      Median follow-up was 32.8 months [95%CI: 5-190]. Median age at the start of ICI was 63 years. 205 patients (64,5%) were males, 103 (32,4%) smokers and 250 (78,6%) with PS ≤1; 206 (64,8%) had adenocarcinoma and 76 (23,9%) squamous; 79 (24,8%) were KRAS mutated, 18 (5,5%) EGFR mutated and 5 (1,6%) ALK positive. PDL1 was ≥ 1% by immunohistochemistry in 86 (27%), negative in 37 (11,6%) and unknown in 196 (61,3%) patients. ICI treatment was median 3rd line (range: 1-12), 89,4% monotherapy PD-(L)1 inhibition.

      72 patients (22,6%) received a thoracic RT: 62 out of the 72 RT patients (87,5%) were irradiated with a curative intent. 53 patients (73,6% of the RT patients) received thoracic 3D-conformal RT or intensity modulated RT (normo- or mildly hypofractionated), whereas 9 received SBRT.

      16,7% of the RT patients (12/72) showed a G1-4 immune-related pneumonitis (with a G=>3 of 11,1%), whereas for never-irradiated patients the G1-3 rate of immune-related pneumonitis was 2,4% (6/246), with only 1 G3 toxicity observed and no G>4 (t-test, p 0,001).

      Median interval between the onset of the immune-related pneumonitis and the end of the RT was 22,4 months.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NSCLC patients treated with ICI may be at higher risk of developing immune-related pneumonitis when previously treated with curative-intent thoracic RT.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-08 - Hyperresponsive Disease: A New Pattern of Response in NSCLC Patients Treated by Anti-PD-1/PD-L1 (ID 13577)

      16:45 - 18:00  |  Presenting Author(s): Nicole Bouchard  |  Author(s): Marie-Pier Gauthier

      • Abstract
      • Slides

      Background

      Immune-checkpoint inhibitors are standard of care for stage IV non-small cell lung cancer. Pembrolizumab, an anti-PD-1 monoclonal antibody, boosts the host anti-tumor response. Some patients have a better benefit, especially with strongly positive PD-L1 tumors. To our knowledge, hyperresponsive disease has never been reported.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We present 3 of these cases.

      4c3880bb027f159e801041b1021e88e8 Result

      A 52-year-old woman with lung adenocarcinoma with peritoneal carcinomatosis presented to her community hospital for vomiting and abdominal pain of 3-days duration. She had received first-line chemotherapy (carboplatine-pemetrexed) and after progression, was switched to pembrolizumab, started 10 days ago. PD-L1 expression was 100%. Narcotics and antiemetic medications relieved her severe symptoms, but she required hospitalization for 11 days. She did not receive any corticosteroid medication. Medical team was considering palliative care. Three weeks later, imaging showed an almost complete response. Pembrolizumab was restarted, without any gastrointestinal symptoms, with an ongoing response persisting after 13 cycles.

      A 73-year-old man with lung adenocarcinoma with bone metastases was started on first-line pembrolizumab. PD-L1 expression was 100%. Two weeks later, he had severe pelvic pain where a bone metastasis had been previously diagnosed, not treated with radiation therapy. He required a 3-weeks hospitalization, with palliative care for pain control. Imaging showed three weeks later a major regression. He was rechallenged with pembrolizumab without recurrent symptoms, currently receiving his 9th cycle.

      A 74-year-old man with squamous cell lung cancer with bone and liver metastases was started on first-line pembrolizumab. PD-L1 expression was 95%. Three weeks later, he had severe nausea and vomiting lasting two weeks, not relieved by outpatient antiemetic medications. He was hospitalized for IV medications during 8 days. While hospitalized, imaging showed a major regression of the lung and liver lesions. He even needed corticosteroid medication to decrease his symptoms for 2 weeks. He was rechallenged without recurrent symptoms.

      No other etiologies were identified for the symptoms of these 3 patients, including immune-related adverse event (especially endocrine and liver tests), radiation therapy, infection, disease progression or medications. We diagnosed hyperresponsive disease on the basis of the severe symptoms, impressive response on the CT scan and rechallenge with the same medication without recurrent symptoms.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A major response to immune checkpoint inhibitors may mimic a progressive disease. Severe symptoms related to the tumor locations should not systematically be attributed to local progression. Clinicians should suspect the possibility of a hyperresponsive pattern and prescribe imaging to confirm or refute this hypothesis.

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      P1.01-09 - Pembrolizumab Plus Ipilimumab or Placebo in 1L Metastatic NSCLC with PD-L1 Tumor Proportion Score (TPS) ≥50%: KEYNOTE-598 (ID 12958)

      16:45 - 18:00  |  Presenting Author(s): Michael Boyer  |  Author(s): Jessica McLean, Lu Xu, Ayman Samkari, David P Carbone

      • Abstract
      • Slides

      Background

      Pembrolizumab monotherapy significantly prolonged survival vs chemotherapy in previously untreated, advanced NSCLC with PD-L1 expressed on ≥50% of tumor cells (TPS ≥50%) in KEYNOTE-024. Pembrolizumab with chemotherapy led to higher objective response rates (ORRs) vs chemotherapy alone in a similar population in KEYNOTE-021. KEYNOTE-598 (NCT03302234) will evaluate the effects of combination immunotherapy with pembrolizumab and ipilimumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligibility for this randomized, double-blind phase 3 study requires patients be ≥18 years of age and have histologically/cytologically confirmed stage IV metastatic NSCLC, PD-L1 TPS ≥50% per IHC analysis on archival/newly obtained tumor sample, measurable disease per RECIST v1.1, ECOG PS 0/1, absence of EGFR/ALK aberration, and no prior systemic therapy. Patients will be randomized 1:1 to up to 35 administrations of pembrolizumab 200 mg Q3W with 18 cycles of either ipilimumab 1 mg/kg or placebo Q6W. Patients may be eligible for 17 and 9 additional administrations of pembrolizumab and ipilimumab/placebo, respectively. Treatment may be discontinued due to disease progression, intolerable toxicity, or consent withdrawal. Randomization is stratified by ECOG PS (0 vs 1), geography (East Asia vs non–East Asia), and histology (squamous vs nonsquamous). Response is assessed every 9 weeks through week 54, then every 12 weeks per RECIST v1.1 by BICR. Treatment-based decisions may utilize modified RECIST v1.1 for immune-based therapy (iRECIST). Site-assessed progression is verified by BICR before treatment discontinuation. AEs are graded per CTCAE v4.0. Primary endpoints are overall survival and progression-free survival. Secondary endpoints are ORR and duration of response by BICR; time to true deterioration in the composite endpoint of cough, pain in chest, and shortness of breath assessed by EORTC QLQ-LC13 and EORTC QLQ-C30; and safety. Approximately 548 patients will be enrolled. Enrollment began on December 18, 2017; as of April 13, 2018, 33 patients have been enrolled.

      4c3880bb027f159e801041b1021e88e8 Result

      "Section not applicable"

      8eea62084ca7e541d918e823422bd82e Conclusion

      "Section not applicable"

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-10 - Stage III Non-Small Cell Lung Cancer Clinical Outcomes with Surgical Resection After Definitive Neoadjuvant Chemoradiotherapy (Now Available) (ID 14264)

      16:45 - 18:00  |  Presenting Author(s): Ilaria Caturegli  |  Author(s): Melissa Ana Liriano Vyfhuis, Whitney Burrows, Mohan Suntharalingam, Shahed Badiyan, Katherine Scilla, Shamus R Carr, Joseph Friedberg, Gavin Henry, Shelby Stewart, Charles B. Simone, Pranshu Mohindra

      • Abstract
      • Slides

      Background

      The role of neoadjuvant CRT followed by surgery (trimodality therapy) continues to evolve in patients with stage III non-small cell lung cancer (NSCLC). To date, limited prospective data exist assessing definitive preoperative radiotherapy doses. We report our clinical experience of high-dose (definitive) radiation-based trimodality therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between January 2000 and December 2016, 107 consecutive patients with stage III NSCLC treated with curative intent at our institution with definitive doses of neoadjuvant chemoradiotherapy (CRT) were analyzed. The primary endpoint was overall survival (OS) and secondary endpoint was freedom from recurrence (FFR), analyzed using the Kaplan-Meier method with log-rank testing. Cox regression with forward-model selection was used for the multivariate analyses (MVA).

      4c3880bb027f159e801041b1021e88e8 Result

      The patients had a median age of 58.5 years (range: 38-82) and were predominantly Caucasian (76%) with baseline performance status of 0 (69%). Stage grouping, according to the 7thedition of American Joint Committee on Cancer (AJCC) Lung Cancer Staging criteria, was IIIA: 78.5%, T3/4: 43.9%, N2: 74.8%, N3: 8.4%. CRT was delivered concurrently in 98% of the patients. Median radiation dose was 61.2Gy (range 39.6-69.6Gy); 89% receiving ≥60Gy. Radiation technique was (3D) conformal (71.0%) or intensity-modulated radiotherapy (IMRT) (27.1%). The 30-day and 90-day surgical mortality rates were 4.7% and 7.5%, respectively. At a median follow-up of 30 months (range: 3-186 months), estimated OS and FFR (median/5-year) were 61 months/ 49% and 29 months/ 35%, respectively. On univariate analysis (UVA), age ≥60 (HR, 1.776; 95% CI, 1.084–2.909; P=0.023) and having no health insurance (HR, 3.071; 95% CI, 1.060–8.902; P=0.039; as compared to those with private insurance) predicted for an increased risk of death, while receiving consolidation chemotherapy was associated with improved survival (HR, 0.472; 95% CI, 0.258–0.864; P=0.015). On MVA, age ≥60 was the only characteristic with a continued association with OS (HR, 1.779; 95% CI, 1.056–2.998; P=0.039). On UVA, lack of health insurance was the only predictor of disease recurrence (HR, 6.059; 95% CI, 2.244-16.360; P<0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In a carefully selected population, full dose neoadjuvant CRT followed by surgery can achieve high OS and FFR even for stage III NSCLC patients, much higher than recent reports of bimodality therapy (RTOG 0617: median OS of 28.7 months and PACIFIC study: median PFS of 16.8 months). Prospective evaluation of high-dose radiation trimodality therapy versus induction chemotherapy alone is warranted.

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      P1.01-11 - Named Patient Use Program for Afatinib in Advanced NSCLC with Progression on Prior Therapy: Experience from Asian Centers (ID 12968)

      16:45 - 18:00  |  Presenting Author(s): Keunchil Park  |  Author(s): Gee-Chen Chang, Chi Leung Lam, Chun-Ming Tsai, Yuh-Min Chen, Jin-Yuan Shih, Shyam Aggarwal, Shuhang Wang, Sang-We Kim, Young-Chul Kim, Ibrahim Wahid, Rubi Li, Wan-Teck Lim, Virote Sriuranpong, Tsz Tong Chan, Robert M Lorence, Philippe Carriere, Christina Raabe, Agnieszka Cseh

      • Abstract
      • Slides

      Background

      A global named patient use (NPU) program for afatinib in patients with advanced/metastatic NSCLC who had progressed during prior therapy was conducted between May 2010 and January 2016 (Cappuzzo F et al, Future Oncol 2018). Here we describe treatment outcomes for patients at Asian centers.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients had progressed after clinical benefit on prior erlotinib/gefitinib and/or had an activating EGFR/HER2 mutation, had exhausted all other treatments, and were ineligible for afatinib trials. Patients received afatinib (starting dose:30-50 mg/day). Dose modifications were allowed as tolerated. Time to treatment failure (TTF) was calculated from treatment initiation to discontinuation. Adverse event (AE) reporting was mandatory.

      4c3880bb027f159e801041b1021e88e8 Result

      Data were collected from 2242 NSCLC patients across 10 Asian countries. Patients were heavily pretreated, 62% received ≥2 prior chemotherapy lines, and for most, afatinib was 4th-line therapy; almost all had received erlotinib/gefitinib (Table 1). 97% of patients with known tumor status were EGFR mutation-positive (m+). Median TTF was 7.6 months overall, and 7.2 months in patients with EGFR m+ tumors (Table 1). TTF was >12 months in patients with EGFR exon20 insertions and Her2 mutations. ORR was numerically higher in patients with exon20 insertions and G719X/L861Q/S761I mutations than other subgroups (Table 1). Disease control rate was 78% overall. The most frequently reported AEs were rash and diarrhea; no new/unexpected safety signals were identified.

      Table 1. Named patient use (NPU) program for afatinib in advanced/metastatic NSCLC: results from Asian centers
      Total number of patients 2242
      Age; years, median 61
      Female/male; % 60/40
      Any prior treatment; n (%) 2223/2242 (99.2)
      Prior erlotinib and/or gefitinib; n (%) 2202/2223 (99.1)
      Prior erlotinib only; n (%) 866/2202 (39)
      Prior gefitinib only; n (%) 927/2202 (42)
      Prior lines of chemotherapy ≥3, 32%; ≥2, 62%; 1, 23%; 0, 15%
      Prior lines of systemic therapy ≥4, 37%; ≥3, 65%; 2, 21%; 1, 14%; 0, 0%
      EGFR m+; n (%) 1240/1281 (97)
      Specified EGFR mutation; n (%) 1101/1240 (89)
      TTF; months* n ORR, % n
      All patients with data available 7.6 1550 24.4 431
      EGFR m+ 7.2 834 27.7 267
      EGFR mutation specified 6.5 740 - -
      Common mutations (Del19 or L858R) 6.4 692 27.4 230
      Uncommon mutations (all) 8.0 84 30.3 33
      T790M 6.0 34 21.1 19
      G719X, L861Q, or S761I 7.8 28 42.9 7
      Exon 20 insertion 18.0 25 42.9 7
      Her2 m+ 12.2 12 14.2 7
      p.A775 G776insYVMA 12.4 7 25.0 4

      *median

      m+ve, mutation-positive; ORR, objective response rate;

      TTF, time to treatment failure

      8eea62084ca7e541d918e823422bd82e Conclusion

      This analysis from Asian countries in the afatinib NPU program revealed clinically meaningful TTF/ORR in this heavily pre-treated and refractory advanced NSCLC patient population, including activity in common and uncommon EGFR mutations. TTF was numerically longer in patients with uncommon mutations (particularly EGFR exon20 insertions) and HER2 mutations than in those with common EGFR mutations. The safety profile of afatinib was consistent with non-Asian centers.

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      P1.01-12 - SWItch Maintenance PEmbrolizumab in Patients with Metastatic Non Small Cell Lung Cancer (SWIPE) (Now Available) (ID 14151)

      16:45 - 18:00  |  Presenting Author(s): Haris Charalambous  |  Author(s): Flora Kyriacou, Ioannis Stylianou, Paris Vogazianos, Maria Allayioti, Demetris Vomvas, Nikos Katodritis, George Orphanos

      • Abstract
      • Slides

      Background

      Pembrolizumab is currently indicated for first line use for patients with >50% PD-L1 overexpression and for pretreated patients with >1% PD-L1 expression with metastatic Non Small Cell Lung Cancer (NSCLC). There are currently no data for its use as maintenance treatment. SWIPE is a prospective single arm, one stage Phase II study offering Pembrolizumab as maintenance therapy to non-progressors after first line palliative chemotherapy with NSCLC. (NCT 02705820)

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Standard inclusion and exclusion criteria for checkpoint inhibitors studies apply, however also patients with WHO Performance Status (PS) 2 were allowed and there was no restriction on PD-L1 expression. Treatment consisted of Pembrolizumab 200 mg fixed dose every 3 weeks. Radiological assessement with CT scans every 9 weeks in the first year. The study employs a one stage phase II Fleming's design using Immune Related (IR) Progression Free Survival (PFS) at 1 year as primary endpoint. Using response hypotheses of H0 < 12 % and Ha> 25%, with a significance level α=0.05 and power 0.8, 48 patients are required to be entered into this study.

      4c3880bb027f159e801041b1021e88e8 Result

      Thirty-six (36) patients have been enrolled so far. 29 patients have more than 6 months follow up data, and are the subjects of this analysis. 23 males and 6 female patients. Median age 65 years (range 40-82). PS WHO 0 for 12 patients, WHO 1 for 15 patients and WHO 2 for 2 patients. Histology: adenocarcinoma in 22 patients and squamous in 7 patients. In terms of best radiological response 2 patients had a partial response and 13 patients stable disease. Median IR PFS is 6.8 months (CI 4.0-17.2). The 6 month and 1 year IR PFS rate is 60.7% and 45.8%. Median OS is 11.3 months (CI 7.4-15.2). The 6 month and 1 year OS rate is 65.5% and 48.0% (SPSS version 23). Toxicity was mainly grade 1-2; commonest being fatigue 18 patients (62%), anorexia, arthralgia and cough 10 patients (34%). One patient developed diabetes mellitus (grade 3) as auto-immune toxicity. Three (3) patients developed grade 3 dyspnoea, none of which were related to Pembrolizumab. There was one death during treatment due to sepsis, unlikely to be related to Pembrolizumab.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Maintenance Pembrolizumab is associated with a clinically meaningful disease control rate of almost 46% at 1 year with manageable toxicity.

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      P1.01-13 - A Study of S-1 Plus Cisplatin in Patients with Advanced Non-Small-Cell Lung Cancer (ID 12886)

      16:45 - 18:00  |  Presenting Author(s): Yuh-Min Chen  |  Author(s): Chun-Liang Lai, Yu-Feng Wei, Te-Chun Hsia, Gee-Chen Chang

      • Abstract
      • Slides

      Background

      Oral administration of S-1 (Tegafur/Gimeracil/Oteracil potassium fixed combination capsules, 1.0:0.4:1.0 in molar ratio) in combination with cisplatin has been proven non-inferior to the standard-of-care doublet regimen containing docetaxel plus cisplatin in a randomized phase III trial in Japanese patients with advanced non-small-cell lung cancer (NSCLC). The aim of the study was to evaluate the efficacy and safety profiles of oral S-1 plus cisplatin in Taiwanese patients with NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with previously untreated stage IIIB or IV NSCLC were treated with 40 to 60 mg (based on body surface area) of oral S-1 twice daily on days 1–21 plus cisplatin 60 mg/m2 on day 8 in a 5-week cycle for up to six cycles.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 55 patients from 5 sites in Taiwan were enrolled and received the study medication. Among the 46 patients who completed at least 2 cycles of treatment and had tumor assessments, disease control rate was achieved at 69.6% (partial response: 19.6%, stable disease: 50.0%), with median overall survival (OS) and progression free survival (PFS) of 15.1 months (95%CI: 11.5, 25.6) and 5.7 months (95%CI: 3.3, 8.4), respectively. Grade ≥ 3 adverse events (AEs) related to study treatment occurred in 11 patients (20.0%). The most commonly observed treatment-related AEs were nausea (41.8%), followed by decreased appetite, anemia and diarrhea. No febrile neutropenia or treatment-related death were observed in this study.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The study demonstrated similar efficacy and well-tolerated safety profiles as the previous Phase III study in Japan for patients with advanced NSCLC who received oral S-1 plus cisplatin as the first-line doublet chemotherapy regimen in Taiwan.

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      P1.01-14 - Immunotherapy (I) for Advanced, Pre-Treated, Non-Squamous NSCLC (APNS-NSCLC). Preliminary Data of a Pooled Analysis (ID 13469)

      16:45 - 18:00  |  Presenting Author(s): Lorenza Landi  |  Author(s): Davide Tassinari, Chiara Cherubini, Michela Pilati, Maximilian Papi, Stefania Vittoria Luisa Nicoletti, Luigi Arcangelo Lazzari Agli

      • Abstract
      • Slides

      Background

      Background. To assess the role of I for second line treatment of APNS-NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Methods. A pooled analysis of the final data of the CA209057, the KEYNOTE-010 and the OAK trial was performed. Overall Survival (OS) was the primary end point of the trial. The outcomes of patients with PD-L1 expression of 1%-49% (PD-L1 1%-49%), PD-L1 expression <1% (PD-L1<1%) or mutated-EGFR (EGFR+) were analyzed comparing any checkpoint inhibitor with standard chemotherapy. An indirect comparison with network meta-analysis was performed between the different checkpoint inhibitors whenever a significant difference was observed in the pooled analysis. Direct and indirect comparisons were performed using a random effect model.

      4c3880bb027f159e801041b1021e88e8 Result

      Results. The outcome of 1720 patients was analyzed. 313 patients had been treated with Atezolizumab (A), 292 with Nivolumab (N), 270 with Pembrolizumab (P), and 845 with Docetaxel (D). The preliminary results were detailed in the table.

      Legend. CI95%: 95% Confidence Interval; *: Pooled Analysis; **: Network Meta-Analysis.

      OS Hazard Ratio

      CI95%

      A vs D (PD-L1 1%-49%)

      0.571

      0.423-0.771

      P<0.001

      N vs D (PD-L1 1%-49%)

      0.62

      0.467-0.882

      P=0.001

      P vs D (PD-L1 1%-49%)

      0.76

      0.604-0.956

      P=0.019

      I vs D (PD-L1 1%-49%)*

      0.66

      0.555-0.786

      P<0.001

      A vs N (PD-L1 1%-49%)**

      0.921

      0.609-1.392

      P=0.696

      A vs P (PD-L1 1%-49%)**

      0.751

      0.541-1.043

      P=0.087

      N vs P (PD-L1 1%-49%)**

      0.816

      0.597-1.116

      P=0.491

      N vs D (PD-L1<1%)

      0.9

      0.66-1.214

      P=0.491

      A vs D (PD-L1<1%)

      1.04

      0.619-1.747

      P=0.882

      I vs D (PD-L1<1%)*

      0.933

      0.72-1.21

      P=0.601

      P vs D (EGFR+)

      0.88

      0.453-1.71

      P=0.706

      N vs D (EGFR+)

      1.18

      0.693-2.004

      P=0.542

      I vs S (EGFR+)*

      1.052

      0.695-1.594

      P=0.81

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusions. Our data seem to confirm the role of I for APNS-NSCLC with PD-L1 1%-49%. On the contrary, not-significant benefits in terms of OS seem to emerge for patients with PD-L1<1% or EGFR+ expression. Likewise, no significant differences seem to emerge from the indirect comparisons between A, N and P for patients with a PD-L1 1%-49% expression. Although all these data need to be analyzed with caution, as expression of indirect comparisons, waiting further conformations from clinical trials they can support clinicians for daily clinical practice.

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      P1.01-15 - ROS1-Rearranged Non-Small Cell Lung Cancer Is Associated with High Rate of Venous Thromboembolism: Analysis of The METROS Trial (ID 12287)

      16:45 - 18:00  |  Presenting Author(s): Biagio Ricciuti  |  Author(s): Rita Chiari, Lorenza Landi, Anna Maira Morelli, Angelo Delmonte, Gianluca Spitalieri, Diego Cortinovis, Francesco Facchinetti, Sara Pilotto, Claudio Verusio, Antonio Chella, Laura Bonanno, Domenico Galetta, Federico Cappuzzo

      • Abstract
      • Slides

      Background

      Patients with lung cancer are at increased risk for venous thromboembolism (VTE) and 8% to 15% of patients with advanced non-small-cell lung cancer (NSCLC) experience a VTE event during the course of their disease. The incidence of VTE in molecularly defined NSCLC is still unknown. However, emerging data suggests that patients harbouring ALKrearrangements are at increased risk of VTE. In light of the high amino-acid sequence and structural homology with ALK protein, we undertook this study to determine the incidence of VTE in patients with ROS1-rearranged NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The METROS trial is a multicentre prospective phase II study designed to assess efficacy, safety and tolerability of Crizotinib in pre-treated metastatic NSCLC with METamplification or METexon 14 mutation or ROS1rearrangement. ROS1-rearranged patients enrolled within cohort A and expansion cohort of the trial were evaluated in this analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 48 patients with ROS1-rearranged lung adenocarcinomas (median [range] age 50 [28-82]); 17 males [35.4%] and 31 females [64.5%]; PS 0-1 [95.8%], 2 [4.2%]; 21 current/former smokers [43.75], 27 never smokers [56.25]) , 20 (41.6%) had at least one VTE event. VTE events consisted in pulmonary embolism (PE) in 11 patients (55%), deep vein thrombosis (DVT) in 11 patients (55%), renal vein thrombosis in 2 patients (10%). Seven patients (35%) had ≥ 1 VTE event. Patients with VTE were more likely to be older than 65 years (P = 0.029). No other associations between clinical characteristics and development of VTE were observed. The occurrence of VTE was not associated with overall survival.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The incidence of VET is 3- to 5-fold higher in patients harbouring ROS1-rearrangment than previously observed for the general NSCLC population. Whether molecular profile of NSCLC should be incorporated into a risk-stratification tool and decision-making algorithm for VTE diagnosis, prophylaxis and treatment remains to be determined prospectively.

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      P1.01-16 - First-Line Pembrolizumab With or Without Chemotherapy in PD-L1 positive NSCLC: A Network Meta-Analysis of Randomized Trials. (ID 12147)

      16:45 - 18:00  |  Presenting Author(s): Mark K. Doherty  |  Author(s): Seanthel Delos Santos, Amanda Putri Rahmadian, Kelvin K.W. Chan

      • Abstract

      Background

      Pembrolizumab has replaced platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer (NSCLC) with tumor PD-L1 expression >/=50%. Among PD-L1 unselected patients, pembrolizumab + chemotherapy is superior to chemotherapy alone. This network meta-analysis compared pembrolizumab alone with pembrolizumab + chemotherapy in patients with >/=50% PD-L1 positive NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using the Keynote 024 and 189 (PD-L1 >/=50% subgroup) trials, an indirect network was constructed to compare pembrolizumab and pembrolizumab + chemotherapy through the chemotherapy control arms of each trial. Baseline characteristics and chemotherapy outcomes in both trials were examined for heterogeneity. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and adverse events (AEs) including immune-related adverse events (irAE) were extracted from trial results. AE results were unavailable for the PD-L1 >/=50% subgroup of KN189, so overall AE results were used. Comparisons were expressed as hazard ratios (HRs) for survival outcomes, and as risk difference (RD) for ORR and toxicity.

      4c3880bb027f159e801041b1021e88e8 Result

      507 patients were included: 154 on pembrolizumab, 357 on chemotherapy and 410 on combination. Baseline characteristics of patients in both trials were similar in age, sex, performance status and smoking history. Both trials also had similar chemotherapy outcomes (PFS 6 vs 5 mos) suggesting similar patient prognosis. Network meta-analysis showed no difference between pembrolizumab + chemotherapy and pembrolizumab alone in OS (HR 0.70, 95%CI 0.38-1.30, p=0.26) or PFS (HR 0.72, 95%CI 0.45-1.16, p=0.18), but combination therapy was associated with higher ORR (+21.5%, 95%CI 4.83-38.2%, p=0.011). Overall and grade 3-5 AE rates were higher with combination treatment compared with pembrolizumab alone, but irAE appeared less common with combination treatment (table).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Among patients with >/=50% PD-L1 positive NSCLC, pembrolizumab + chemotherapy did not improve OS or PFS compared with pembrolizumab alone, but was associated with higher ORR. Lower rates of irAE with combination therapy are interesting and warrant further study.

      Adverse events for Pembrolizumab + Chemotherapy vs Pembrolizumab Alone

      All Grade Adverse Events

      Grade 3-5 Adverse Events

      Risk Difference (%)

      95% CI

      p-value

      Risk Difference (%)

      95% CI

      p-value

      Any

      17.4

      8.8, 26.0

      <0.001

      18.2

      4.8, 31.5

      0.008

      Led to Discontinuation

      9.4

      1.3, 17.6

      0.023

      5.7

      -1.2, 12.7

      0.11

      Led to Death

      2.1

      -2.7, 6.9

      0.40

      2.1

      -2.7, 6.9

      0.40

      Nausea

      37.2

      24.7, 49.7

      <0.001

      2.0

      -1.8, 5.8

      0.31

      Anemia

      38.4

      26.4, 50.5

      <0.001

      18.3

      9.2, 27.4

      <0.001

      Fatigue

      20.9

      8.9, 32.9

      <0.001

      5.2

      0.6, 9.8

      0.025

      Decreased appetite

      14.9

      3.5, 26.2

      0.01

      3.7

      0.7, 6.7

      0.017

      Diarrhea

      8.6

      -2.0, 19.2

      0.11

      -0.4

      -5.1, 4.4

      0.89

      Neutropenia

      24.9

      14.9, 34.9

      <0.001

      17.3

      9.4, 25.1

      <0.001

      Vomiting

      18.3

      8.4, 28.3

      <0.001

      0.8

      -2.7, 4.2

      0.67

      Pyrexia

      -0.4

      -9.1, 8.3

      0.93

      NA

      Constipation

      10.6

      0.7, 20.5

      0.036

      NA

      Thrombocytopenia

      15

      7.1, 23.0

      <0.001

      6.3

      0.6, 12.0

      0.029

      All Grade Immune-Related Adverse Events

      Grade 3-5 Immune-Related Adverse Events

      Any

      -13.7

      -23.7, -3.74

      0.007

      -4.6

      -11.2, 1.6

      0.15

      Hypothyroidism

      -3.6

      -9.4, 2.3

      0.23

      NA

      Hyperthyroidism

      -5.5

      -11, 0.1

      0.051

      NA

      Pneumonitis

      -3.2

      -8.1, 1.7

      0.20

      -1.2

      -5, 2.5

      0.54

      Infusion reaction

      -1.7

      -6.0, 2.5

      0.43

      NA

      Severe skin reaction

      -4.4

      -8.4, -4.3

      0.03

      -0.4

      -7.8, -0.1

      0.047

      Colitis

      0.3

      -2.3, 2.9

      0.84

      -0.6

      -2.5, 1.4

      0.58

      Myositis

      -1.7

      -3.9, 0.5

      0.14

      NA

      Hypophysitis

      0.1

      -1.4, 1.6

      0.91

      NA

      Nephritis

      1.1

      -0.7, 2.9

      0.24

      0.8

      -0.9, 2.6

      0.35

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-17 - Immune-Related Adverse Events in Patients with Metastatic Non-Small Cell Lung Cancer: Sex Differences and Response to Therapy. (Now Available) (ID 12642)

      16:45 - 18:00  |  Presenting Author(s): Narjust Duma  |  Author(s): Abdel-Ghani M. Azzouqa, Siddhartha Yadav, Katherine Hoversten, Clay T. Reed, Andrea N. Sitek, Elizabeth A. Enninga, Jonas Paludo, Jesus Vera Aguilera, Yanyan Lou, Julian R. Molina, Konstantinos Leventakos, Lisa A. Kottschade, Haidong Dong, Aaron S. Mansfield, Rami Manochakian, Roxana S Dronca, Alex Adjei

      • Abstract
      • Slides

      Background

      Sex differences in non-small cell lung cancer (NSCLC) outcomes have been described. Immune-related adverse events (IRAEs) have emerged as a serious clinical problem in the use of immune checkpoint inhibitors (ICI). Risk factors for IRAEs and their association with response to therapy remain controversial. Therefore, we studied sex differences in IRAEs and their association with response to therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients with metastatic NSCLC treated with anti-PD1 and anti-PDL1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Patients receiving treatment at an outside facility or with history autoimmune disorders were excluded. Kaplan-Meier method was used for time-to-event analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      231 patients were identified, 120 (52%) were women and 111 (48%) were men. Baseline characteristics and ICI distribution were similar among groups (Table 1). Women were more likely to experience IRAEs compared to men (48% vs. 31%, p<0.008). Among patients with IRAEs, women were more likely to be prescribed systemic steroids (63% vs. 41%, p<0.02). Women were more likely to develop pneumonitis (23% vs. 12%, p<0.03) and arthralgia (17% vs. 3%, p<0.04). However, dermatologic toxicities (35% vs. 9%, p<0.002) were more commonly seen in men. In 17% of women the ICI was discontinued due to toxicity (men 7%). Besides sex, no other clinical characteristic was associated with increased IRAEs. Women with IRAEs were more likely to have a radiographic response compared with women without IRAEs (78% vs. 23%, p<0.0001), although this was not observed in men (37% vs. 26%, p>0.22). Better PFS was observed in women with IRAEs (10 months vs. 3.3 months, p<0.0006) compared to women without IRAEs.

      Women % (n)

      Men % (n)

      p value

      PD-L1 expression ≥1%

      30 (36)

      34 (38)

      0.29

      Adenocarcinoma

      77 (92)

      66 (73)

      0.02

      Bone metastasis

      34 (41)

      47 (52)

      0.05

      Brain metastasis

      20 (24)

      22 (24)

      0.76

      Liver metastasis

      13 (15)

      10 (11)

      0.53

      Prior chemotherapy

      74 (89)

      85 (94)

      0.06

      Prior palliative radiation

      53 (63)

      57 (63)

      0.52

      IRAEs

      48 (57)

      31 (34)

      0.006

      ≥3 grade IRAEs

      42 (24)

      29 (10)

      0.22

      Received systemic steroids

      63 (36)

      41 (14)

      0.02

      Required intravenous steroids

      30 (17)

      24 (8)

      0.47

      8eea62084ca7e541d918e823422bd82e Conclusion

      Women with metastatic NSCLC are more likely to experience IRAEs compared to men. In women, an association between IRAEs and response to therapy was observed. Larger studies are needed to investigate the mechanisms underlying these associations.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-18 - Immunosenescence Correlates with Progression upon PD-(L)-1 Blockade (IO) in Advanced Non-Small Cell Lung Cancer (aNSCLC) Patients. (ID 14074)

      16:45 - 18:00  |  Presenting Author(s): Roberto Ferrara  |  Author(s): Marie Naigeon, Eduard Auclin, Boris Duchemann, Lydie Cassard, Jouniaux Medhi, Lisa Boselli, Jonathan Grivel, Aude Desnoyer, Laura Mezquita, Frank Aboubakar Nana, Lizza Hendriks, David Planchard, Caroline Caramella, Jordi Remon, Maud Ngocamus, Claudio Nicotra, Benjamin Besse, Nathalie Chaput

      • Abstract

      Background

      Immunosenescence is a progressive remodeling of immune functions with a multifactorial etiology (i.e. aging, chronic inflammation, cancer). Although a CD28-CD57+KLRG1+ phenotype on peripheral T-lymphocytes is a potential hallmark of immunosenescence, the characterization of such phenotype in IO-treated NSCLC patients and the correlation with clinical characteristics and benefit from immunotherapy are unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A senescent immune phenotype (SIP) defined as a percentage of circulating CD8+CD28-CD57+KLRG1+ T-lymphocytes was assessed by flow cytometry (FC) on fresh blood samples from IO-treated aNSCLC patients (03/2017–04/2018). A log-rank maximization method was used to identify a SIP cut-off level and dichotomize patients accordingly. The objective was to correlate SIP with clinical characteristics and RECIST response by univariate logistic regression analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      39 aNSCLC patients were evaluable for SIP before IO: 38% ≥ 65 years, 87% non-squamous, 38% KRAS mutated, 54% with PD-L1 expression ≥1%, 13% chemotherapy naïve. Among 30 patients evaluable for IO response, 53% had progression (PD), 27% stability (SD), 20% partial response (PR). Median PFS was 1.9 months (95% CI 1.5; 2.5). OS was not calculated due to the short follow-up [6 months (95% CI 4-11)]. SIP (% CD28-CD57+KLRG1+) median value on circulating CD8+ lymphocytes was 15.26% (min 1.87%, max 56.28%). Overall, 13 (33%) of 39 patients had >22.25% CD8+ lymphocytes with a CD28-CD57+KLRG1+ phenotype, being classified as SIP+. SIP status did not correlate with age, IO-baseline patients’ characteristics or chemotherapy exposure. Among patients evaluable for IO response, only 1 (10%) of 10 SIP+ experienced disease control (PR/SD), compared to 13 (65%) of 20 SIP- patients; similarly, PD rate was significantly higher in SIP+ compared to SIP- patients (90% vs 35%, p=0.007) (Figure).

      plot-pd.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Immunosenescence, monitored by FC measurement of 3 surface molecules on circulating CD8 + lymphocytes, is observed in 33% of aNSCLC patients, is independent of age and correlates with lower IO disease control rate.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-19 - Efficacy of Tyrosine Kinase Inhibitors in EGFR Mutated Non-Small Cell Lung Cancer with Leptomeningeal Metastases. (ID 13820)

      16:45 - 18:00  |  Presenting Author(s): Ronan Flippot  |  Author(s): Eduard Auclin, Pamela Biondani, Emilie Le Rhun, Julien Adam, David Planchard, Caroline Caramella, Cecile Le Pechoux, Ludovic Lacroix, Anas Gazzah, Laura Mezquita, Benjamin Besse

      • Abstract
      • Slides

      Background

      Leptomeningeal dissemination (LM) in patients with non-small cell lung carcinoma (NSCLC) is usually associated with dismal prognosis. However, survival data and optimal management of tyrosine kinase inhibitors (TKI) in EGFR-mutated (EGFRm) patients (pts) are unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Pts with EGFRm NSCLC with LM treated in 2 institutions were included. Clinical, pathological and radiological data were retrospectively collected. We performed overall survival (OS) analysis from LM diagnosis. We assessed survival, clinical response rate (CRR) and disease control rate (DCR; stable disease > 2 months or clinical response) in patients who received a subsequent TKI after experiencing LM progression with first-line TKI.

      4c3880bb027f159e801041b1021e88e8 Result

      Seventy pts were included between Apr. 2003 and Feb. 2018. Median age was 54 [26-79], 60 (85%) were non-smokers, 51 (73%) female and median number of prior systemic treatments before LM diagnosis was 2 [1-7].

      Median OS from LM diagnosis was 7 months (m) [95% CI 6-9], with a 1 year-OS of 29%. Pts received a median of 2 [1-6] lines of subsequent systemic therapy and 19 had additional intrathecal treatment.

      At first LM progression, 40 pts received subsequent TKI treatment with a median PFS of 3m [95% CI 2-not reached]. DCR and CRR were 73% and 38%, respectively. In patients without T790M mutation (N=36), median OS was 7 months [95% CI 4-7] with 2nd-line erlotinib (N=21) and 3 months [2-17] with 2nd-line afatinib or gefitinib (N=5). Eight patients received high-dose erlotinib as 2nd-line treatment after prior erlotinib with a median OS of 3 months [1-3] and a DCR of 75%. Four patients with T790M mutation received 2nd-line osimertinib with a median OS of 10 months [6-10] and a DCR of 100%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pts with LM from EGFRm NSCLC have prolonged survival with 1st generation TKI. Second-line erlotinib after LM progression is an efficient approach in T790M-negative pts. Erlotinib dose increase is a suitable strategy in erlotinib-refractory T790M-negative pts.

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      P1.01-20 - Phase III Study Comparing Gefitinib (G) to Gefitinib Combined with Carboplatin and Pemetrexed (GCP) for NSCLC with EGFR Mutations (NEJ009). (ID 11263)

      16:45 - 18:00  |  Presenting Author(s): Tatsuro Fukuhara  |  Author(s): Akira Inoue, Satoshi Morita, Shunichi Sugawara, Yukio Hosomi, Satoshi Ikeda, Akihiko Gemma, Kazuhisa Takahashi, Yuka Fujita, Toshiyuki Harada, Koichi Minato, Kei Takamura, Kunihiko Kobayashi, Toshihiro Nukiwa

      • Abstract
      • Slides

      Background

      Although EGFR-TKI alone has been a standard first-line treatment for patients with advanced NSCLC with EGFR mutations, our phase II study (NEJ005) showed promising efficacy of GCP. NEJ009, an open-label, randomized phase III study, was conducted to evaluate the superiority of GCP vs G in progression-free survival (PFS), PFS2, and overall survival (OS).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with newly diagnosed stage III/IV/recurrent NSCLC harboring EGFR activating mutations (exon 19 deletion or exon 21 L858R) were randomized 1:1 to G 250 mg PO QD or GCP (G 250mg PO QD combined with carboplatin AUC 5 + pemetrexed 500mg/m2, every 3 weeks). The primary endpoints consisting of PFS, PFS2, and OS were sequentially analyzed according to a preplanned gate-keeping method. Secondary endpoints included objective response rate, safety, and quality of life.

      4c3880bb027f159e801041b1021e88e8 Result

      In Sep 2017, a preplanned required number of events of PFS2 was observed. The ITT population included 344 patients with baseline characteristics fairly well balanced between the arms. Although GCP demonstrated significantly better PFS compared to G, there was no difference in PFS2 between the arms as below. Additional OS analysis (G:101 events vs GCP:83 events) revealed that median survival time of GCP was much longer than that of G (52.2 months vs 38.8 months, HR: 0.695, p=0.013).

      8eea62084ca7e541d918e823422bd82e Conclusion

      NEJ009 was the first phase III study which evaluated the efficacy of a combination of EGFR-TKI and platinum doublet chemotherapy in untreated advanced NSCLC patients with EGFR mutations. Although GCP regimen failed to demonstrate its superiority in PFS2, it may increase long survivors.

      ITT Population GCP (N=169) G (N=172)
      Median (months) Median (months) HR
      PFS 20.9 11.2 0.493
      [95%CI: 18.0, 24.2] [95%CI: 9.0, 13.4] [95%CI: 0.390, 0.623]
      P<0.001
      PFS2 20.9 21.1 0.891
      [95%CI: 18.0, 24.2] [95%CI: 17.9, 24.9] [95%CI: 0.708, 1.122]
      P=0.806
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      P1.01-21 - Safety of Durvalumab Retreatment in Advanced NSCLC Patients Who Progressed Following Initial Disease Control In ATLANTIC (ID 12386)

      16:45 - 18:00  |  Presenting Author(s): Marina Chiara Garassino  |  Author(s): Byoung Chul Cho, Joo-Hang Kim, Julien Mazieres, Johan F. Vansteenkiste, Hervé Lena, Jesus Corral, Jhanelle Elaine Gray, John Powderly, Christos Chouaid, Paolo Bidoli, Paul Wheatley-Price, Keunchil Park, Ross Soo, Yifan Huang, Catherine Wadsworth, Phillip A. Dennis, Naiyer A Rizvi

      • Abstract
      • Slides

      Background

      In ATLANTIC, patients who completed a year of durvalumab (anti-PD-L1) treatment but later progressed off therapy were eligible for retreatment. We evaluated safety in these patients compared with the overall study population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      ATLANTIC (NCT02087423) was a Phase 2, open-label, single-arm trial in patients with Stage IIIB–IV NSCLC who had received ≥2 prior systemic treatment regimens, including one platinum-based. The study included three independent cohorts. In C1 (EGFR+/ALK+) and C2 (EGFR−/ALK−), enrollment was enriched for patients with ≥25% of tumor cells (TC) expressing PD-L1, while patients in C3 (EGFR−/ALK−) only had PD-L1 TC ≥90%. Patients received durvalumab 10 mg/kg q2w for ≤12 months. Patients who achieved and maintained disease control but then progressed after completing the initial 12-month treatment period were offered retreatment for a maximum of 12 months of further treatment. Safety and tolerability was a secondary outcome.

      4c3880bb027f159e801041b1021e88e8 Result

      As of November 7, 2017, of 442 patients in the ATLANTIC full analysis set, 102 (23.1%) had completed 12 months of initial treatment and 95 (21.5%) had disease control at the end of initial treatment. A total of 40 patients started retreatment. The median actual duration of exposure to durvalumab was 16.0 weeks (range 1–62; 40.1% of patients on treatment for ≥24 weeks) during initial treatment and 18.1 weeks (range 2–52; 37.5% of patients on retreatment for ≥24 weeks) during retreatment. The table shows safety during initial treatment and retreatment.

      Initial treatment (n=444)

      Retreatment phase (n=40)

      Cohort,* n (%)

      C1 (EGFR+/ALK+)

      111 (25.0)

      7 (17.5)

      C2 (EGFR−/ALK−)

      265 (59.7)

      26 (65.0)

      C3 (EGFR−/ALK−; TC ≥90%)

      68 (15.3)

      7 (17.5)

      Any TRAE, n (%)

      256 (57.7)

      19 (47.5)

      Grade ≥3 TRAEs

      42 (9.5)

      6 (15.0)

      TRAEs leading to death

      0

      2 (5.0)

      Serious TRAEs

      28 (6.3)

      4 (10.0)

      TRAEs leading to discontinuation

      10 (2.3)

      4 (10.0)

      Safety analysis set. *A more detailed analysis of exposure and safety by cohort will be presented. Causes of death were: pneumonitis and respiratory failure; cardiac arrest. TRAE=treatment-related adverse event.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A large proportion of patients (37.5%) maintained retreatment for ≥24 weeks, suggesting that patients who originally completed 12 months of treatment can tolerate sustained retreatment. The tolerability profile of durvalumab upon retreatment was similar to that seen during initial treatment, although there were two treatment-related deaths during the retreatment phase. Retreatment with anti-PD-L1 may be feasible for selected patients with NSCLC who demonstrate original benefit and progress off therapy.

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      P1.01-22 - Effect of Basal Lymphopenia on Outcome of Non Small Cell Lung Cancer Patients Treated with Immunotherapy (Now Available) (ID 14003)

      16:45 - 18:00  |  Presenting Author(s): Giulia Galli  |  Author(s): Marta Poggi, Giovanni Fucà, Martina Imbimbo, Giuseppe Lo Russo, Claudia Proto, Diego Signorelli, Monica Ganzinelli, Nicoletta Zilembo, Filippo De Braud, Marina Chiara Garassino, Milena Vitali

      • Abstract
      • Slides

      Background

      The advent of immunotherapy (IO) induced profound change in treatment paradigm of metastatic non small cell lung cancer (mNSCLC). Different agents proved efficacy against the disease, leading to an improvement in patients’ (pts) survival. Nonetheless, only a minority of treated pts actually derives a benefit from IO. Some predictive factors, such as PD-L1 and tumor mutation burden, have been identified. Contradictory evidences have shown a potential negative predictive role of basal lymphopenia (BL). We investigated this topic in a retrospective cohort of mNSCLC pts.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data about all consecutive mNSCLC pts treated with IO at Istituto Nazionale dei Tumori, Milan, Italy, between 04/2013 and 01/2018 were retrospectively collected. Pts were stratified according to lymphocyte (Lp) count at the first IO administration. BL was considered as a categorical variable, using the Institutional cutoff of 900 Lps/mL. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analysis was performed with Cox proportional model.

      4c3880bb027f159e801041b1021e88e8 Result

      One hundred fifty pts were analyzed, for a median follow-up of 28.6 mos. IO consisted in an anti-PD1 agent in 64.0% of cases, in an anti-PDL1 agent in 31.3% of cases, in a combination anti-PDL1+anti-CTLA4 in 4.7% of cases. First-line IO was administered in 23 cases, second-line IO in 66 cases, third- or more advanced-line IO in 61 cases. Median progression free survival (PFS) and overall survival (OS) of the global population were 3.2 and 11.2 months (mos), respectively. Thirty pts (20.0%) had any grade BL. These group had a significantly worse PFS (1.9 vs 3.0 mos, p.0010) and OS (4.5 vs 13.5 mos, p<.0001) than the control one. Also disease control rate (DCR) showed a significant difference in favor of non-BL pts (58.3% vs 30.0%, p.0074); response rate had a similar trend (25.0% vs 10.0%), without reaching significance (p.0881). The impact of BL on outcome remained significant after correction for the effects of performance status (p. 0045), which was the only other variable influencing OS. No factors other than BL had an influence on PFS at univariate analyses.

      8eea62084ca7e541d918e823422bd82e Conclusion

      BL had a detrimental impact on DCR, PFS and OS in our population. Given the limitations of this retrospective analysis, such results deserves confirmation in larger cases series. However, if BL was confirmed as a negative predictive factor for response to IO, it may become part of a multivariable tool to indentify the best treatment option for each pt with mNSCLC.

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      P1.01-23 - High PD-L1 Expression is Less Common Than Expected Among Advanced NSCLC in Brazil. Are We Missing the Target? (ID 13620)

      16:45 - 18:00  |  Presenting Author(s): Ana Caroline Zimmer Gelatti  |  Author(s): Vladmir Cláudio Cordeiro De Lima, Helano Freitas, Gustavo Werutsky, Ana Maria Gaiger, Clovis Klock, Patricia Pacheco Viola, Christina Shiang, Mariana Petaccia De Macedo, Lisandro Ferreira Lopes, Facundo Zaffaroni, Luiz H. Araujo, Eldsamira Mascarenhas, Clarissa Mathias, Fernando Moura, Giuliano Borges, Carlos Barrios, Mauro Zukin

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors improved outcomes of patients with advanced non-small cell carcinoma (NSCLC). In clinical trials 30% of patients had programmed death receptor ligand-1 (PD-L1) expression above 50% and this frequency may vary through different regions of the world. We aim to describe the real world dada on prevalence of PD-L1 expression, EGFR mutation and ALK translocation in Brazil.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Immunohistochemistry (IHC) for PD-L1, antibody 22C3 PharmDx Dako, was performed in 5 laboratories in Brazil from Aug/2017 through Apr/2018 in cases of advanced NSCLC considered for treatment with immunotherapy. Mutations in EGFR (exons 18 to 21) by Cobas®(Roche), NGS, or other non-specified tests and ALK by IHC (antibodies 5A4 or D5F3) or FISH (Vysis System) were performed in non-squamous cases. All analyses were with SAS (version 9.4). P-values <0.05 were deemed to be statistically significant.

      4c3880bb027f159e801041b1021e88e8 Result

      PD-L1 expression was assessed in 1382 samples of advanced NSCLC. The median age was 67 years, and 55.6% were male. 56.6% had adenocarcinoma, 18.0%, squamous, 20.7%, non-specified NSCLC, 2.5%, other histologies, 1.9%, missing. Of the 1380 cases, 17.4% presented PD-L1 expression ≥50%, 25.4%, 1-49%, and 57.1% <1%. The histological subtype showed association with the expression of PD-L1 (p=0,0431). In adenocarcinoma, 60.7% had no PD-L1 expression, 23.1%, had 1-49%, and 16.1%, ≥50%, while in squamous, 47.3% had no PD-L1 expression, 30.5% had 1-49%, and 22.0%, ≥50%. Among 885 samples with EGFR data, 10.9% were mutated. Both sex and histology showed association with EGFR mutation (p=0.0410 and p<0.0001). Among the men, 9.7% were mutated, while 13,4% of women were mutated. 16.4% of adenocarcinoma and 3.1% of squamous had EGFR mutation. In 855 samples with ALK data, 3.5% were rearranged. ALK rearrangement was associated with sex and age (p=0.0388 and p=0.0088) and was 2.2% in men and 4.8% in women. The group with age <50 had a higher prevalence of ALK rearrangement (8.6%). Among 735 patients without EGFR mutations or ALK rearrangements, 16.8% had PD-L1 ≥50% and 24.0% had 1-49%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results indicate a lower overall prevalence of PD-L1 expression in advanced NSCLC in Brazil as compared with clinical trial data. Among other potential factors, inadequate sample handling, pre-analytical issues, or epidemiology of the biomarker may impact PD-L1 expression. Prevalence of EGFR mutations and ALK translocations was within the range of prior publications in the country. Further regional and institutional analysis will be presented to better characterize the variations in prevalence of these biomarkers outside clinical trials.

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      P1.01-24 - Clinical Efficacy of Immunotherapy in Metastatic Non-Small Cell Lung Cancer Patients Treated with Prior Radiotherapy (Now Available) (ID 13530)

      16:45 - 18:00  |  Presenting Author(s): Daniel Glick  |  Author(s): Elaine Wai, Mary Lesperance, Nicole Croteau, Edward Brooks, Dave Fenton, Leathia Fiorino, Georgia Geller, Zia Poonja, Doran Ksienski

      • Abstract
      • Slides

      Background

      Pivotal clinical trials (KEYNOTE-001) have demonstrated improved survival in non-small cell lung cancer (NSCLC) patients treated with both radiotherapy (RT) and immunotherapy (IO). The purpose of this study was to document response rates and survival in patients receiving both RT and IO in routine clinical practice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All metastatic NSCLC patients treated with Nivolumab or Pembrolizumab between 11/2015 and 10/2017 in one Canadian province were identified. Demographic, tumor, treatment, toxicity, and response data were collected. Fisher’s Exact Test and Chi Squared Test were used to assess the relationship between treatment characteristics and outcome. Log Rank Test and Cox Regression were used to assess overall survival (OS) and progression free survival (PFS).

      4c3880bb027f159e801041b1021e88e8 Result

      271 patients treated with IO were identified of which 202 were treated with previous RT (75%) including 153 treated with chest radiotherapy. Median follow up from initiation of IO was 30.3 (0.3-139.9) weeks. At time of last follow up, 56% of patients had died. There were no statistically significant differences in physician assessed response rates in patients treated with prior radiotherapy (52 vs 58%, p=0.41) or prior chest radiotherapy (52% vs 55%, p=0.71). Median PFS was 11 weeks in patients who received RT and 13.9 weeks in patients who did not (p=0.73). Median OS was 41.3 weeks in the radiotherapy cohort versus 42.9 weeks (p=0.50). On univariate analysis, ECOG (p<0.001) and CCI (p<0.001) were associated with OS while prior chest radiotherapy, prior curative radiotherapy, brain metastases, type of IO, squamous histology, smoking status and age did not.

      8eea62084ca7e541d918e823422bd82e Conclusion

      There were no statistically significant differences in response rates, PFS or OS in patients receiving IO for mNSCLC treated with or without prior RT.

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      P1.01-25 - Carboplatin and Pemetrexed Plus Bevacizumab After Failure of First-Line EGFR-TKI Therapy for NSCLC Harboring EGFR Mutation (CJLSG 0908) (Now Available) (ID 12798)

      16:45 - 18:00  |  Presenting Author(s): Yasuhiro Goto  |  Author(s): Kosuke Takahashi, Hiroshi Saito, Tomohiko Ogasawara, Joe Shindoh, Tomoki Kimura, Yasuteru Sugino, Eiji Kojima, Fumio Nomura, Toru Nakanishi, Yasuhiro Nozaki, Yoshihiro Takeyama, Kazuyoshi Imaizumi, Yoshinori Hasegawa

      • Abstract
      • Slides

      Background

      Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is a standard treatment for untreated, advanced non-small cell lung cancer (NSCLC) harboring an activating EGFR mutation. Many patients who had disease progression after EGFR-TKI are treated with chemotherapy including a platinum agent, but optimal regimen has not been established. This study was designed to evaluate the efficacy and safety of combination therapy with pemetrexed, carboplatin and bevacizumab after the failure of EGFR-TKI treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This study was a multicenter, phase II trial. Patients who experienced disease progression after first-line EGFR-TKI treatment for stage IIIB/IV or recurrent non-squamous NSCLC patients with an activating EGFR mutation (exon 19 deletions or exon 21 L858R point mutation) were eligible. Patients were treated with pemetrexed (500 mg/m2), carboplatin (AUC=5), and bevacizumab (15 mg/kg) intravenously on day 1 every 3 weeks. After 4 cycles, patients who had achieved disease control received a maintenance therapy with pemetrexed and bevacizumab every 3 weeks until disease progression or unacceptable toxicity. Response was evaluated by CT scans after every 2 cycles, and toxicity was assessed. Primary endpoint was response rate. Secondary endpoint included disease control rate, progression-free survival, overall survival, and safety.

      4c3880bb027f159e801041b1021e88e8 Result

      Twenty-seven patients were enrolled between March 2011 and April 2015. The median age was 64 years (range: 44-74), and 21 patients were female. All the patients had adenocarcinoma, 17 patients had exon 19 deletion, and 10 had L858R mutation. 9 patients were ex-smoker, and 18 patients were nonsmoker. There were 11 partial responses with an response rate of 41% (95%CI, 22 – 61%). Stable Disease was observed in 16 patients and disease control rate was 100% (95%CI, 87 - 100%). 22 patients (81%) subsequently underwent maintenance therapy. The median progression-free survival was 7.8 months. The median overall survival from enrollment and from the start of first-line EGFR-TKI were 21.6 months and 36.9 months, respectively. Major adverse event was grade 3 and 4 neutropenia in 5 patients (19%), grade 3 hypertension in 3 patients (11%). Grade 3 gastrointestinal hemorrhage occurred in one patient, and grade 1 epistaxis occurred in 6 patients. No treatment-related death was observed.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The present study reveals that carboplatin and pemetrexed plus bevacizumab therapy is effective and feasible for the patients with NSCLC after the failure of first-line EGFR-TKI.

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      P1.01-26 - Single-Centre Experience of Clinical Outcomes for Advanced Lung Cancer Patients in Phase I Clinical Trials. (ID 13932)

      16:45 - 18:00  |  Presenting Author(s): Donna Marie Graham  |  Author(s): Thomas Jordan, Nadina Tinsley, Sreeja Aruketty, Alexander John Vickers, Claire Kelly, Roopa Kurup, Alison White, Amy Smith, Aisling Walsh, Chloe Thomson, Sinead O'Reilly, Michelle Norfolk, Dilshad Chang, Fiona Blackhall, Yvonne Summers, Raffaele Califano, Paul Taylor, Fiona Thistlethwaite, Natalie Cook, Louise Carter, Matthew G Krebs

      • Abstract

      Background

      Response rates for patients enrolled in early phase clinical trials have historically been reported as 5-10%. An unprecedented number of novel therapeutic options and emerging therapies in lung cancer (LC) have resulted in greater emphasis on early phase clinical trials and molecular stratification.

      We aimed to evaluate outcomes for patients with LC treated since 2015 with novel agents or combination strategies within an expanding early phase clinical trials unit at The Christie Hospital, Manchester, UK.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A database of patients consented to phase I clinical trials was interrogated for LC patients recruited over a three-year period. Clinical characteristics including histological sub-type, line of therapy, molecular phenotype, smoking status and ECOG performance status (PS) were collected for each patient. Patient records were reviewed for clinical trial allocation, treatment response, progression-free survival (PFS), and overall survival (OS).

      4c3880bb027f159e801041b1021e88e8 Result

      Over a three-year period to March 2018, 153 lung cancer patients were consented to Phase I clinical trials of Investigational Medicinal Products, of whom 113 (74%) commenced treatment. The median age of patients treated was 64y (range 28-84) with a male predominance (54%). All patients had a PS of 0-1 and 25% were non-smokers. Histological subtypes included non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and mesothelioma. The overall response rate (RR) by RECIST criteria was 27% across all patients, with a disease control rate of 73%. Median PFS was 6 months, and median OS was 11 months in the entire cohort. Compared with patients with NSCLC, patients with SCLC had worse PFS (7mo vs 3mo, p=0.001) and RR (35% vs 0%). The 28 trials recruiting LC patients in the unit during this period involved therapies targeting EGFR and ROS1, PI3K-mTOR-AKT and RAS-RAF-MEK signalling, DNA repair genes, cell-surface protein overexpression and genes implicated in immune signalling. Novel agents included small molecule inhibitors, monoclonal antibodies, and antibody-drug conjugates, in addition to targeted agents combined with chemotherapy or immune checkpoint inhibitor combinations. Patients had between 0-5 prior lines of therapy with no difference in PFS, OS or RR regardless of prior treatment lines.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data demonstrate clear benefit for lung cancer patient participation in early phase clinical trials. Novel therapeutic agents and evolution of early phase clinical trial design have resulted in promising options for patients with NSCLC, with RR>30% within our unit, regardless of prior treatment status. However, outcomes for SCLC patients lag behind and new therapeutic options are urgently needed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-27 - Influence of EGFR-TKIs Treatment Lines and PFS on the Emergence of T790M Mutation (Now Available) (ID 13584)

      16:45 - 18:00  |  Presenting Author(s): Xiaorong Dong  |  Author(s): Wanqiu Jia, Dejian Gu, Renhua Guo, Liyun Miao, Wenxian Wang, Chunwei Xu, Rongrong Chen, Xuefeng Xia

      • Abstract
      • Slides

      Background

      For sensitizing EGFR mutation positive lung cancer patients, EGFR-TKIs can be used as the first-line or second-line (after chemotherapy) therapy according to NCCN guideline. However, whether different lines of EGFR-TKIs therapy or different PFS would affect the emergence of T790M, the leading cause of resistance to first and second generation of EGFR-TKIs was unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed 142 advance NSCLC patients with 93 patients received 1st-line EGFR-TKIs, and 49 patients received 2nd-line EGFR-TKIs after chemotherapy. EGFR sensitizing mutation and T790M mutation was detected simultaneously by hybridization capture-based NGS panel sequencing with tumor biopsy , ctDNA or pleural effusion samples.

      4c3880bb027f159e801041b1021e88e8 Result

      For the patients received 1st-line EGFR-TKIs, 47 carried L858R mutation and 46 carried EX19del mutation; while patients received 2nd-line EGFR-TKIs, 24 carried L858R mutation and 25 carried EX19del mutation. When those patients progressed on TKIs, T790M emerged in 25 of the 47 (53.19%) L858R carriers, and 23 of the 46 (50.00%) EX19del carriers with 1st-line EGFR-TKIs (p=0.76). However, only 6 of the 24 (25.00%) L858R carriers yet 16 of the 25 (64.00%) EX19del carriers with 2nd-line EGFR-TKIs had T790M detected (p=0.006). The incidence of T790M was significant lower in L858R carrier treated with 2nd-line compared with 1st-line EGFR-TKIs (25.00% vs 53.19%, p=0.023), however, there was no difference for EX19del carrier (50.00% vs 64.00%, p=0.26). To further analyzed whether different PFS affected the appearance of T790M, we divided patients into 3 groups as PFS≥13 months (n=48), PFS≤8 months (n=60) and the between (n=34). The incidence of T790M was significantly lower in the PFS≤8 months group compared with the PFS≥13 months (31.67% vs 62.5%, p=0.001). The difference was also significant if only counting the L858R carriers (18.52% vs 59.26%, p=0.002), but not significant in the EX19del carriers (42.42% vs 66.67%, p=0.082).

      8eea62084ca7e541d918e823422bd82e Conclusion

      1st-line or 2nd-line EGFR-TKIs generally did not significantly alter the emergence of T790M. But for the L858R mutation carriers, the incidence of T790M is significantly decreased if treated as a 2nd-line EGFR-TKIs therapy. In addition, patients with longer PFS were associated with higher incidence of T790M mutation.

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      P1.01-28 - Impact of Afatinib Dosing on Safety and Efficacy Real-World in Patients with EGFR Mutation-Positive Advanced NSCLC (ID 13276)

      16:45 - 18:00  |  Presenting Author(s): Balazs Halmos  |  Author(s): Eng-Huat Tan, Ross Soo, Jacques Cadranel, Min Ki Lee, Pascal Foucher, Te-Chun Hsia, Maximilian Johannes Hochmair, Frank Griesinger, Toyoaki Hida, Edward S Kim, Barbara Melosky, Angela Märten, Enric Carcereny

      • Abstract
      • Slides

      Background

      Tolerability-guided dose adjustment of afatinib reduced incidence and severity of adverse drug reactions (ADRs) without affecting efficacy in the LUX-Lung (LL) studies in patients with EGFR mutation-positive (EGFRm+) NSCLC. We evaluated the impact of modifying the recommended starting dose of afatinib (40mg) on efficacy and safety in a real-world setting.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This non-interventional, observational, multi-country/site study used medical records of TKI-naïve patients with EGFRm+ (Del19/L858R) NSCLC treated with first-line afatinib. Primary outcomes were % patients with ADRs by severity, time on treatment (TT), and time to progression (TTP), relative to LL3. Secondary outcomes were % of patients with/reasons for modified starting dose.

      4c3880bb027f159e801041b1021e88e8 Result

      228 patients from 13 countries were included. Baseline characteristics were generally similar to LL3, but with more Del19 patients (78% vs 49%) and fewer Asian patients (44% vs 72%); 12% had ECOG PS 2–3. 31% of patients received an afatinib starting dose of <40 mg; 20% of patients starting with <40 mg increased their dose during the study. 67% of 40 mg starters underwent dose reductions, with 86% of those occurring in the first 6 months. Dose reductions were more frequent in females, Eastern Asian patients, and those with lower body weight. The main reason for dose modification was ADRs. In <40 mg starters, overall ADR incidence was similar to that in ≥40 mg starters, with fewer G3 (17% vs 25%) and no G4 ADRs. There were no new safety signals, and fewer ≥G3 ADRs and serious adverse events (SAEs) than in LL3 (28% vs 49% and 5% vs 14%, respectively). >60% of patients received medications to treat diarrhea and manage skin AEs. Median TT and TTP were 18.7 months and 20.8 months, respectively, and were not impacted by reduced starting dose or dose modification (19.4/17.7/19.5 and 25.9/20.0/29.0 months for patients who started on ≤30 mg/reduced to <40 mg/remained on ≥40 mg, respectively). The efficacy of afatinib was demonstrated across all patient subgroups analysed (ECOG PS 0/1 vs 2/3, age <75 yrs vs 75 yrs, EGFR mutational status); TT and TTP were significantly longer in patients with ECOG PS0/1 versus PS2/3.

      8eea62084ca7e541d918e823422bd82e Conclusion

      As in pivotal trials, dose adjustments with afatinib in real-world practice reduced the frequency and intensity of ADRs without impacting efficacy. RealGido demonstrated long TT/TTP regardless of afatinib dose adjustment or reduced starting dose, and an acceptable safety profile. The results highlight the benefit of tailoring afatinib dose based on individual patient characteristics and ADRs to optimize outcomes.

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      P1.01-29 - Crizotinib in Advanced Lung Adenocarcinoma Patients with ALK or ROS-1 Rearrangement: Is it the Same? (ID 12929)

      16:45 - 18:00  |  Presenting Author(s): Baohui Han  |  Author(s): Bo Zhang, Jianlin Xu, Yanwei Zhang, Xueyan Zhang, Tianqing Chu, Shuyuan Wang, Rong Qiao, Jie Qian, Jun Lu, Lele Zhang

      • Abstract
      • Slides

      Background

      Crizotinib is an orally taken tyrosine kinase inhibitor (TKI) targeting both ALK and ROS1 rearrangement, which have defined two different molecular subgroup patients. The aim of the study was to compare the therapeutic efficacy of crizotinib in advanced lung adenocarcinoma patients diagnosed with ALK or ROS1 mutation.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients diagnosed with ALK (Group A) or ROS1 (Group B) mutation were identified from our standardized registration system. The effectiveness of crizotinib in eligible patients was retrospectively analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 5348 and 4695 patients were screened and 393 (7.3%, 95% CI, 6.6%-8.0%) and 105 (2.2%, 95% CI, 1.8%-2.7%) positive patients were identified among the two groups, respectively. There were 141 and 32 eligible patients were included for survival analysis. The ORR is 53.0% (95% CI, 43.0%-63.0%) in group A, without statistical significance compared with group B (71%, 95% CI, 51.2%-90.4%, P=0.11). Similar result was also observed in terms of DCR (86%, [95% CI, 79.1%-92.9%] vs. 92.0%, [95%, CI, 80.0%-100.0%], P=0.74). The median PFS in group A was 12.4 months (95% CI, 10.2 -14.7 months), which was statistically worse than patients in group B (18.2 months, 95% CI, 6.3 -29.0 months, P=0.02). The OS was too immature to analyze.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients harboring ROS1 rearrangement derived better prognosis compared with these who had ALK rearrangement when treated with crizotinib.

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      P1.01-30 - Crizotinib in Advanced Non-Adenocarcinoma, NSCLC (NA-NSCLC) Patients with ALK Rearrangement: A Retrospective Study and Literature Review (ID 12942)

      16:45 - 18:00  |  Presenting Author(s): Baohui Han  |  Author(s): Bo Zhang, Yanwei Zhang, Jianlin Xu, Xueyan Zhang, Tianqing Chu, Shuyuan Wang, Jie Qian, Rong Qiao, Jun Lu, Lele Zhang

      • Abstract
      • Slides

      Background

      The aim of the study was to investigate the prevalence of anaplastic lymphoma kinase (ALK) rearrangement in non-adenocarcinoma, non-small cell lung cancer (NA-NSCLC) patients and therapeutic efficacy of crizotinib in these patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From January 2013 to January 2017, NA-NSCLC patients who were diagnosed with ALK rearrangement were screened. The effectiveness of crizotinib in positive patients was retrospectively analyzed. A literature review was performed and eligible cases were analyzed combined with our data.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 1212 NA-NSCLC patients were screened during the period with 25 positive patients identified (2.1%, 95% CI, 1.3%-2.9%). A statistically higher percentage of female patients (40.0% vs. 10.4%, P< 0.01), non-smoker (72.0% vs.43.2%, P< 0.01), containing adenocarcinoma component (36.0% vs. 7.1%, P< 0.01) and advanced stage (68.0% vs. 45.6%, P=0.03) were observed in ALK positive group. The median PFS of the 9 eligible patients in our institution was 7.0 months (95% CI, 0-15.6 months). We combined our data with the sporadic cases from 10 previous case reports (total n=19) and found that the median PFS was 7.0 months (95% CI, 5.6-8.4 months).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study suggested the opportunity to test ALK rearrangement in NA-NSCLC patients, especially in female, non-smoker and patients containing adenocarcinoma component. Crizotinib provides an option for the treatment of NA-NSCLC patients who diagnosed with ALK rearrangement.

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      P1.01-31 - Weekly Regimen of PAXUS-PM, a Novel Cremophor-Free, with Carboplatin in Patients with Advanced Non-Small-Cell Lung Cancer in Vietnam (ID 11869)

      16:45 - 18:00  |  Presenting Author(s): Mi-Ryung Jin  |  Author(s): Tuan Hang Quoc

      • Abstract

      Background

      The rationale for developing an alternative paclitaxel formulation concerns Cremophor EL-related side effects, and a novel paclitaxel delivery system might augment its therapeutic efficacy. PAXUS PM (or also known as GENEXOL-PM) is a novel polymeric micelle formulated paclitaxel free of Cremophor. The polymeric micelle formulation is composed of hundreds of low molecular weight, non-toxic, and biodegradable amphiphilic diblock copolymers which include monomethoxy poly (ethylene glycol)-block-poly(D,L-lactide). PAXUS-PM is used to breast cancer, non-small cell lung cancer, and ovarian cancer as 3 week regimen. In other words the data of weekly therapy in NSCLC is not published.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This prospective, single-arm, clinical study was designed to evaluate the efficacy and safety of the combination of Genexol-PM and carboplatin for the treatment of advanced non-small-cell lung cancer (NSCLC).

      Subjects with non‑small cell lung cancer who met the inclusion/exclusion criteria underwent the tests required per treatment plans and then received Genexol-PM 100mg/m2 and carboplatin 5 AUC(or 6AUC) on day 1, 8, 15 of every 3-week cycle for a maximum of six cycles as first-line therapy.

      The study evaluated the objective response rate as primary objective, and other variables including overall survival (OS), progression free survival (PFS), time to tumor progression (TTP), duration of overall response and adverse events.

      4c3880bb027f159e801041b1021e88e8 Result

      Thirty patients were enrolled and analyzed intermittently in this study. The median number of administered cycles was 6. Overall response rate was 76.67% with 2 complete responses (CR) and 21 partial responses (PR). There weren’t any patients with progressive disease.

      The Hematological toxicities were manageable and the major hematological toxic effects were grade 1/2 neutropenia(n=12, 40.0%), grade1 thrombocytopenia(n=1, 3.3%) and grade 1/2 anemia(n=8, 26.7%). There were no grade3/4 adverse events, such as neutropenia and hypersensitivity reactions. The major non-hematologic toxic effects included grade 2 nausea, vomiting and alopecia in all 30 patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Genexol-PM plus carboplatin combination chemotherapy showed excellent antitumor activity. In this study, there was no significant risk of hematologic and non-hematologic adverse events of grade 3/4. Among the paclitaxel formulations developed to allow high doses, there were limitations as an intermediate result, but good efficacy and safety results were obtained in lung cancer. Therefore, the use of CrEL-free, polymeric micelle formulation of paclitaxel allowed administration of higher doses of paclitaxel and showed safe and efficacious results.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-32 - A Multicenter, Open-Label, Phase II Trial of S-1 Plus Carboplatin in Advanced Non-Small Cell Lung Cancer Patients with Interstitial Lung Disease (ID 12544)

      16:45 - 18:00  |  Presenting Author(s): Masaki Hanibuchi  |  Author(s): Soji Kakiuchi, Shinji Atagi, Fumitaka Ogushi, Eiji Shimizu, Takashi Haku, Yuko Toyoda, Masahiko Azuma, Mayo Kondo, Hiroshi Kawano, Kenji Otsuka, Satoshi Sakaguchi, Hiroshi Nokihara, Hisatsugu Goto, Yasuhiko Nishioka

      • Abstract

      Background

      The clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) remain unclear. We conducted a phase II study to elucidate the efficacy of S-1 in combination with carboplatin (CBDCA) in NSCLC patients with ILD.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 33 advanced or recurrent NSCLC patients with ILD were prospectively enrolled in this multicenter, open-label, phase II study (UMIN000011046). Every 4 weeks, CBDCA at a dose of AUC 5 on day 1 and S-1 at a dose of 80 mg/m2 daily for 14 days were administered. The primary endpoint was the investigator-assessed objective response rate.

      4c3880bb027f159e801041b1021e88e8 Result

      The median age at initiating chemotherapy was 70. Sixteen patients (48.5%) had squamous cell carcinoma histology. With respect to the types of ILD, the usual interstitial pneumonia pattern was dominant (66.7%). The median number of cycles administered was 3, and the overall response rate and disease control rate were 33.3% and 78.8%, respectively. The median progression-free survival, the median survival time and the 1-year survival rate were 4.8 months, 12.8 months and 51.4%, respectively. Acute exacerbation of ILD caused by chemotherapy was noted in 2 patients (6.1%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the first and largest prospective study designed to evaluate the efficacy of a specific chemotherapeutic regimen as the primary endpoint in patients with advanced NSCLC with ILD. The combination of S-1 with CBDCA may be a treatment option for advanced NSCLC patients with ILD.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-33 - Randomized Phase 2 Study Comparing CBDCA+PTX+BEV and CDDP+PEM+BEV in Treatment-Naïve Advanced Non-Sq NSCLC (CLEAR study) (Now Available) (ID 12448)

      16:45 - 18:00  |  Presenting Author(s): Toshiyuki Harada  |  Author(s): Hibiki Udagawa, Eri Sugiyama, Shinji Atagi, Ryo Koyama, Satoshi Watanabe, Yukiko Nakamura, Daijiro Harada, Osamu Hataji, Fumihiro Tanaka, Akio Niimi, Hiroshi Kida, Miyako Satouchi, Akira Inoue, Yoshiko Urata, Yuki Yamane, Kiyotaka Yoh, Hiroshige Yoshioka, Takeharu Yamanaka, Koichi Goto

      • Abstract
      • Slides

      Background

      Bevacizumab (BEV) combined with platinum-based chemotherapy is a standard treatment for advanced non-squamous non-small-cell lung cancer (non-Sq NSCLC). Cisplatin (CDDP) + pemetrexed (PEM) is suggested as the most promising chemotherapy regimen combined with BEV. However, no study has been conducted to evaluate the efficacy and safety of CDDP+PEM+BEV compared with carboplatin (CBDCA) + paclitaxel (PTX) + BEV for advanced non-Sq NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Treatment-naïve patients with advanced or recurrent EGFR/ALK-negative non-Sq NSCLC from 55 sites across Japan were randomly assigned in a 2:1 ratio to either CDDP+PEM+BEV (4 cycles of CDDP [75 mg/m2] + PEM [500 mg/m2] + BEV [15 mg/kg] q3wk, followed by maintenance PEM + BEV q3wk until progression) or CBDCA+PTX+BEV (4 cycles of CBDCA [AUC 6] + PTX [200 mg/m2] + BEV q3wk, followed by maintenance BEV q3wk until progression). The primary endpoint was progression-free survival (PFS) by central review. The secondary endpoints were PFS by investigators, overall survival (OS), overall response rate (ORR) and safety profile. The target numbers of patients and events were determined to be 210 and 170, respectively, to observe a point estimate of HR for PFS (CDDP+PEM+BEV/CBDCA+PTX+BEV) <0.83 with a high probability (80%) when the true HR was 0.72.

      4c3880bb027f159e801041b1021e88e8 Result

      Between May 2014 and May 2016, 199 patients were randomly assigned to receive CDDP+PEM+BEV (N=132) or CBDCA+PTX+BEV (N=67). The median follow-up duration was 20.6 months. PFS events occurred in 171 patients. The HR for PFS by central review (CDDP+PEM+BEV/CBDCA+PTX+BEV) was 0.825 (95% CI 0.600-1.134, median PFS, 7.6 vs 7.0 months). The median PFS by investigators was longer with CDDP+PEM+BEV than with CBDCA+PTX+BEV (HR 0.634, 95% CI 0.464-0.867, median PFS, 7.4 vs 6.8 months). The median OS was 24.5 months for CDDP+PEM+BEV and 23.6 months for CBDCA+PTX+BEV (HR 0.955, 95% CI 0.620-1.470). The ORR was 57% for CDDP+PEM+BEV and 55% for CBDCA+PTX+BEV. The most common ≥G3 adverse events in both arms (CDDP+PEM+BEV/CBDCA+PTX+BEV) were neutropenia (24%/64%), hyponatraemia (11%/9%) and hypertension (30%/23%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      CDDP+PEM is the most effective chemotherapy regimen combined with BEV for advanced non-Sq NSCLC.

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      P1.01-34 - Docetaxel Plus Ramucirumab with Prophylactic PEG-G-CSF Support for Chemo-NaïVe Elderly NSCLC Patients: A Phase II Study (WJOG9416L) (ID 12400)

      16:45 - 18:00  |  Presenting Author(s): Akito Hata  |  Author(s): Nobuyuki Katakami, Mototsugu Shimokawa, Shunichi Sugawara, Kazumi Nishino, Satoshi Hara, Hideyuki Nakagawa, Masamichi Mineshita, Motoko Tachihara, Koichi Azuma, Osamu Hataji, Hiroshi Tanaka, Toshiaki Takahashi, Toyoaki Hida, Akihiro Bessho, Eriko Tabata, Hiroshi Watanabe, Naoyuki Nogami, Toshihide Yokoyama, Hidetoshi Hayashi, Hiroaki Akamatsu, Isamu Okamoto, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Kazuhiko Nakagawa

      • Abstract

      Background

      Docetaxel monotherapy is the standard of care for chemo-naïve Japanese elderly patients with advanced non-small cell lung cancer (NSCLC), according to our results of phase III trial comparing docetaxel and vinorelbine monotherapies (WJTOG9904). In a pivotal phase III study (REVEL), docetaxel plus ramucirumab demonstrated superior response rate (RR) and progression-free survival (PFS) over docetaxel monotherapy in second-line setting for advanced NSCLC. These differences in RR and PFS were translated into overall survival (OS) benefit. This evidence prompted us to investigate docetaxel plus ramucirumab for chemo-naïve elderly patients. However, in a similarly designed Japanese randomized phase II trial (JVCG trial), febrile neutropenia (FN) was observed in 34.2% of docetaxel plus ramucirumab arm. This high incidence of FN is a clinical concern when using docetaxel plus ramucirumab for elderly patients. The ASCO practice guideline recommends primary prophylactic granulocyte-colony stimulating factor (G-CSF) when the risk of FN is 20% or higher. PEGylated-G-CSF (pegfilgrastim) administered once a cycle demonstrated reduction of FN incidence in many types of cancers. Based on the above background, we considered that primary prophylactic PEG-G-CSF would be beneficial for elderly NSCLC patients who received docetaxel plus ramucirumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a prospective multicenter, single-arm, phase II study conducted by West Japan Oncology Group (WJOG). Main inclusion criteria includes: chemo-naïve; aged ≥75; histologically or cytologically confirmed NSCLC; ECOG PS 0/1; adequate organ functions; with measurable disease; without contraindication of ramucirumab; written informed consent; and estimated life expectancy of at least 3 months. Intravenous docetaxel (60 mg/m2, day 1) plus ramucirumab (10 mg/kg, day 1) with subcutaneous PEG-G-CSF (3.6 mg, day 2) every 3 weeks is administered until progression. Continuous docetaxel or ramucirumab monotherapy is permitted when intolerable toxicities occur but clinical benefit is obtained by each drug. The primary endpoint is objective response rate (ORR). Secondary endpoints are PFS, OS, disease control rate, and safety. We assumed that the threshold and expected ORR were 20% and 35%, respectively. Based on this, the number of patients was calculated to be 59 to provide a power of 80% with probability of one-sided type I error being 0.05. Taking ineligible patients into account, the sample size was set at 65. When the study results are promising, we plan to conduct a phase III trial to compare docetaxel plus ramucirumab with PEG-G-CSF support vs. docetaxel monotherapy for chemo-naïve elderly NSCLC patients. Clinical trial information: UMIN000030598.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion


      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-35 - Tumor Volume Analysis In ALK-Rearranged NSCLC Treated with Crizotinib: Identifying an Early Marker for Clinical Outcome (ID 11720)

      16:45 - 18:00  |  Presenting Author(s): Tomoyuki Hida  |  Author(s): Christine A Lydon, Hiroto Hatabu, Bruce E Johnson, Mark M. Awad, Mizuki Nishino

      • Abstract

      Background

      Targeted inhibition of anaplastic lymphoma kinase (ALK) has been widely used for the treatment of advanced non-small-cell lung cancer (NSCLC) with ALK-rearrangement. We performed tumor volume analysis of ALK-rearranged advanced NSCLC treated with crizotinib to identify an early imaging marker that can predict clinical outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Forty-two patients with advanced NSCLC harboring ALK-rearrangement (15 men, 27 women; median age: 55.7 years) treated with crizotinib as their first ALK-directed therapy at Dana-Farber Cancer Institute between November 2008 and June 2016. All patients had a follow-up chest CT scan at 8 +/- 3 weeks of therapy and had a dominant measurable lesion in the lung (≥1 cm) on baseline CT. Tumor volume of the dominant lung lesion was measured on baseline CT and follow-up CT at 8 +/- 3 weeks of therapy, using the previously validated technique on the volume analysis software (Vitrea ; Vital Images, Minnetonka, MN). The relationships between the 8-week volume change (%) and overall survival (OS) measured from the 8-week scan date were studied.

      4c3880bb027f159e801041b1021e88e8 Result

      The 8-week tumor volume change ranged from -99.3% to 117.5% (median: -57.7%). Using the 25 percentile of the 8-week volume change of -74%, 11 patients with >74% volume decrease at 8 weeks had a significantly longer OS compared to 31 patients with ≤74% decrease (Median OS: 92.0 months vs. 22.8 months, log-rank p=0.0048). In multivariable analyses using Cox proportional hazards models, the 8-week volume decrease of >74% remained as a significant factor associated with prolonged OS (HR=0.14, 95%CI: 0.03-0.59; Cox p=0.008) after adjusting for other significant variables including tumor stage at presentation (stage IV vs. others, HR=5.6, 95%CI: 1.29-24.3; p=0.02). Of the 31 patients with ≤74% decrease on the 8-week scan, best overall response by RECIST was partial response (PR) in 21 (68%), stable disease in 9 (29%), and progressive disease (PD) in one (3%). None of the 42 patients experienced RECIST-PD prior to the 8-week scan.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The 8-week tumor volume decrease of >74% on CT is significantly associated with longer OS in patients with ALK-rearranged NSCLC treated with crizotinib. The 8-week tumor volume analysis helps to identify patients who may benefit from alternative therapy in the early course of crizotinib therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-36 - Thoracic Surgery in Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutant After Tyrosine Kinase Inhibitor Therapy (Now Available) (ID 11170)

      16:45 - 18:00  |  Presenting Author(s): Chen-Hao Hsiao  |  Author(s): Shuenn-Wen Kuo, Ke-Cheng Chen, Jin-Shing Chen

      • Abstract
      • Slides

      Background

      Advanced stage non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor (EGFR) mutation have benefit form treatment with tyrosine kinase inhibitors (TKI). However, the role of multidisciplinary management including neoadjuvant TKI therapy and thoracic surgery is uncertain in advanced stage NSCLC. This retrospective study assessed the impact of the multidisciplinary management in advanced stage EGFR mutation positive NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Advanced stage NSCLC patients were retrospectively identified at Department of Surgery, National Taiwan University Hospital from 2006 to 2013 and prospectively observed. Patients with stage IIIA N2 (unresectable), IIIB, and IV EGFR mutation positive NSCLC treated with neoadjuvant TKI without tumor progression followed by thoracic surgery (NT group) were evaluated. Patients with stage IIIA N2 NSCLC treated with cisplatin-based neoadjuvant chemotherapy without tumor progression followed by thoracic surgery (NC group) were also evaluated. Progression-free survival (PFS) and overall survival (OS) were analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      figure.jpeg

      There were total 88 NSCLC patients in this study. There were 41 men and 47 women. The median age was 58 years. 66 patients were the NC group and 22 patients were the NT group. 60 patients and 20 patients were adenocarcinoma in the NC group and the NT group, respectively. Other patients were squamous cell carcinoma. In the NT group, EGFR status was identified before receiving neoadjuvant TKI therapy. Twelve patients (54.5%) were exon 19 deletion and ten patients were exon 21 L858R mutation. PFS was not significantly different between NC group and NT group (p = 0.645). OS was significantly longer in the NT group than in the NC group (p = 0.028). Exon 19 deletion of the NT group patients had significantly longer OS than the NC group (p = 0.014).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The multidisciplinary management including neoadjuvant TKI therapy and thoracic surgery may possibly have benefit in selected advanced stage NSCLC patients haboring exon 19 deletion.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-37 - BPI-9016M, a Novel c-Met Inhibitor, in Pretreated Advanced Solid Tumor: Results from a First-In-Human, Phase 1, Dose-Escalation Study (ID 12317)

      16:45 - 18:00  |  Presenting Author(s): Xingsheng Hu  |  Author(s): Xin Zheng, Hongnan Mo, Xinhe Cui, Lieming Ding, Fenlai Tan, Pei Hu, Yuankai Shi

      • Abstract
      • Slides

      Background

      BPI-9016M (Betta Pharmaceuticals Co, Ltd, Hangzhou, China) is a potent targeted therapy that inhibits MET and Axl. This first-in-human study is to assess the safety, tolerability, and pharmacokinetics (PK) of BPI-9016M in patients with advanced solid tumor, and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for the phase Ib/II study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients were enrolled into sequential dose-escalating cohorts from 100 mg to 1000 mg given orally once per day continually following the conventional 3+3 design. The primary endpoint was safety and tolerability. MTD was defined as the highest dose level resulting in <1 of 3 dose limiting toxicities (DLTs). Blood levels of BPI-9016M were evaluated after single and multiple administration (NCT02478866).

      4c3880bb027f159e801041b1021e88e8 Result

      Twenty patients were enrolled and treated in 6 of 7 predefined dose cohorts (100 mg n=4, 200 mg n=3, 300 mg n=3, 450 mg n=4, 600 mg n=3, 800 mg n=3), dose escalation stopped at 800 mg due to saturation. All had stage IV non-small cell lung cancer (NSCLC) progressed on previous systemic therapy (including previous EGFR TKI in 16 patients). BPI-9016M was well-tolerated in all dose cohorts without DLT. The incidence of overall and grade 3/4 TRAEs was 85% and 45%, respectively. Common TRAEs included elevated ALT (45%), constipation (30%), elevated bilirubin (25%), and oral paresthesia (25%). Tumor response was seen in 1 patients in the 800 mg dose cohort. Systemic exposure to BPI-9016M (maximum plasma concentration and AUC) increased with increasing dose. Mean time to maximum plasma concentration and half-life were 2 to 5.33 hours and 8.09 to 22.3 hours, respectively. Two metabolites (M1, M2-2) were detected.

      8eea62084ca7e541d918e823422bd82e Conclusion

      BPI-9016M was well tolerated in patients with advanced solid tumor. A phase Ib study is ongoing to investigate the safety and activity of BPI-9016M in patients with c-Met-dysregulated advanced NSCLC (NCT02929290).

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-38 - A Phase II With a Lead-In Phase I Study to Examine Safety and Efficacy of Hydroxychloroquine and Gefitinib in Advanced NSCLC   (Now Available) (ID 11325)

      16:45 - 18:00  |  Presenting Author(s): Yiqing Huang  |  Author(s): Alvin Wong, Ross Soo, Thomas Soh, Angela Pang, Chee Seng Tan, Winnie Ling, Pei Jye Voon, Joline Lim, Raghav Sundar, Nesaretnam Kumarakulasinghe, Hong Liang Lim, Boon Cher Goh, Tan Min Chin

      • Abstract
      • Slides

      Background

      Tyrosine kinase inhibitors (TKIs) benefit advanced non-small cell lung cancer (NSCLC) patients that harbor epidermal growth factor receptor (EGFR) mutations, but resistance invariably develops. Preclinical work demonstrated re-sensitization to EGFR-TKIs in cells with acquired resistance, and increased sensitivity of EGFR-mutant cells to erlotinib and hydroxychloroquine (HCQ) combination. We examine the safety and efficacy of HCQ with gefitinib in an Asian cohort of NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We enrolled stage IIIB/IV lung adenocarcinomas with sensitizing EGFR mutations. In the early phase of the study, non-smokers with unknown EGFR status were allowed. In the phase I lead-in study (Nov 2008-Jan 2010), maximum tolerable dose (MTD) of HCQ and gefitinib was ascertained via a 3+3 dose escalation schema.

      In the phase II single-arm study (March 2010-May 2016), all patients were treated with gefitinib 250mg om and MTD (600mg om) of HCQ, and stratified into TKI-naïve and TKI-treated cohorts. In the TKI-treated cohort, patients must have prior response to gefitinib for more than 12 weeks and developed resistance. Primary end point (PEP) in the TKI-naïve cohort was objective response rates (ORR) and progression-free survival (PFS). In the TKI-treated cohort, PEP was ORR, and to determine if combination treatment can re-sensitize acquired resistance to EGFR TKIs.

      4c3880bb027f159e801041b1021e88e8 Result

      75 patients were treated. EGFR mutations were identified in 77.3%. In the phase I cohort (n=13), MTD of HCQ was 600mg. HCQ-gefitinib combination was well tolerated. Common adverse events were rash and diarrhea, mainly from gefitinib. There was no dose-limiting toxicity. In TKI-naïve cohort (n=37) of the phase II study, ORR was 75.8% (95% CI 57.7-88.9). Median PFS was 9.4 months (95% CI 6.8-12.0). Four patients who were non-evaluable had early toxicities, including pneumonitis and hepatitis flare. In the TKI-treated cohort (n=25), 52% had received 2 or more lines of prior treatment. Disease control rate with TKI re-challenge was 50% (95% CI 21.9-70.9), ORR was 4.2% (95% CI 0.1-21.1). Median PFS was 2.4 months, and median overall survival was 9.9 months (95% CI 5.7-14.0). Three patients achieved a progression-free interval of more than 7 months after re-challenge (7.6; 11.2; 15.9 months).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Combination of HCQ-gefitinib is safe. In the TKI-naïve cohort, combination treatment did not improve PFS over reported average of 10 months for 1st-generation EGFR TKIs. However, in the TKI-treated cohort, re-responses and disease control to 1st-generation EGFR TKIs were seen, suggesting either a re-treatment effect or disease stabilization with addition of HCQ in acquired EGFR resistance.

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      P1.01-39 - Cost-Effectiveness of Crizotinib Versus Chemotherapy as First-Line Treatment of ALK Positive Advanced NSCLC -- A Real World Study (ID 12860)

      16:45 - 18:00  |  Presenting Author(s): Meijuan Huang  |  Author(s): Yuke Tian, Mingmin He, Li Ren, Youling Gong, Feng Peng, Yongsheng Wang, Zhenyu Ding, Jin Wang, Jiang Zhu, Yong Xu, Yongmei Liu, Lanting Li, You Lu

      • Abstract
      • Slides

      Background

      It was reported that crizotinib was a cost-effective alternative compared to pemetrexed plus platinum chemotherapy with the patient assistance program (PAP) in a model-based economic analysis using PROFILE 1014 trial data analysis. However, the cost-effectiveness of crizotinib in the real-world scenario remains unknown, which could be different from RCT results due to continued use of crizotinib beyond progression, anti-angiogenesis drugs combination in clinical practice, and influence from medical insurance (MI) policy change. The aim of study was to assess the cost-effectiveness of crizotinib vs platinum doublet chemotherapy as the first-line treatment for patients with ALK positive NSCLC in the real-world setting.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data from 163 advanced ALK positive NSCLC patients were collected from West China Hospital, Sichuan University (Chengdu, China) between Jun 2010 and Oct 2016 with a median follow-up of 27.67 months. The median progression-free survival (m-PFS) as primary clinical outcome was analyzed by Kaplan–Meier method. Direct medical costs were collected from hospital information systems. Since the medical insurance(MI) changed during the study, two situations, including patient's entry period, and follow up period were assessed. Crizotinib, premetrexed, and angiogenesis drugs were not covered by MI in entry period. However, crizotinib and all chemotherapy drugs were MI covered during follow up period. PAP and MI reimbursement referred to local MI policy. Incremental cost-effectiveness ratio(ICER) from perspective of local healthcare systems was calculated with both costs and quality-adjusted life-years (QALYs), as well as the costs discounted at 3% annually.

      4c3880bb027f159e801041b1021e88e8 Result

      Crizotinib improved PFS vs chemotherapy in ALK positive patients. (median PFS 19. 67 m vs. 5.47 m, P < 0.001). Moreover, crizotinib obtained ICER of $36,285.39 before the end of 2016, when crizotinib, pemetrexed and anti-angiogenesis drugs were not MI covered. This is more than Willingness to pay(WTP) threshold (3-times of GDP per capita in mainland China or Sichuan Province). However, ICER was $7,321.16 which is less than WTP when crizotinib and all chemotherapy drugs were covered by MI from the end of 2016. Sensitivity analysis demonstrated a 99.7% probability for crizotinib to be more cost-effective than chemotherapy, when crizotinib and all anti-cancer drugs were MI covered. In addition, one-way sensitivity analysis for reimbursement ratio of crizotinib indicated that cost-effective tendency for crizotinib increased as reimbursement ratio increased.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our real-world analysis suggests crizotinib could be an effective, and cost-effective first-line treatment for ALK positive advanced NSCLC compared to chemotherapy with the MI coverage currently in Chengdu, China.

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      P1.01-40 - Randomized Phase II Study of Docetaxel Plus Bevacizumab or Pemetrexed Plus Bevacizumab for Elderly pts with Untreated Advanced NSCLC: TORG1323 (ID 12868)

      16:45 - 18:00  |  Presenting Author(s): Kentaro Ito  |  Author(s): Osamu Hataji, Shigeru Tanzawa, Toshiyuki Harada, Nobukazu Fujimoto, Akihiro Bessho, Kei Takamura, Kazuhisa Takahashi, Tetsu Shinkai, Toshiyuki Kozuki, Miyako Satouchi, Terufumi Kato, Nobuhiko Seki, Takehito Shukuya, Natsumi Yamashita

      • Abstract
      • Slides

      Background

      The addition of bevacizumab (B) to platinum doublets prolongs the survival for non-squamous NSCLC. The role of monotherapy with B is unclear for elderly non-squamous NSCLC pts.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Pts were pathologically diagnosed untreated elderly (≥75 years old) non-squamous NSCLC, who were stage IIIB, IV, or recurrent disease, and PS 0-1. EGFR mutation or ALK rearranged pts were allowed after receiving each tyrosine kinase inhibitor. Pts were randomized 1:1 to receiving either docetaxel (D) or pemetrexed (P) with B. The primary endpoint was progression-free survival (PFS) assessed by independent review committee. B was administered 15 mg/kg, D was 50 mg/m2, or P was 500 mg/m2 every 3 weeks until disease progression or unacceptable toxicity based on our previous studies. Selection design was adopted for this study. The planned sample size was 120 pts to yield 80% power to select an optimal regimen correctly and PB is chosen for the further evaluation if the point estimate of hazard ratio (HR) for PFS was ≤1.20.

      4c3880bb027f159e801041b1021e88e8 Result

      Enrollment was terminated in early at the end of March 2017 because of slow accrual. Total 103 pts (DB/PB= 51/52 pts) were enrolled and 99 pts (49/50 pts) were full analysis set. Patient characteristics were well balanced between two arms. Median age was 78 (range: 75-88) in DB and 79 (75-94) in PB. EGFR mutation+/ALK translocation+/wild type/unknown= 13/0/34/2 in DB and 13/2/33/2 in PB. Total 77 events occurred at data cut-off, which corresponded to 77.7% power. The median PFS of DB and PB were 6.1 months and 4.6 months (HR 1.03, 95%C.I. 0.66-1.61: p=0.901). The response rates were 43% and 40% (p=0.840), respectively. The incident of ≥Grade 3 leukopenia (69% vs. 27%, p<0.001), neutropenia (86% vs. 44%, p<0.001) and fatigue (10% vs. 0%, p=0.027) were higher in DB. However, the frequency of febrile neutropenia was not different (16% vs.12%, p=0.578). One patient in PB was died of rupture of abdominal aortic aneurysm.

      8eea62084ca7e541d918e823422bd82e Conclusion

      PB is less toxic and the efficacy is comparable between two arms for elderly (≥75 years old) advanced non-squamous NSCLC. PB is a candidate for the further evaluation. Clinical Trial information: UMIN000012786.

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      P1.01-41 - A Phase 2 Study of DS-8201a in HER2-Overexpressing or -Mutated Advanced Non-Small-Cell Lung Cancer (ID 12939)

      16:45 - 18:00  |  Presenting Author(s): Pasi A Jänne  |  Author(s): Bob T. Li, Haruyasu Murakami, Ryota Shiga, Caleb C. Lee, Kongming Wang, David Planchard

      • Abstract
      • Slides

      Background

      Approximately 30% of non-small-cell lung cancers (NSCLC) are human epidermal growth factor receptor 2 (HER2)-overexpressing (immunohistochemistry [IHC] 2+ or 3+) and approximately 2% have HER2-activating mutations. Although HER2 is considered a potential target for NSCLC, no HER2-targeted therapies are approved for the treatment of NSCLC. DS-8201a is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload (DXd) by a cleavable peptide-based linker, and with a high drug-to-antibody ratio of 7 to 8. In preliminary results from the ongoing phase 1, DS8201-A-J101 trial, DS-8201a (5.6 and 6.4 mg/kg) had a confirmed objective response rate (ORR) of 20.0% (1/5) in HER2-expressing NSCLC (Tsurutani et al, ESMO 2017). In addition to NSCLC, DS-8201a also showed substantial antitumor activity with a manageable safety profile in multiple other HER2-expressing tumors such as breast, gastric, and colorectal cancers.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This multicenter, open-label, 2-cohort, phase 2 study will assess the efficacy and safety of DS-8201a in subjects with HER2-overexpressing or -mutated unresectable and/or metastatic nonsquamous NSCLC that is relapsed/refractory to standard treatment or for which no standard treatment is available (NCT03505710). Overall, approximately 80 subjects will be enrolled; 40 subjects in each of 2 cohorts (cohort 1: HER2-overexpressing [IHC 3+ or IHC 2+]; cohort 2: HER2-mutated including exon 20 insertions and single-nucleotide variants in kinase, transmembrane, and extracellular domains [eg, L755S, V659E, S310F]). To be eligible for inclusion in cohort 1, HER2-overexpression must be assessed and confirmed by central testing based on archival samples. To be eligible for inclusion in cohort 2, any HER2-activating mutation must be documented based on archival tumor samples analyzed by Clinical Laboratory Improvement Amendment-certified laboratory or equivalent. All enrolled subjects will receive a 6.4 mg/kg dose of DS-8201a once every 3 weeks; study treatment will be continued until progressive disease or unacceptable toxicity. The primary endpoint is ORR based on RECIST version 1.1 (percentage of complete and partial response) by an independent radiologic facility. Secondary efficacy endpoints include progression-free survival, duration of response, disease control rate, and overall survival. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. The study will enroll subjects in North America, Europe, and Japan. Recruitment began in May, 2018.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

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      P1.01-42 - Real-World Evaluation of Tolerability in Older Adult Patients (≥75 Years Old) with EGFR-mutated NSCLC (Now Available) (ID 13289)

      16:45 - 18:00  |  Presenting Author(s): Shirley Xue Jiang  |  Author(s): Manjusha Hurry, Katrina Hueniken, Catherine Labbe, M Catherine Brown, Lawson Eng, Hiten Naik, Mindy Liang, Devalben Patel, Penelope Bradbury, Natasha B Leighl, Frances A Shepherd, Wei Xu, Geoffrey Liu, Ryan N. Walton, Grainne Mary O'Kane

      • Abstract
      • Slides

      Background

      NSCLC patients carrying EGFR mutations are diagnosed across a wide age distribution. Although EGFR tyrosine kinase inhibitors (TKIs) are generally well tolerated, there remains a paucity of real-world data on toxicity and health utility scores (HUS) in older patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A longitudinal observational study evaluated health-related quality of life (HRQoL) using HUS through the EQ-5D questionnaire, and common EGFR-TKI toxicities using PRO-CTCAE in NSCLC outpatients carrying EGFR mutations. Patients were classified into two groups: older (>75 years) and younger (<75 years). Patient characteristics and outcomes were extracted from chart review; patients were classified as having stable or progressive disease according to imaging findings. HUS and PRO-CTCAE results were compared descriptively.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 240 patients and 774 encounters, 52 patients (22%; comprising 157 encounters) were aged ≥ 75 years. Gender and race were similarly distributed in both age groups: 63% of older patients and 70% of younger (<75 years) were female; 56% of older patients and 53% of younger patients were Asian. Use of gefitinib in older patients was much higher than other drugs: among 147 patients who received gefitinib, 27% (40 patients) were older, compared to 15% (5/33) for osimertinib and 15% (3/20) for erlotinib. Of patients receiving afatinib (n=11) and chemotherapy (n=32), none were ≥ 75 years. The following table describes HUS and PRO-CTCAE results by treatment and age group for stable patients.

      Older Adults (75 years)

      Younger Adults (<75 years)

      N

      HUS, mean (SD)

      PRO-CTCAE*, median [IQR]

      N

      HUS, mean (SD)

      PRO-CTCAE*, median [IQR]

      Stable on gefitinib

      34

      0.83 (0.20)

      4.5 [0,16]

      77

      0.80 (0.15)

      4 [0,15]

      Stable on osimertinib

      5

      0.80 (0.23)

      13.5 [0,17]

      22

      0.87 (0.12)

      0 [0,13.5]

      Stable on erlotinib

      3

      0.82 (0.08)

      0 [0,9]

      11

      0.80 (0.14)

      0 [0,16]

      *Higher PRO-CTCAE indicates more severe toxicities/symptoms.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In a real-world evaluation, patients 75 years or older comprised almost a quarter of all patients with EGFR-mutant advanced NSCLC. Afatinib and chemotherapy were not used at all in this population. Gefitinib was used most commonly, with similar toxicities and health utilities between older and younger patients. Osimertinib and erlotinib were used too infrequently in this study for conclusive age comparisons.

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      P1.01-43 - Next-Generation Sequencing in the Exploration of Genetic Heterogeneity for Lung Adenocarcinoma Patients with EGFR Activating Mutations (Now Available) (ID 11194)

      16:45 - 18:00  |  Presenting Author(s): Ying Jin  |  Author(s): Xun Shi, Ming Chen, Yun Fan, Xinmin Yu

      • Abstract
      • Slides

      Background

      Increasing evidence leads to a ratiocination that genetic heterogeneity of the lung adenocarcinoma patients with sensitive EGFR mutations may impact clinical responses and outcomes to EGFR-TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed targeted NGS with a gene panel covering 416 cancer-related genes to profile genetic characteristics of 69 lung adenocarcinoma patients with activating EGFR mutations and assessed the contribution of targeted NGS to exploration of genetic heterogeneity of such cohort.

      4c3880bb027f159e801041b1021e88e8 Result

      We detected total 200 actionable genetic alterations (mean 2.9 variations per patient, range: 1-7 variations) in tumor DNA and 140 actionable genetic alterations (mean 2.0 variations per patient, range: 0-5 variations) in matched plasma ctDNA, respectively. The concurrent genes with the highest mutation rate were TP53 (observed in 72.5% patients), other uncommon EGFR mutations (observed in 21.7% patients), EGFR amplification (observed in 20.3% patients), RB1 (observed in 10.1% patients), PIK3CA (observed in 7.2% patients), and MYC (observed in 5.8% patients). NGS provides EGFR mutation detection in plasma with a test sensitivity of 88.2% and specificity of 100.0%. Novel mutations potentially related to primary drug resistance were identified including: CDC73, SMAD4, and CTNNB1 missense mutations; RB1, ARID1A, ARID2, DNMT3A, STK11, and ATR frameshift indel; CDKN2B-PATA31D1, NFKBIA-OR11H12 fusion gene; PRKCI, CCNE1, MCL1, ARAF copy number gain; RB1 loss. The pathways analysis showed that unique pathways in the primary resistant cohort included: 1) immune related pathways: Toll-like receptor signaling pathway, T cell receptor signaling pathway; 2) epithelial-mesenchymal transition (EMT) related pathways: TGF-beta signaling pathway; 3) downstream pathway of EGFR: PIK3CA/AKT/mTOR signaling pathway; 4) cell function related pathways: Mismatch repair pathway, AMPK signaling pathway, TNF signaling pathway, Notch signaling pathway, and Transcriptional misregulation in cancer.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In conclusion, we note the complexity and heterogeneity of activating EGFR-mutant lung adenocarcinoma that may confer primary resistance to EGFR TKI using NGS platform. This study highlights the advantage of the NGS than traditional methods on testing EGFR mutations, enabling further refinement in sub-classification for the improved personalization of lung cancer treatment.

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      P1.01-44 - Outcome of Uncommon EGFR Mutation Positive Newly Diagnosed Advanced NSCLC Patients: A Single-Centre Retrospective Analysis (ID 13955)

      16:45 - 18:00  |  Presenting Author(s): Shruti Kate  |  Author(s): Anuradha Choughule, Amit Joshi, Vanita Noronha, Vijay Patil, Rohit Dusane, Priyanka Tiwrekar, Leena Solanki, Vaishakhi Trivedi, Kumar Prabhash

      • Abstract
      • Slides

      Background

      The significance of uncommon EGFR mutations in newly diagnosed advanced NSCLC patients is incompletely known. We aimed to analyze the demographic profile, outcome and treatment attributes of these patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively surveyed 5738 advanced NSCLC patients who underwent EGFR testing in our centre from 2013 to 2017 by in-house primer probes on real time PCR platform. Descriptive data was accumulated from electronic medical records. Survival plot was calculated from Kaplan Meir and compared between groups using Log Rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      Out of 1260 EGFR mutation positive patients, 83 (6.58%) had uncommon mutations in isolation or in various combinations. Uncommon mutations were more frequent in men than in women (59% vs.41%), in never smokers than in smokers (65.1 % vs. 20.5%) and in adenocarcinomas than non -adenocarcinomas (96.4% vs. 3.6%). Overall Exon18G719X, Exon20insertion, Exon20T790M, Exon20S768I , Exon21(L858R/L861Q ) were present in 9.6%, 19.3%, 12%, 3.6% and 3 .6% patients respectively . Dual mutation positivity was found in 50.6% patients. One patient (out of 83) had triple mutations: Exon18G719X, Exon20S768I and Exon21L858R. On classifying patients as per TKI sensitivity, it was found that TKI sensitive single and dual mutations were found in 15.7 % and 4.8% respectively .TKI insensitive single mutations were found in 31.3% and a combination of TKI sensitive and insensitive mutations was found in 48.2 % patients. The median duration of follow up was 13 months. Five patients were lost to follow up. Overall 50.6% patients received oral TKI and 34.9% received chemotherapy as first line therapy. Response to first line therapy could be assessed in 54 patients, out of whom 28 had partial response, 14 had stable disease and 12 had progression. Median progression free survival (PFS) on first line therapy was 8.3 months (CI 5.3-12.9). Median overall survival of patients who received TKI during the course of their disease was 20.2months (CI 11.4 -28.9). Median overall survival of the entire cohort was 15.8 months (CI 10.1-21.5). Among all uncommon mutations, patients with dual mutations did better, with a median overall survival time of 22.6 months (CI 8.2-37.0, P=0.005) . It was observed that TKI Sensitive/ TKI Insensitive Dual mutations had a superior overall survival of 28.2 months (CI 15.2-41.2,P=0.042) as compared to TKI Sensitive (single or dual) and TKI Insensitive single uncommon EGFR mutations.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Uncommon EGFR mutations constitute a distinct heterogeneous group, hence it is imperative to understand each subgroup more to define optimal treatment.

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      • Abstract

      Background

      ALK mutation is observed in 4% of patients diagnosed with NSCLC. The present study aimed to evaluate the efficacy of crizotinib, an ALK inhibitor, and clinical characteristics of ALK-positive NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this multicenter, retrospective study, data of ALK-positive advanced stage NSCLC patients who received crizotinib were retrieved from hospital records.

      4c3880bb027f159e801041b1021e88e8 Result

      Data of 353 ALK-positive metastatic NSCLC patients receiving crizotinib in any treatment line were analyzed. The mean age of the patients was 53.2±12.6 years [median, 53 years (21-85 years)] and 193 (54.7%) patients were male. Age at diagnosis was significantly higher in males than in females (54.8±11.8 years and 51.3±13.2 years, respectively; p=0.044). The rate of patients who never smoked was 50.1%. The most common histological subtype was adenocarcinoma (96%). The frequency of brain metastasis at the time of diagnosis was 23.4%. The most common initial symptoms were cough (56%) and dyspnea (53%). Initial ECOG score was 0 or 1 in 80% of the patients. Crizotinib had been used in 37% of the patients in the 1st-line treatment, in 45% of the patients in the 2nd-line treatment, and in 18% of the patients in the ≥3rd-line treatment.

      Table 1. Response rates of the patients

      Treatment line

      Overall
      N (%)

      1
      N (%)

      2
      N (%)

      3
      N (%)

      Other
      N (%)

      Complete response

      28 (7.9)

      9 (7.3)

      14 (8.9)

      4 (9.8)

      1 (5.6)

      Partial response

      217 (61.5)

      78 (62.9)

      103 (65.2)

      25 (61.0)

      10 (55.6)

      Stable disease

      50 (14.2)

      18 (14.5)

      21 (13.3)

      7 (17.1)

      4 (22.2)

      Progressive disease

      67 (13.3)

      19 (15.3)

      20 (12.7)

      5 (12.2)

      3 (16.7)

      Undefined

      11 (3.1)

      ORR

      245 (69.4)

      87 (70.2)

      117 (74.1)

      29 (70.8)

      11 (61.2)

      DCR

      295 (83.6)

      105 (84.7)

      138 (87.4)

      36 (87.1)

      7 (83.4)

      Undefined

      11 (3.1)

      ORR was 69.4% and DCR was 83.6% (Table 1). ORR and DCR in the patients received crizotinib were 70.2% and 84.7% in the 1st-line treatment, respectively and were 74.1% and 87.4% in the 2nd-line treatment, respectively. The frequency of brain metastasis was 40.2% at 12 months. Of these patients, the median PFS and OS were 11.3 and 28.0 months, respectively.

      The most common side effects were fatigue, visual disturbances, nausea, abdominal discomfort, and pretibial edema.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Clinical characteristics of ALK-positive patients and crizotinib efficacy are consistent with studies. Response rates and survival outcomes are similar regardless of treatment lines. Crizotinib is safely used in these patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-46 - Circulating Tumor DNA Analysis for Predicting Response to Osimertinib and Disease Progression in EGFR-Mutant Non-Small-Cell Lung Cancer (ID 14242)

      16:45 - 18:00  |  Presenting Author(s): Udayan Guha  |  Author(s): Chul Kim, Liqiang Xi, Constance M Cultraro, Trinh Hoc-Tran Pham, Nitin Roper, Mohammadhadi Bagheri, Arun Rajan, John Beeler, Greg Jones, Mark Raffeld

      • Abstract

      Background

      Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive modality to detect biomarkers associated with a broad array of malignancies, including lung cancer. We aimed to assess whether ctDNA could be used to predict response to EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and disease progression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Plasma samples were serially collected at every clinic visit from patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC) enrolled in a clinical trial of osimertinib treatment, local ablative therapy (LAT) upon progression, followed by osimertinib re-challenge (NCT02759835). Patients with no prior EGFR-TKI treatment or patients with T790M-positive NSCLC after EGFR-TKI treatment receive osimertinib. Upon progression, patients with ≤5 progressing sites undergo LAT and resume osimertinib. ctDNA was detected using droplet-digital PCR EGFR mutation detection assays. The changes in ctDNA mutant allele levels were correlated with response to treatment and tumor progression. To identify additional genetic changes that may be related to osimertinib resistance, an enhanced Tagged-Amplicon Sequencing NGS assay (InVisionSeqTM) was utilized which covers SNVs, InDels and amplifications in 36 genes commonly mutated and therapeutically actionable in NSCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      353 samples from 17 patients were analyzed. At baseline, EGFR mutations were detected in 15 (88%) patients. One patient with overall low metastatic tumor burden and another patient with most tumor burden in the brain did not have detectable ctDNA at baseline. For patients treated with osimertinib before first progression, 12 (86%) achieved a partial response (PR) and 2 (14%) had stable disease (SD) as their best response. ctDNA decreased after initiation of osimertinib in these patients with 7 (50%) patients having no detectable ctDNA within 28 days. In those with ongoing PR (n=5) and prolonged stable disease (n=1), ctDNA remains undetectable (n=5) or low (n=1). Among 7 patients who had first progression, 5 (71%) patients had an increase in corresponding mutant EGFR allele in ctDNA 2-4 months before radiographic progression. While exploration of osimertinib resistance mechanisms by InVisionSeqTM is ongoing, early results demonstrate that allele frequencies of mutations in genes, including EGFR, PIK3CA, and TP53 closely reflected response and resistance to osimertinib. MET and EGFR amplification, as well as emergence of EGFR C797S mutant were identified as key resistance mechanisms by ctDNA analysis. Full details on all patients will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Quantitative assessment of plasma ctDNA is a relatively non-invasive tool to monitor the therapeutic response to treatment with EGFR-TKI and for early detection of resistance mechanisms for clinical decision making.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-47 - Phase I/II Trial of Dasatinib and Osimertinib in Patients with Advanced EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 14220)

      16:45 - 18:00  |  Presenting Author(s): Chul Kim  |  Author(s): Stephen V Liu, Deepa S Subramaniam, Giuseppe Giaccone

      • Abstract

      Background

      The presence of epidermal growth factor receptor (EGFR) mutations is associated with sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but a subset of patients (pts) do not respond to EGFR-TKIs or have very short duration of response, suggesting intrinsic resistance. Moreover, acquired resistance to EGFR-TKIs is inevitable for most patients. We showed that overexpression of Cripto-1, a member of the EGF–CFC family, contributes to the development of intrinsic resistance to EGFR-TKIs through the activation of the Src pathway and that the combination of EGFR-TKI therapy and Src inhibition works synergistically in preclinical models.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This was an open-label, phase I/II trial of osimertinib and dasatinib, a multi-kinase inhibitor with activity against Src, in EGFR-TKI treatment-naïve pts with advanced EGFR-mutant NSCLC (NCT02954523). Pts with pleural or pericardial effusions at study entry were excluded. The primary endpoint of the phase I part was to establish a safe and tolerable phase II dose of osimertinib and dasatinib. Dose escalation included 2 dose levels (dose level 1: osimertinib 80 mg QD, dasatinib 50 mg BID, dose level 2: osimertinib 80 mg QD, dasatinib 70 mg BID). In addition, 2 dose levels below the starting dose level could be explored if dose reductions were necessary.

      4c3880bb027f159e801041b1021e88e8 Result

      7 pts (4 at dose level 1, 3 at dose level 2) were enrolled to date. None of them had dose limiting toxicities (DLTs), but given frequent dose reductions and toxicities beyond the DLT period at dose level 2, dose level 1 is being further assessed (up to 6 pts at dose level 1). The most common treatment-related adverse events (TRAEs) included pleural effusion (n=6), AST elevation (n=5), ALT elevation (n=5), rash (n=5), and diarrhea (n=4), most of which were grade 1 or 2. 3/2/1 pts had grade 1/2/3 pleural effusion, respectively. 4 pts had grade 3 TRAEs, which included pleural effusion, fatigue, neutropenia, anemia, and headaches. No grade 4 or 5 toxicities were observed. Among 6 evaluable pts, 4 confirmed partial response (PR)/1 unconfirmed PR/1 stable disease were observed. Responses were durable with all the PRs ongoing.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The combination of dasatinib and osimertinib showed no new safety signals and demonstrated evidence of anticancer activity. Treatment-related toxicities were manageable with dasatinib dose reductions and supportive measures. The safety and efficacy of dasatinib and osimertinib will continue to be explored.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-48 - Nab-Paclitaxel Plus Gemcitabine in Advanced NSCLC After Platinum-Based Chemotherapy: Final Results and Caveolin-1 Expression (ID 12872)

      16:45 - 18:00  |  Presenting Author(s): Tatsunori Kiriu  |  Author(s): Motoko Tachihara, Akito Hata, Yukihisa Hatakeyama, Tatsuya Nagano, Masatsugu Yamamoto, Kazuyuki Kobayashi, Hisashi Ohnishi, Nobuyuki Katakami, Yoshihiro Nishimura

      • Abstract
      • Slides

      Background

      Nab-Paclitaxel (PTX) plus gemcitabine significantly improved overall survival, progression-free survival, and response rate in patients with metastatic pancreatic adenocarcinoma. Anti-tumor synergy between nab-PTX and gemcitabine was recently demonstrated in mouse model. Combination treatment increases intra-tumoral gemcitabine levels attributable to a decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase. Higher caveolin-1 expression in tumor-associated stroma was associated with improved overall survival and response rate in patients with advanced non-small-cell lung cancer (NSCLC) treated with nab-PTX. Based on these data, we planned to assess the efficacy and safety of combination with nab-PTX plus gemcitabine in patients with NSCLC previously treated with platinum-based chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with advanced NSCLC with progressive disease to platinum-based chemotherapy, ECOG performance status (PS) 0 or 1, and adequate kidney, liver and bone marrow function were eligible. Treatment consisted of nab-PTX (100 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 of each 3-week cycle until progression disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Archived tumor blocks, if available, were collected for caveolin-1 expression analysis using immunohistochemistry.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 28 patients enrolled, 28 were evaluable for response and toxicity. The median age was 68 years (range 47-79), 23 males and 5 females. Histology subtypes were: adenocarcinoma 19 patients, squamous cell carcinoma 9 patients. Seventeen patients had ECOG PS 1 and 11 patients had PS 0. Twenty-four patients were 2nd line and 4 patients were 3rd line. The median number of cycles administered was 4 (range 1-10). The overall response rate was 17.9%. The disease control rate was 67.9%. The median progression-free survival was 3.1 months (95% confidence interval [CI] = 1.6-4.1). The median overall survival was 11.7 months (95% CI = 8.0-19.3). Five patients (17.9%) had grade 4 neutropenia, 4 patients (14.3%) had grade 3 anemia, 3 patients (10.7%) had grade 3 thrombocytopenia. However, no patients developed febrile neutropenia. Remarkable non-hematologic toxicity was interstitial pneumonia with grade 3 in 4 patients (14.3%), neuropathy with grade 3 in 2 patients (7.1%) and infections with grade 3 in 2 patients (7.1%). Caveolin-1 expression analysis will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The efficacy of nab-Paclitaxel in combination with gemcitabine in advanced second or third-line NSCLC patients was limited and the high onset of interstitial pneumonia was unacceptable.

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      P1.01-49 - irAE, Possible Predictive Markers for Immune Checkpoint Inhibitors (Now Available) (ID 12709)

      16:45 - 18:00  |  Presenting Author(s): Kazutoshi Komiya  |  Author(s): Tomomi Nakamura, Haruki Hirakawa, Shinsuke Ogusu, Chiho Nakashima, Koichiro Takahashi, Shinya Kimura, Naoko Sueoka-Aragane

      • Abstract
      • Slides

      Background

      Although an immune-related adverse event (irAE) in immune checkpoint inhibitors (ICIs) is a major cause of discontinuation of ICIs, few reports have examined detailed clinical background in clinical practice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Sixty-one patients with non-small cell lung cancer who underwent treatment with ICIs (nivolumab or pembrolizumab) at the Saga University Medical School Hospital from December 2015 to January 2018 were included. Clinical background, therapeutic effect, and progression free survival (PFS) were retrospectively examined between AE discontinuation group (AEg) and progressive disease (PD) discontinuation group (PDg).

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 41 patients receiving nivolumab, nine cases (22.5%) were discontinued due to AE and 22 cases (55.0%) were PD. Of 21 patients receiving pembrolizumab, nine cases (42.9%) were discontinued due to AE and 8 cases (38.1%) were PD. There was no significant difference between nivolumab and pembrolizumab in the discontinuation rate due to AE (p=0.14). When comparing the clinical background between the AEg and the PDg, the response rate was 50.0% in the AEg and 6.7% in the PDg, which was significantly higher in the AEg (p=0.001). The median PFS was significantly longer in the AEg, 301 days (95% CI: 193-336) in the AEg and 60 days (95% CI: 74-178) in the PDg (Log-Rank, p=0.009). Among irAE, the incidence of interstitial lung disease (ILD) was 3/49 (6.1%) in cases without interstitial pneumonia (IP) or radiation pneumonitis as the underlying diseases, whereas it was significantly higher at 6/12 (50.0%) in cases with those underlying diseases (p=0.001). Among nine patients who developed ILD, grade3 or more was 2 cases, of which 1 case was grade5.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Discontinuation due to AE during treatment of ICIs may be a predictive marker of good response to ICIs and favorable outcome since anti-cancer effect continued even after discontinuation. However, the presence of IP or radiation pneumonitis as the underlying disease is a risk factor for the onset of ILD, so it is necessary to carefully consider the indication for treatment of ICIs.

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      P1.01-50 - Real World Experience of Nivolumab in Patients with Metastatic Nonsmall Cell Lung Cancer (mNSCLC) (Now Available) (ID 14187)

      16:45 - 18:00  |  Presenting Author(s): Doran Ksienski  |  Author(s): Elaine Wai, Mary Lesperance, Nicole Croteau, Leathia Fiorino, Zia Poonja, Georgia Geller, Dave Fenton, Edward Brooks, Daniel Glick

      • Abstract
      • Slides

      Background

      Immune related adverse events (irAE) from immunotherapy in metastatic melanoma have been correlated with efficacy; this association is less clear in mNSCLC. We aimed to evaluate the correlation between irAE and clinical efficacy of Nivolumab (N) in mNSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All mNSCLC patients (pts) treated with N between 11/2015 to 10/2017 at BC Cancer were identified. Demographic, tumor, treatment details, and frequency and grade (Gr, CTCAE v4.0) of irAE, were collected from chart review. Kaplan-Meier curves of overall survival (OS) from initiation of N based on the development of irAE and utilizing a 6-week landmark analysis were evaluated using the log-rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      Characteristics of cohort (n=230): median age 64y (range 39-82), primary histology: non-squamous (74%), brain metastases rate: 13%, ECOG PS>1: 31% at start of N, and median Charlson Comorbidity Index (CCI) 6, and 72% of pts had received 1 prior line of systemic therapy. 100 pts (44%) experienced 143 separate irAE of Gr 1(64), Gr 2(54), Gr 3(12), Gr 4(9), and Gr 5(4). Three treatment related deaths were due to pneumonitis, hepatitis and colitis. 48 pts (21%) required treatment interruption due to irAE, of whom 28 discontinued N completely. With a median follow-up of 7.0 months (range: 0.07-30), 136 pts died and median OS from initiation of N was 9.2 months (95% CI 7.8-12.9). Median OS was 12.9 months and 8.6 months for patients requiring treatment interruption due to irAE or not, respectively. For landmark analysis, 15 pts were excluded as they died within 6 weeks from initiation of N. Using 6-week landmark analysis, there was no significant difference in OS amongst pts who developed any irAE (median 8.1 months, 95% CI: 6.1-not reached) compared to those who did not (median 10.8 months, 95% CI: 8.6-14.5; log rank test p=0.567). Development of colitis was associated with a lower median OS (4.4 months, 95% CI: 3.8-not reached) versus pts who did not (10.8 months, 95% CI: 8.6-14.5; p=0.0103). Thyroid changes (p=0.473), dermatitis (p=0.29), pneumonitis (p=0.318), hepatitis (p=0.135), and arthralgias (p=0.465) were not associated with different OS compared to those without irAE.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Despite 31% of pts having PS>1 and a high CCI, N was well tolerated. In the studied cohort, development of any irAE was not associated with improved survival. The finding of worse survival amongst pts with colitis requires further study.

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      P1.01-51 - Real world Experience of Pembrolizumab in Patients with Metastatic Nonsmall Cell Lung Cancer (mNSCLC) (Now Available) (ID 14223)

      16:45 - 18:00  |  Presenting Author(s): Doran Ksienski  |  Author(s): Elaine Wai, Mary Lesperance, Nicole Croteau, Leathia Fiorino, Zia Poonja, Dave Fenton, Georgia Geller, Edward Brooks, Daniel Glick

      • Abstract
      • Slides

      Background

      Immune related adverse events (irAE) from immunotherapy in metastatic melanoma correlate with efficacy; this association is less clear in mNSCLC. We aimed to evaluate the correlation between irAE and clinical efficacy of pembrolizumab (P) in mNSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All mNSCLC patients (pts) treated with P between 11/2015 to 10/2017 at BC Cancer were identified. Demographic, tumor, treatment details, and frequency and grade (Gr, CTCAE v4.0) of irAE, were collected from chart review. Kaplan-Meier curves of overall survival (OS) from initiation of P based on the development of irAE and utilizing a 6-week landmark analysis were evaluated with the log-rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      Characteristics of cohort of 41 pts were: median age 68y (range 50-81), females 49%, non-squamous histology 81%, PD-L1 status <1%/1-49%/>50%/unknown 0/12%/83%/5%, brain metastases rate 15%, and liver metastases rate 12%. ECOG PS>1 at start of IO 32% and median Charlson Comorbidity Index (CCI) 4. P was delivered to 42% in first line setting. With a median of follow-up of 6.6 months (range: 0.7-32.3), 17 pts (41%) had died and 16 (39%) were still receiving drug. 16 pts (39%) experienced a total of 24 irAE; Gr of irAE 1/2/3/4/5: 10/12/1/1/0. The most common irAE were arthralgias (5pts), pneumonitis (4pts), and dermatitis (4pts). Treatment was temporarily held in 4pts (10%) due to irAE and permanently discontinued in 3 pts (7%). Median OS from initiation of P was 22.6 months (range: 10.6-not reached, NR). On univariate analysis, male gender (HR=3.36, 95% CI: 1.08-10.48) and ECOG>1 (HR=3.24, 95% CI: 1.13-9.35) correlated with worse OS. Median OS amongst pts requiring treatment interruption due to irAE was NR and for those treated continuously was 14.0 months. 1 pt was excluded from landmark analysis as they died within 6 week from initiation of P. Using 6 week landmark analysis, there was no significant difference in OS amongst pts who developed any irAE (median NR, 95% CI: 4.8 months-NR) compared to those who did not (14.0 months, 95% CI: 10.6-NR, log rank test p=0.84). Thyroid changes (p=0.411) and dermatitis (p=0.951) were not associated with differences in OS compared to those without irAE.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Despite 32% of pts having PS>1 and a high CCI, the incidence of serious irAE was low. The impact of gender on response to P requires more study. Development of irAEs was not correlated with improved survival.

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      P1.01-52 - BR-34- Randomized Trial of Durvalumab & Tremelimumab +/- Platinum Chemotherapy in Patients with Metastatic Squamous or Non-Squamous NSCLC (Now Available) (ID 11791)

      16:45 - 18:00  |  Presenting Author(s): Swati Kulkarni  |  Author(s): Scott A. Laurie, Glenwood Goss, Francesco Perrone, Brett G.M Hughes, Nick Pavlakis, Martin R Stockler, Andre Blais, Labib Zibdawi, Francisco E. Vera - Badillo, Natasha B Leighl

      • Abstract
      • Slides

      Background

      Background- Immunotherapy improves survival of patients with non-small cell lung cancer (NSCLC). Current clinical trials are studying various combinations of PD-1/PD-L1 inhibitors and CTLA-4 agents with or without chemotherapy, to enhance treatment efficacy. This trial will determine the effects of adding platinum chemotherapy to combination of check point blockade with durvalumab and tremelimumab in the first line treatment of advanced non-small cell lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Method- BR-34 is a CCTG led randomized proof-of-concept trial of durvalumab and tremelimumab, with or without platinum-based chemotherapy in patients with metastatic squamous or non-squamous NSCLC. Patients who have histologically confirmed Stage IV NSCLC and wild type EGFR and ALK, PDL-1 unselected, with measurable disease by RECIST 1.1, and available tissue for biomarker testing are eligible and are stratified by stage, histology and smoking status. Primary end point is overall survival. Secondary end points include progression free survival at 1 year, overall response rate, quality of life, cost effectiveness and correlative studies on tissue and blood (including PD-L1, tumour mutation burden and cell-free DNA) with outcomes and response, and PFS by iRECIST (exploratory). In total 300 patients will be recruited from Canada, Australia and Italy. Arm A will receive 4 cycles of fixed doses of tremelimumab (T) 75 mg plus durvalumab (D) 1500 mg every 28 days IV, followed by durvalumab (D) maintenance and Arm B will receive standard platinum-doublet chemotherapy in combination with T+D every 21 days for 4 cycles, followed by maintenance D (with pemetrexed for those with non-squamous histology), until progression.

      4c3880bb027f159e801041b1021e88e8 Result

      Results- BR-34 was initiated in February 2017 in Canada and total 150 patients have been randomized as of April 2018, including 137 from Canada and 13 from Australia. 28 sites are open to accrual in Canada, 15 in Australia the trial will soon be opened in Italy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusion- At the current rate of accrual, the CCTG BR-34 trial should be fully accrued by Q1 2019. This is the first randomized trial of combination checkpoint blockade +/- platinum-doublet chemotherapy in advanced non-small cell lung cancer.

      Acknowledgements: BR-34 is an academic, co-operative group trial led by Canadian Cancer Trials Group (CCTG) in collaboration with ALTG and NHMRC Clinical Trials Centre, with support from AstraZeneca and Canadian cancer society. NCT03057106

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      • Abstract

      Background

      Approximately 40% of NSCLC patients develop bone metastases (BoM). Bone has active functions in regulating immune system. To date, no trial evaluated the role of BoM in modulating response to immunotherapy. Aim of the present study was to investigate whether presence of BoM impact on immunotherapy efficacy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Two different cohorts of pretreated NSCLC patients (cohort A: Non-squamous; cohort B: Squamous) were evaluated for nivolumab efficacy in terms of objective response rate (ORR), progression free survival (PFS), and overall survival (OS) according to presence or absence of BoM. All patients received nivolumab at standard dose of 3 mg/kg every 2 weeks within the Italian Expanded Access Program.

      4c3880bb027f159e801041b1021e88e8 Result

      Cohort A accounted for 1588 patients with non-squamous NSCLC: 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 370 patients with squamous histology: 102 BoM+ (32%) and 251 BoM- (68%). In Cohort A, BoM+ had a significantly lower ORR (12% versus 34%; p < 0.0001), shorter PFS (2.0 versus 4.0 months, p < 0.0001) and shorter OS (7.4 versus 15.3 months, p <0.0001). In cohort B, BoM+ had significantly lower ORR (15% versus 22%; p < 0.04), shorter PFS (2.7 versus 5.4 months, p <0.0001) and shorter OS (5.0 versus 10.9 months, p <0.0001). Presence of BoM negatively affected outcome irrespective of PS (OS cohort A: PS-0 BoM+ 12.0 versus 20.9 months in PS-0 BoM-, p<0.0001; OS cohort B: PS-0 BoM+ 5.8 versus 16.4 months in PS-0 BoM-, p<0.0001). Multivariate analysis confirmed that presence of BoM independently associated with higher risk of death with HR 1.64 and HR 1.78, for Cohort A and B, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results, the first assessing BoM in patients treated with immunotherapy, suggested that BoM predict lower efficacy of immunotherapy. BoM should be included as stratification factor in clinical trials.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-54 - A Phase I/Ib Study of Binimetinib (MEK162), a MEK Inhibitor Plus Carboplatin/Pemetrexed in Non-Squamous NSCLC (ID 14205)

      16:45 - 18:00  |  Presenting Author(s): Natasha B Leighl  |  Author(s): Donna Graham, Eric Chen, Katherine Pisters, Penelope Bradbury, Mateya Trinkaus, Melissa Chan, Saroosh Arif, Urszula Zurawska, Jeffrey Rothenstein, Diane Zawisza, Stephanie Effendie, Maggie Sawczak

      • Abstract

      Background

      MEK remains an important potential target in RAS/RAF dependent tumours. Binimetinib (MEK16) is a highly selective oral inhibitor of MEK1/2, which has shown activity in melanoma and other cancers. Data from preclinical models suggest greater activity with intermittent versus continuous dosing of MEK inhibitors when added to chemotherapy. This dose escalation study combines intermittent binimetinib with pemetrexed plus carboplatin in chemotherapy naive patients with advanced non-squamous NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A standard 3+3 dose-escalation design was used with planned dose expansion at RP2D (N=30) in genotypically defined cohorts (KRAS G12C mutant (mt), non-G12C mt and wild type). The primary endpoint was to define the RP2D of binimetinib using an intermittent dosing schedule in combination with standard doses of pemetrexed and carboplatin. Secondary objectives included safety, pharmacokinetics (PK), response and exploring potential biomarkers of response or toxicity. Binimetinib (30-45 mg BID) was commenced on day 1 cycle 1 for 5 days followed by a 48-hour washout period. If well tolerated, pemetrexed/carboplatin (500 mg/m2/AUC 5 mg*min/mL) were added on day 8 cycle 1 and binimetinib resumed from days 8-26 with a 48 hour drug washout before cycle 2. For subsequent cycles, pemetrexed/carboplatin were administered on day 1, binimetinib on days 1-19 every 21 days. Key eligibility criteria included ECOG performance status 0-1, adequate organ function, measureable disease by RECIST and no active CNS metastasis. Patients with EGFR/ALK mt lung cancer were permitted in the dose escalation phase after progression on standard TKI therapy.

      4c3880bb027f159e801041b1021e88e8 Result

      Between 03/2017 and 04/2018, 11 patients have been enrolled in 2 dose escalation cohorts (4 KRAS mt, 4 EGFR mt including 1 ex20ins). Six patients were treatment-naive, 3 received prior EGFR TKI and 2 prior pembrolizumab. To date, 7 have experienced grade 3 adverse events (AEs) deemed at least possibly related to binimetinib (anemia, neutropenia, abdominal pain, diarrhea, nausea, vomiting, fatigue, transaminitis). No grade 4/5 AEs have been seen. Related AEs seen in >20% of patients include: rash, mucositis, diarrhea, fatigue, transient visual changes, nausea, edema, neutropenia and vomiting. Antitumour activity was seen at each dose level of binimetinib. Final data on toxicity, response, PK and confirmation of RP2D will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The addition of binimetinib to pemetrexed/carboplatin appears to have manageable toxicity with evidence of activity in non-squamous NSCLC. Dose expansion in genotypically defined cohorts will continue and a cohort combining binimetinib with pembrolizumab is planned.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-55 - Unique Genetic Profiles from Cerebrospinal Fluid Could Predict Survival of EGFR-Mutant NSCLC with Leptomeningeal Metastases (ID 12369)

      16:45 - 18:00  |  Presenting Author(s): Yangsi Li  |  Author(s): Ben-Yuan Jiang, Meimei Zheng, Hai-Yan Tu, Jin -Ji Yang, Xu-Chao Zhang, Jun-Yi Ye, Qing Zhou, Wen-Zhao Zhong, Chao Zhang, Shannon Chuai, Yi-Long Wu

      • Abstract
      • Slides

      Background

      Leptomeningeal metastases (LM) are more frequent in NSCLC with EGFR mutations;and cerebrospinal fluid (CSF) could reveal the unique genetic profiles of LM in our previous studies, but whether they could predict the overall survival (OS) of LM remains unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      EGFR-mutant NSCLC patients with LM were enrolled,and clinical data and genetic profiles detected by Next-generation sequencing were collected. We further drew nomogram with endpoint of OS after LM, then performed index of concordance (C-index) and survival analysis to evaluate predictive role.

      4c3880bb027f159e801041b1021e88e8 Result

      In total, 61 patients were enrolled and all with genetic profiles from CSF. Patents with high copy number variations (CNVs) or harboring CDK6, TP53 exon5 or FGF19 in CSF demonstrated significant poorer OS than those without (Fig. 1). Cox regression analysis indicated CNVs, CDK6,CDKN2A,TP53,MET and NTRK1 as prognostic factors and further selected for nomogram (Fig. 2). C-index of nomogram was 0.743, indicating the moderate predictive effect. In the calibration curves, we scored the patients based on the model, using bisection and trisection methods to divide into low and high points groups; and low, medium and high points groups (Fig. 3), and significant difference were found in both the survival analyses (NA versus 7.47months, P<0.01) and (NA, 10.33 versus 4.43 months, P<0.01) respectively. Patients who received Osimertinib after LM seemed to have longer OS than those who did not (14.5 months versus 7.7 months) but without significant difference(P=0.10); however interestingly, in those with EGFR T790M negative who took Osimertinib after LM by themselves obtained survival benefit than those who did not(NA versus 7.7 months, P=0.04), and the results needed to be validated.

      figure.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Unique genetic profiles from CSF could well predict OS of LM. High CNVs, CDK6, TP53 exon5 or FGF19 in CSF in CSF may be related to poor prognosis of LM.

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      P1.01-56 - Concurrent Mutations in Chinese Lung Cancer Patients Carrying HER2 Genomic Aberrations (ID 13756)

      16:45 - 18:00  |  Presenting Author(s): Xuefeng Xia  |  Author(s): Jun Zhao, YUE Li, Xiaorong Dong, Xinghao Ai, Yu Chen, Gen Lin, Xiaotong Zhang, Wenxian Wang, Chunwei Xu, Rongrong Chen

      • Abstract
      • Slides

      Background

      Although human epidermal growth factor receptor 2 (HER2, ERBB2) genomic aberration has been identified as therapeutic targets, clinical trials of HER2-directed therapies have disappointing results in lung cancer. We hypothesize that the concurrent alterations might be one of the reasons, thus the aim of this study was to describe frequent concurrent alterations in Chinese lung cancer patients harboring HER2 mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 147 cancer patients with HER2 mutations were enrolled in the study. Tumor biopsy, ctDNA and pleural effusion samples were collected for detection alterations using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (59-1021).

      4c3880bb027f159e801041b1021e88e8 Result

      Sixty-two of 147 patients with HER2 genomic aberrations were diagnosed as lung cancer. The HER2 gene was amplified in 11 (18%) patients, whereas HER2 mutations were detected in 48 patients, co-occurrence of HER2 amplification and mutations were in 3 patients. Thirty of the 62 patients (48.39%) had concurrent actionable mutations across 18 genes, which involved in RTK-PIK3CA-mTOR signaling pathways, cell-cycle pathway, DNA repair pathway, RAS-RAF-MAPK pathway and some others (details in table). Moreover, 7 patients had more than 2 concurrent mutations besides HER2 mutation/amplification.

      Table 1. concurrent genetic alterations in HER2-altered lung cancer patients

      Signaling pathway

      Concurrent

      actionable

      mutations

      Number of

      patients

      RTK-PIK3CA-mTOR

      EGFR 11
      PIK3CA 4
      STK11 2
      FBXW7 1
      TSC1 1
      FLCN 1
      C11orf30 1
      Cell-cycle CDKN2A 5
      CCND1 2
      RB1 1
      DNA repair BRCA2 1
      ATM 1
      RAS-RAF-MAPK BRAF 1
      KRAS 1
      Others MDM2 2
      JAK2 2
      SMARCA4 2
      PTCH1 1

      8eea62084ca7e541d918e823422bd82e Conclusion

      Concurrent of actionable genetic alterations in HER2-altered Chinese lung cancer patients was common. The complex molecular profiles elucidate the importance of comprehensive analysis of genetic mutations when considering anti-HER2 targeted therapy.

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      P1.01-58 - Variants Distribution and Heterogeneity of Outcomes to Crizotinib in ALK-Rearranged Chinese Non-Small Cell Lung Cancers (Now Available) (ID 13940)

      16:45 - 18:00  |  Presenting Author(s): Naixin Liang  |  Author(s): Puyuan Xing, Yudong Su, Xiang Long, Yang Gao, Peng Chen, Hao Liu, Tengfei Zhang, Bing Li, Lu Zhang, Xinru Mao, Zhe Zhang, Jing Liu

      • Abstract
      • Slides

      Background

      ALK-rearranged NSCLC is a unique molecular subgroup with high sensitivity to ALK inhibitors. Crizotinib, a FDA-approved tyrosine kinase inhibitor for ALK-rearranged NSCLCs, showed remarkable response in ALK-positive NSCLC. However, the magnitude and duration of clinical responses to crizotinib among different ALK variants are found to be heterogeneous, and studies about the clinical outcomes showed contradict conclusions.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We collected sequencing information from 110 ALK-positive Chinese NSCLC patients, whose tissue or plasma biopsies were sequenced in a CLIA-certified genomic profiling laboratory. Sequencing results were reviewed with the intent of studying ALK rearrangement distribution and clinical outcomes to crizotinib.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 134 ALK rearrangements were identified in this cohort, with 39 unique rearrangements. EML4 was the most common ALK rearrangement partner, with variant 3 (v3) as the most frequent variants (42.7%) of EML4-ALK fusion, accounting for 71.6% (96/134) of all the rearrangements in 87.3% (96/110) patients. For EML4-ALK positive patients after crizotinib treatment (n=96), survival analysis revealed that patients with EML4-ALK only displayed favorable PFS (10.0 vs 7.2 months, p=0.037) and OS (36.0 vs 20.0 months, p=0.037) than those combined with other fusions. In vitro data reported that variant v3 and v5 was structurally stable and less sensitive to ALK inhibitors due to the lack of TAPE domain. In this study, patients harboring v3 and v5 displayed significantly inferior OS than those with other variants (31 vs 37.6 months, p=0.010). For all the ALK-rearranged patients (n=110), no significant difference was observed between the survival of EML4-ALK and non-EML4-ALK (PFS, 9.4 vs 14.5 months, p=0.61; OS, 35.1 vs 35.5 months, p=0.58), below and above 40-years (PFS, 7.3 vs 11.3 months, p=0.23; OS, 25.4 vs 35.5 months, p=0.69).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study demonstrated the distribution pattern of ALK rearrangements in Chinese NSCLCs, and illustrated the clinical outcomes of ALK-positive patients in different sub-groups. We hope this study could improve basic knowledge of ALK rearrangement and might be helpful for clinicians in choosing patients for appropriate medical treatment. Moreover, these findings advocate for more comprehensive ALK genomic profiling and validation of current results of clinical outcomes in large populations.

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      P1.01-59 - A Better Real World Practice for ROS1 Positive NSCLC Patients, Driven by the Targeted Next Generation Sequencing(NGS) and the Targeted TKI (ID 11766)

      16:45 - 18:00  |  Presenting Author(s): Yongchang Zhang  |  Author(s): Zeng Liang, Nong Yang, yizhi Li

      • Abstract

      Background

      Methodologically, Targeted NGS had been shown comparable to classical testing methods in testing sensitivity and specificity in several driver genetic aberrations. However, Data of standard TKI treatment outcome in NGS identified ROS1-positive NSCLC was rare, especially in TKI confirmatory clinical trials, thus it is practical and necessary to evaluate it in the real world.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We carried out a real word retrospective study in our center. From September 2015 to December 2017, NSCLC in-patients with targeted NGS testing (Burning Rock Dx; 8 genes or 56 genes panel) results were included in our study. Data of NGS multiple genes testing, crizotinib efficacy and potential clinical and genetic influential factors, and safety were analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      1104 NSCLC patients with targeted NGS testing (Burning Rock Dx; 8 genes or 56 genes panel) results were included in our study. All testing was based on tumor biopsy and adenocarcinoma is the domain histology. The occurrence rate of ROS1 rearrangement was 1.5 %( N=17). Seven phenotypes of ROS1 rearrangement were detected and the most common one was CD74-ROS1, which accounted for 45% (9 of 20). Furthermore, three patients were found carrying two different ROS1 rearrangements. 41% (7 of 17) patients were discovered with other concomitant mutations: including TP53 &PIK3CA mutation(n=1), TP53&CDKN2A mutation(n=1), TP53 & BRCA2 mutation(n=1), PIK3CA &ALK missense mutation (p.R311H)(n=1), MET amplification(n=1) ,TP53 mutation(n=1), ERBB2 mutation(n=1), Among all NSCLC patients with ROS1 rearrangement, 13 patients were diagnosed at stage IV and 12 patients received crizotinib treatment. The average follow-up period since crizotinib initiation was 12.7 months (range from 1.5 to 28 months). The ORR and DCR of crizotinib were 75% and 83% (9 PR, 1 SD and 2 NA) respectively. The median progression-free survival (mPFS) of crizotinib treatment was 14 months. Of influential factors analysis, it was shown that NSCLC patients with exclusive ROS1 rearrangement had a longer PFS than those carrying concomitant mutations (mPFS 15.5months vs 8.5months; p=0.0213) and there was no significance impact on PFS considering brain metastasis, crizotinib treatment lines or rearrangement subtypes. No grade 3 and 4 adverse events were observed in this retrospective study.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Crizotinib is highly effective and tolerant in NGS identified ROS1 rearrangement advanced NSCLC in real-word clinical practice and the data is consistent with that in the previous clinical trials applying IHC/FISH/RT-PCR as ROS1 companion diagnosis. NSCLC patients with exclusive ROS1 rearrangement had better PFS under Crizotinib treatment compared to those with concomitant mutations.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-60 - Preventing and Treating Brain Metastases with Three First-Line EGFR-TKI in Patients with EGFR Mutation Advanced NSCLC (ID 12010)

      16:45 - 18:00  |  Presenting Author(s): Chien-Chung Lin  |  Author(s): Wu-Chou Su, Yi-Lin Wu

      • Abstract
      • Slides

      Background

      Brain metastases (BM) are common in advanced non-small cell lung cancer (NSCLC), and the prognosis is poor with few therapeutic options. This retrospective study evaluated the efficacy of three epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in preventing and treating BM in patients with EGFR mutation-positive advanced NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients with EGFR mutation-positive advanced NSCLC who visited a tertiary referral center from December 1, 2013, to November 30, 2017, were analyzed retrospectively. These patients received gefitinib, erlotinib, or afatinib until disease progression, death, or intolerable adverse events. The cumulative incidence of subsequent BM and the progression-free survival (PFS) and overall survival (OS) of both the BM patients and non-BM patients were estimated by the Kaplan-Meier method and compared using the log-rank test. We performed Cox proportional hazards regression for the predictors of subsequent BM and determinants of PFS and OS.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 306 patients with newly diagnosed or recurrent NSCLC were enrolled. Among these patients, 116, 75, and 115 received first-line gefitinib, erlotinib, and afatinib, respectively. The patients who received afatinib had a better PFS (12.7 versus 9.8 months, p=0.001) and OS (39.1 versus 22.0 months, p=0.035) than those who received gefitinib. The cumulative incidences of subsequent BM were similar among the patients who received different TKIs (p=0.80). Patients with initial BM were associated with a shorter PFS (p < 0.001) and OS (p=0.015) than those without BM. Among the initial BM patients, there were no differences in median PFS (p=0.34) and median OS (p=0.46) in the three EGFR-TKI groups.

      figure 2.tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data suggested afatinib provided significant benefits in terms of PFS and OS as well as preventing subsequent BM compared to gefitinib, in addition to providing the same effectiveness in treating BM as gefitinib

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      P1.01-61 - Clinical Characterization of ERBB2 Exon 20 Insertions and Heterogeneity of Outcomes to Afatinib in Chinese Lung Cancers (Now Available) (ID 13066)

      16:45 - 18:00  |  Presenting Author(s): Zhefeng Liu  |  Author(s): Yi Hu, Lin Wu, Jun Cao, Zhe Yang, Cheng Zhi Zhou, Liming Cao, Hao Wu, Haibo Shen, Meiling Jin, Yong Zhang, Xinru Mao, Jianxing Xiang, Ke Ma, Bing Li, Tengfei Zhang

      • Abstract
      • Slides

      Background

      Background: Human epidermal growth factor 2 (HER2, ERBB2) gene alterations have been identified as oncogenic drivers in 2-5% of lung cancers. ERBB2 In-frame insertions in exon 20 (20ins) lead to constitutive activation of receptor and downstream pathways. However, response heterogeneity of different exon 20 insertions to ERBB2 inhibitor afatinib exists. In vitro and structural modeling results suggested that Glycine778 may facilitate inhibitor binding to ERBB2. In this study, our aim was to improve our understanding of clinical characteristics in ERBB2-mutated Chinese lung cancer and investigate the clinical outcomes of specific ERBB2 exon 20 insertions in response to afatinib.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Methods: We reviewed 7520 lung cancer patients whose tissue or plasma biopsies were sequenced in a CLIA-certified sequencing laboratory between 2015 to 2018. Clinical records of 19 patients (18 adenocarcinomas and 1 squamous cell carcinoma) with several different ERBB2 20ins after afatinib treatment were collected for clinical outcomes evaluation.

      4c3880bb027f159e801041b1021e88e8 Result

      Results: ERBB2 20ins were identified in 2.27% (171/7,520) in this Chinese lung cancer cohort. It occurred with a high proportion in females with adenocarcinoma histology. 11.7% (20/171) ERBB2 20ins-positive patients harbored concomitant ERBB2 amplification. Y772_A775dup (119/171, 69.6%) was the most frequently occurred 20ins subtype, followed by G778_P780dup (18/171, 10.5%). For the 19 patients treated with afatinib, they had a median PFS of 4.5 months and median OS of 11.5 months. The overall response rate in this cohort was 15.8% (3/19) and disease control rate was 68.4% (13/19). Next, we interrogated the clinical outcomes of specific 20ins subtype responding to afatinib. We found that patients harboring G778_P780dup (G778) achieved longer median PFS (10 vs 3.3 months, p=0.32) and median OS (19.7 vs 7 months, p=0.16) than non-G778 patients, consisting with in vitro results. Although statistical significance was not achieved due to limited number of G778_P780dup patients, this result warranted further investigation into this phenomenon. Moreover, to the best of our knowledge, we identified the first case of a lung squamous cell carcinoma patient harboring ERBB2 20ins from this cohort. He displayed favorable response to afatinib and achieved partial response with significant tumor shrinkage.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusion: We interrogated the characteristics of ERBB2 exon 20 insertions in a large cohort from single ethnicity. It demonstrated the response heterogeneity to afatinib among different ERBB2 exon 20 insertion subtypes. It highlighted the importance to correlate drug efficacy with specific ERBB2 exon 20 insertion variants in clinical application.

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      P1.01-62 - The Third Generation Irreversible EGFR Inhibitor HS-10296 in Advanced Non-Small Cell Lung Cancer Patients (ID 13138)

      16:45 - 18:00  |  Presenting Author(s): Shun Lu  |  Author(s): Ross Camidge, Cheng-Ta Yang, Jianying Zhou, Renhua Guo, Chao-Hua Chiu, Gee-Chen Chang, Her-Shyong Shiah, Yan Chen, Chin-Chou Wang, David Berz, Wu-Chou Su, Nong Yang, Ziping Wang, Jian Fang, Jianhua Chen, Petros Nikolinakos, You Lu, Hongming Pan, Ajit Maniam, Lyudmila A Bazhenova, Keisuke Shirai, Mohammad Jahanzeb, Maurice Willis, Nehal Masood, Naveed Chowhan, Te-Chun Hsia, James Chih-Hsin Yang

      • Abstract
      • Slides

      Background

      The epidermal growth factor receptor (EGFR) T790M mutation is the most common mechanism of drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. The third generation irreversible EGFR inhibitor HS-10296 has been shown to be safe and effective against both EGFR TKI-sensitizing and T790M resistance mutations in preclinical studies.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A Phase I, open-label, multi-center clinical trial was conducted in patients with locally advanced or distant metastatic NSCLC who have progressed following prior therapy with EGFR TKIs. The study was consisted of dose-escalation cohorts (55, 110, 220 and 260 mg) and dose-expansion cohorts (55, 110 and 220 mg) with once daily oral administration of HS-10296. In each expansion cohort, tumor biopsies were collected for central determination of EGFR T790M status. Patients were assessed for safety, tolerability, pharmacokinetics and efficacy of HS-10296.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 117 patients (median age 60) received at least one dose of HS-10296 across multiple sites in China (43 patients), Taiwan (69 patients) and the United States (5 patients). Maximum tolerated dose(MTD)has not been reached in this study. The most common adverse events were grade1/2 rash, pyrexia, upper respiratory tract infection, constipation, diarrhoea and blood creatine phosphokinase elevation. Drug-related serious adverse events were anemia (0.8%), blood creatinine elevation (0.8%), anemiarhabdomyolysis (0.8%) and blood creatine phosphokinase elevation (0.8%) occurred mainly in the cohorts with higher doses at 220 mg or 260 mg, respectively. These data demonstrated favorable tolerability and safety of HS-10296 in patients enrolled. The pharmacokinetics of HS-10296 was dose proportional and the plasma half-life was 30.7~37.5 hours. Among 82 evaluable patients (18 in escalation cohorts and 64 in expansion cohorts) with the EGFR T790M mutation, the overall objective response rate (ORR) was 52.4% (43/82; 95% CI, 41.6 to 63.3), while disease control rate (DCR) was 91.5% (75/82; 95% CI, 85.4 to 97.5). 110mg cohort showed better DCR (97.2% VS. 86.1%) than 55mg cohort. Phase II study is ongoing with the dose at 110 mg.

      8eea62084ca7e541d918e823422bd82e Conclusion

      HS-10296 has the potential to provide clinical benefit to locally advanced or distant metastatic NSCLC patients with EGFR T790M mutation who had disease progression following prior therapy with EGFR TKIs.

      (The study was sponsored by Jiangsu Hansoh Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT02981108)

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      • Abstract

      Background

      Immune-checkpoint inhibitors (ICIs) are a standard treatment in advanced non-small cell lung cancer (NSCLC). However, ICIs can induce immune-related adverse events (irAEs) that may compromise treatment continuation. Here we report our experience in patients with NSCLC, the incidence of irAEs and its correlation with efficacy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We have retrospectively analyzed 101 patients with advanced NSCLC receiving ICIs in our institution from March 2014 to January 2018. IrAEs were graded following CTCAE v4.0. Kaplan Meier and log-rank tests were used to evaluate progression-free (PFS) and overall survival (OS). Analyses were performed using SPSS v24 package.

      4c3880bb027f159e801041b1021e88e8 Result

      Median age was 66.4 [37-85] years, 74.3% were male. 33 (32.7%) patients presented squamous and 68 (67.3%) non-squamous histology. Most frequent ICIs were nivolumab (50%), pembrolizumab (31%) and atezolizumab (16%), used as monotherapy (79.2%) or in combination with chemotherapy (20.8%). 37.6% patients were treated with ICIs in first line setting, while 62.4% in second or beyond. Median duration of treatment was 2.7 [0.6-26.2] months.

      61 (60.4%) patients developed 106 irAEs, with a mean of 1.02 [0-4] irAEs per patient. Most frequent irAEs were rash (24.5%), pruritus (22.6%), diarrhea (21%), arthritis (8.5%), hypothyroidism (7.6%), hyperthyroidism (2.9%), hepatitis (2.9%) and pneumonitis (2%). 8 (7.5%) patients experienced grades (G) 3-4 irAEs: 1 G3 pneumonitis, 4 G3 diarrhea, 1 G3 mucositis, 1 G3 nephritis and 1 G3 hemolytic anemia. One treatment-related death due to pneumonitis was reported.

      Patients receiving ICIs in second line or beyond experienced significantly less irAEs (54.1%) than those treated in first line (73.7%), p 0.04.

      47 (46.5%) patients received systemic corticosteroids during immunotherapy, 29.8% for irAEs management. 11 patients (10.9%) discontinued treatment due to irAEs. At the time of data analysis, 86.8% of irAEs had improved.

      With a median follow-up of 8.9 [0.6-48.2] months, median OS was superior in patients experiencing irAEs: not reached (NR) vs 7.8 [95%CI, 5.2-10.5] months (p 0.001). Similarly, PFS was significantly longer: 6.2 [95%CI, 2.3-10.1] vs 2.7 [95%CI, 1.8-3.5] months (p <0.0001). OS was higher in patients who did not receive steroids during ICIs therapy: NR vs 9.9 [95%CI, 6.8-13.0] months (p 0.024). No association was found between efficacy and the use of antibiotics in the 3 months before first ICIs injection or during treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In our series, the presence of irAEs in patients with advanced NSCLC treated with ICIs was associated with efficacy in terms of PFS and OS. A negative correlation between usage of systemic corticosteroids and outcomes was found.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-64 - Impact of STK11 Co-Mutation on Outcomes Following Immunotherapy Among Patients with TP53 and KRAS Mutated Stage IV NSCLC (Now Available) (ID 12581)

      16:45 - 18:00  |  Presenting Author(s): Melina Elpi Marmarelis  |  Author(s): Erin Bange, Stephen Bagley, Wei-Ting Hwang, Yu-Xiao Yang, Jeffrey C Thompson, Joshua Michael Bauml, Christine Ciunci, Evan Alley, Jennifer Morrissette, Roger B Cohen, Corey J Langer, Erica Carpenter, Charu Aggarwal

      • Abstract
      • Slides

      Background

      Mutations in LKB1/STK11 may predict a poor response to immunotherapy in NSCLC. We previously showed that pretreatment neutrophil-to-lymphocyte ratio (NLR) >5 predicted a poor response to immunotherapy in NSCLC. We evaluated the impact of STK11 mutation (MT) alone, and co-existing MTs in KRAS and TP53 on outcomes in patients (pts) treated with immunotherapy at the University of Pennsylvania. The role of NLR was also evaluated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with metastatic NSCLC that underwent NGS and who received 2nd-line immunotherapy were identified (2/2013 – 12/2016). Patient demographics, tumor characteristics, and outcomes were analyzed from the electronic medical record. Chi-square and the Wilcoxon Rank-Sum test were used to assess correlation between NLR and MT status. Median overall survival (mOS) and median progression free survival (mPFS) times are estimated from Kaplan-Meier curves. A Cox proportional hazard model (HR) was used to assess the effect of mutation status on survival outcomes.

      4c3880bb027f159e801041b1021e88e8 Result

      110 pts were included with the following MT status: 5 STK11, 16 KRAS, 29 TP53, 13 KRAS/TP53, 7 KRAS/STK11, 9 TP53/STK11, 7 KRAS/TP53/STK11, 24 no STK11, KRAS or TP53 MT. In univariate and multivariable analyses, STK11 MT was not independently associated with mPFS or mOS after immunotherapy. Among pts with TP53 MT, the presence of a STK11 MT was associated with improved mPFS (4.3 vs. 2 mo, HR 0.416, p=0 .035, (95% CI 0.18 –0.94)) and statistically similar mOS (13.1 vs 6.8 mo, HR 0.43, p=0.09 (95%CI 0.16–1.14)) compared with STK11 wild type (WT). Conversely, among pts with KRAS MT, the presence of a STK11 MT was associated with similar mPFS (2.2 vs 2.8 mo, HR 1.64, p=0.247 (95% CI 0.7–3.8)) and mOS (3.5 vs 7.7 mo, HR 2.3, p=0.09 (0.16–1.14)) compared with STK11 WT. NLR did not correlate with MT status. After stratifying for NLR (<5 and >5), the effect of STK11 MT on mOS in the TP53 MT group was amplified in pts with NLR<5 (n=46, HR 0.05, p=0.021, 95% CI 0.004-0.63) compared to TP53 MT with STK11 WT (HR 4.3, p=0.036 (95% CI 1.1-16.9)).

      8eea62084ca7e541d918e823422bd82e Conclusion

      STK11 mutation status alone does not correlate with pre-treatment NLR and is not independently associated with survival outcomes after immunotherapy. PFS following immunotherapy is improved in patients with co-existing TP53 and STK11 MT compared to STK11 WT. An OS benefit after immunotherapy is amplified in patients with NLR<5, TP53 MT, and STK11 co-MT.

      * Authors Marmarelis and Bange contributed equally

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      P1.01-65 - PII of Pemetrexed or Pemetrexed Plus Bevacizumab for Previously Untreated Elderly (>=75) Non-Squamous NSCLC (LOGIK1201) (ID 11305)

      16:45 - 18:00  |  Presenting Author(s): RIICHIRO Maruyama  |  Author(s): Minoru Fukuda, Takeshi Kitazaki, Daiki Ogawara, Masao Ichiki, Hiroshi Mukae, Noriaki Nakagaki, Junji Kishimoto, Yukito Ichinose, Kenji Sugio

      • Abstract

      Background

      Pemetrexed (P) provided equivalent or more efficacy to docetaxel with fewer side effects against NSqNSCLC and subset analysis revealed elderly patients receiving P had a longer time to progression and OS than those treated with docetaxel (JCO 22:1589, 2004). Bevacizumab (B), antibody binding with VEGF, is expected additional effect to chemotherapy for patients with NSqNSCLC. To evaluate the efficacy and safety, we conducted randomized phase II study of P and P/B for elderly patients with NSqNSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligibility criterias were: NSqNSCLC, no prior therapy, stage IIIB, IV, postoperative recurrence, age ≥75 years, PS 0-1, adequate bone marrow function. Patients were randomly assigned in a 1:1 ratio to P or P/B. Primary endpoint was PFS. Secondary were RR, OS, toxicity and cost-effect. Stratified log-rank test was used. Assuming PFS of median 3.3 (P) and 7.4 (P/B) months, significance level bilateral 20%, power ≥80%, estimated required number was 32 and target sample size was set 40.

      4c3880bb027f159e801041b1021e88e8 Result

      Forty-one patients from 12 institutions were enrolled between 8/31/2012 and 6/30/2016 and 40 patients (P 20, P/B 20) were assessable. Patients’ characteristics were as follows: male/female = 23/17; median age (range) = 78 (75-83); stage IIIB/IV/postOp = 1/30/9; PS 0/1 = 11/29; all adenocarcinoma. The median PFSs (95%CI) were 5.4 (3.0-7.4) and 5.5 (3.6-9.9) months, respectively, and there is no significant difference (p=0.66). RR was significantly higher in P/B (15% vs. 55%, p=0.0146) and there was no significant difference in OS (median 16.0 vs. 16.4 months, p=0.58). G3/4 leukopenia, neutropenia, thrombocytopenia and fatigue (%) were 10, 20, 5, 25 and 30, 55, 5, 45, respectively. Costs were higher in P/B (median 1,522,008 vs. 3,368,428 JPY, p=0.01). No treatment-related deaths occurred.

      8eea62084ca7e541d918e823422bd82e Conclusion

      P showed similar PFS and OS with favorable toxicity and low cost compare with P/B in elderly (>=75) patients with NSqNSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-66 - Randomized Phase II Evaluating EGFR-TKI Associated with Anti-Estrogen in Women with Non-Squamous Advanced Stage NSCLC: IFCT-1003 LADIE Trial. (ID 13740)

      16:45 - 18:00  |  Presenting Author(s): Julien Mazieres  |  Author(s): Fabrice Barlesi, Isabelle Rouquette, Benjamin Besse, Isabelle Monnet, Clarisse Audigier-Valette, Anne Claire Toffart, Aldo Renault, Severine Moreau, Sandrine Hiret, Bertrand Mennecier, Didier Debieuvre, Virginie Westeel, Philippe Masson, Anne Madroszyk, Elodie Amour, Franck Morin, Gerard Zalcman, Denis Moro-Sibilot, Pierre Jean Souquet

      • Abstract

      Background

      The incidence of lung cancer is increasing dramatically in women with recent findings as the preferential involvement of the EGFR pathway and the potential impact of hormonal factors in women. Preclinical data have shown that the combination of an EGFR-TKI with an anti-estrogen could overcome resistance to EGFR-TKI.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      IFCT-1003 LADIE Trial was a 2x2 arms parallel open-label randomized phase II trial. PS 0-2 post-menopausal women with advanced stage lung adenocarcinoma were treated with gefitinib (G 250 mg/day) vs. G + fulvestrant 500 mg / month with a supplementary dose at day 15 (G+F) in the EGFR mutated group (EGFR+) in 1st or 2nd line setting or with erlotinib (E 150 mg/day) vs. E + fulvestrant (E+F) in the EGFR wild-type group (EGFR WT) in 2nd or 3rd line setting until progression or unacceptable toxicity. Primary objective was progression-free survival (PFS) at 3 and 9 months for EGFR WT and EGFR+ patients, respectively.

      4c3880bb027f159e801041b1021e88e8 Result

      From 02/2012 to 03/2017, 204 pts (G 104, G+F 100) and 175 (E 87, E+F 88) were enrolled in the EGFR+ and EGFR WT cohorts respectively. The median number of fulvestrant injections was 10 in the G+F group and 3 in the E+F group. The tolerance was correct (grade 3/4: 24.2% in the G+F group vs 21.3% in the G group, 16.0% in the E+F group vs 13.8% in the E group) and no treatment-related death. In the EGFR+ cohort, the primary endpoint was reached as 54 pts in the G+F group were non-progressive at 9 months. Nevertheless, addition of F to G was not associated with significant better PFS (9.9 vs 10.1 months) or OS (22.1 vs 29.9 months). In the EGFR WT cohort, the primary endpoint was not reached as 29 patients were non-progressive at 3 months. Here also, addition of F to E was not associated with better outcome (PFS 1.8 vs 2.0 and OS 10.0 vs 7.3 months). No PFS difference was observed in the subgroup of patients with positive staining for REα.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Addition of fulvestrant to EGFR-TKI is feasible and is associated with good PFS in the EGFR mutated group. Nevertheless, the lack of benefit associated with the combination of fulvestrant to EGFR-TKI does not support its future development in a phase 3 trial in women with NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-67 - Clinical Relevance of ALK/ROS1 Resistance Mutations and Other Acquired Mutations Detected by Liquid Biopsy in Advanced NSCLC Patients (ID 14279)

      16:45 - 18:00  |  Presenting Author(s): Laura Mezquita  |  Author(s): Aurélie Swalduz, Cecile Jovelet, Sandra Ortiz-Cuaran, David Planchard, Virginie Avrillon, Gonzalo Recondo, Solène Marteau, Vincent Plagnol, Karen Howarth, Clive Morris, Emma Green, Ludovic Lacroix, Luc Odier, Etienne Rouleau, Pierre Fournel, Caroline Caramella, Claire Tissot, Julien Adam, Maurice Pérol, Luc Friboulet, Pierre Saintigny, Benjamin Besse

      • Abstract

      Background

      Liquid biopsies (LB) for circulating tumor DNA (ctDNA) can be a tool for somatic mutation detectionin NSCLC patients. However, the applicability and clinical relevance of ALK/ROS1 and other acquired mutation detected by LB is poorly described. We evaluated ALK/ROS1 and other acquired mutations detected by ctDNA in a large cohort of ALK/ROS1+ NSCLC patients described to date.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Advanced ALK/ROS1+ NSCLC patients were prospectively enrolled from October 15 to April 2018 in 9 French institutions. ctDNA anlaysis was performed using ctDNA using InVisionFirst™ (36-gene panel) for ALK (EML4 variants v1, v2, v3), ROS1 (CD74, SLC34A2, SDC4 and EZR) fusions, and other somatic mutations.

      4c3880bb027f159e801041b1021e88e8 Result

      120 patients were included: 96 ALK, 24 ROS1. The median prior tyrosine kinase inhibitors (TKI) received was 2 (0-4). Blood samples (n=402) were collected: tyrosine kinase inhibitors (TKI)-naive (n=30), during (n=257) or at progression (PD) under TKI (n=73. Prior treated patients received at least 1 TKI (1-6). Preliminary results are available for the first 54 patients; ALK/ROS1 status was confirmed by ALK IHC (39), FISH (56) and RNAseq (2).

      ALK mutations were detected in 36% of blood samples at PD to TKI (12/33): 8% (1/13) post-crizotinib and 55% (11/20) post next-generation TKI (F1174/F1174V/D1203N/R1192P/G1202R (6)/F1174L+G1202/G1202R+F1174L+C1156Y). Complex ALK mutations were observed in 2/12 samples (17%) post next-generation TKI (G1202R+F1174L+C1156Y/F1174L+G1202R). Other acquired mutations were found in 36% (12/33) of samples at PD: TP53 (10), NFE2L2 (4), PTEN (2), PI3KCA (1), CDKN2A (1). Complex ALK mut.+ non-ALK mut. were found in 6/33 (18%) samples, 1 post crizotinib (G1269A+R1264K+L1196Q+F1164L+C1156Y+NFE2L2(4)), and 5 samples post next-gen TKI (G1202R+PTEN/G1202R+TP53/F1174L+G1202R+TP53/TP53(2)+D1203N/TP53+R1192P). Non-ALK mut. were exclusive and could explain TKI resistance in 6/33 (18%) samples.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Routine liquid biopsies can assess the heterogeneity of the TKI resistance, detecting ALK resistance and other acquired mutations in pretreated advanced ALK & ROS1 NSCLC patients. This could have an impact on clinical outcomes. The association of ALK mut. and complex ALK mut. +/- other acquired mut. with clinical outcomes will be presented at the congress.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-68 - Correlation of the Lung Immune Prognostic Index (LIPI) and PDL1 Status with Outcomes for Immune Checkpoint Inhibitors in Advanced NSCLC Patients (ID 14256)

      16:45 - 18:00  |  Presenting Author(s): Laura Mezquita  |  Author(s): Wungki Park, Kathryn C Arbour, Edouard Auclin, Lizza Hendriks, David Planchard, Diana Saravia, Santiago Ponce Aix, Ernest Nadal, Clarisse Audigier-Valette, Simona Carnio, Julien Adam, José Carlos Ruffinelli, Gerard Zalcman, Gianmauro Numico, Ivana Sullivan, Luis Paz-Ares, Anne-Marie C. Dingemans, Silvia Novello, Matthew D. Hellmann, Gilberto de Lima Lopes, Benjamin Besse

      • Abstract

      Background

      Baseline LIPI, based on derived NLR (neutrophils/[leucocytes-neutrophils]) and lactate dehydrogenase (LDH) was associated with outcomes for immune checkpoint inhibitors in advanced NSCLC patients. We assessed the correlation between LIPI and PDL1 for ICI outcomes in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Baseline dNLR and LDH and clinical data were retrospectively collected in advanced NSCLC patients, treated with PD1/PDL1 +/- CTLA4 inhibitors from Nov. 2012 to Mar. 2018, in a multicentric cohort (N=794) from 11 centers. LIPI stratified 3 groups: good (dNLR<3+LDH<upper limit of normal (ULN), intermediate (dNLR>3 or LDH>ULN), poor risk (dNLR>3+LDH>ULN). PDL1 positivity was defined as ≥ 1% tumor cells expression by immunohistochemistry.

      4c3880bb027f159e801041b1021e88e8 Result

      476 patients (60%) were male, 693 (87%) smokers, 695 (88%) had PS ≤1, with median age 65; 576 (73%) had nonsquamous histology. PDL1 was ≥ 1% in 195 (70%) patients, negative in 82 (30%), and unknown in 517. The median of prior lines was 1 (0-11). The median PFS and OS were 4 months (m) [95% CI 4-5] and 12 m [10-15]. dNLR was>3 in 276 (35%) and LDH>ULN in 290 (37%) patients. LIPI stratified 349 patients as good (44%), 323 (41%) as intermediate and 121 (15%) as poor LIPI risk groups. LIPI was an independent factor for OS (table) and PFS (HR 2.58; CI 1.3-5.2, P=0.02). ≥ 1% PDL1 and ≥ 50% PDL1 were not correlated with OS and PFS. Median OS for good, intermediate, and poor LIPI risk groups were 21 m [17-23], 11 m [9-14] and 4 m [2-6], respectively (P=<0.0001). Median PFS for good, intermediate, and poor risk was 5 m [5-7], 4 m [3-5], and 2 m [1-3], respectively (P=0.0005). No differences were observed in LIPI groups according to the PDL1 expression.

      Multivariate analysis for OS

      HR

      95% CI

      P value

      Immunotherapy line

      >2

      2.117

      0.641

      6.992

      0.219

      N# Metastasis sites

      ≥2

      1.242

      0.727

      2.121

      0.428

      Performance status

      ≥2

      2.141

      1.059

      4.332

      0.034

      Albumin

      >35 g/dL

      0.867

      0.507

      1.48

      0.6

      LIPI

      Intermediate

      Poor

      1.697

      4.178

      0.917

      1.956

      3.142

      8.925

      0.001

      PDL1 IHC

      ≥1%

      0.713

      0.406

      1.252

      0.239

      8eea62084ca7e541d918e823422bd82e Conclusion

      Baseline LIPI is associated with ICI outcomes in advanced NSCLC, regardless the PDL1 expression. LIPI should be evaluated in prospective clinical trials.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-69 - Validation of the Lung Immune Prognostic Index (LIPI): Useful to Identify Resistance to PD-1 Checkpoint Inhibitors in Pretreated Lung Cancer (ID 14122)

      16:45 - 18:00  |  Presenting Author(s): Xabier Mielgo-Rubio  |  Author(s): María Sereno Moyano, Miguel Jhonatan Sotelo-Lezama, Rafael Lopez Castro, Judit Rubio-Martínez, Alejandro Velastegui, Clara Olier-Garate, Sandra Falagan, Isabel Gómez-Barreda, Alejandro Riquelme, Ana Cardeña-Gutiérrez, Juan Moreno Rubio, Cynthia López, Coralia Bueno, Jorge Silva-Ruiz, Estefanía Zhan Zhou, Luis Enrique Chara

      • Abstract
      • Slides

      Background

      Derived neutrophils/(leukocytes-neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level have been correlated with immune checkpoint inhibitors´ (ICI) outcomes. A lung immune prognostic index (LIPI) that showed association with ICI outcomes was developed by Mezquita L et al. based on these 2 systemic inflammation indicators (dNLR <3 and LDH > upper limit of normal (ULN)), characterizing 3 prognostic groups: good, 0 factors; intermediate, 1 factor; poor, 2 factors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a multicenter retrospective study with the aim to validate prognostic value of LIPI score in pretreated advanced-stage non-small-cell lung cancer (NSCLC) treated with ICI. We included consecutive patients treated with nivolumab or pembrolizumab between March 2015 and April 2018 from 7 medical centers in Spain. Investigators at each institution retrospectively reviewed patients´medical records. Pretreatment LIPI score was calculated for all subjects and the primary endpoint was correlation with OS.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 168 patients were included. Median age 65 years (39-85). 134(79,8%) were male and 121 (72%) were PS≦1. Predominant histologies were adenocarcinoma (50%), and squamous-cell carcinoma (42,9%). 92,3% were treated with nivolumab and 7,7% with pembrolizumab. Median number of prior lines was 1 (1-5). Median number of cycles: 11 (1-68). Most were current or former smokers (94,6%). Only 2,3% had EGFR mutations, and 0,6% ALK rearrangement. PD-L1 immunohistochemistry was only available in 25% of patients (<1%: 36,6%; 1-49%: 39%; >=50%: 24,4%). After calculating LIPI score, 56,4% were LIPI 0 (good prognosis), 38,5% LIPI 1 (intermediate prognosis), and 5,1% LIPI 2 (poor prognosis). Response rate (RR) was 30,4% and disease control rate (DCR) 52%. The median PFS and OS were 5,6 months (m) (3,9-7,3) and 11,4 m (9,4-13,5). Median OS for good, intermediate, and poor was 14m (95% CI, 11,2-16,7), 6,3m (95% CI, 0,6-12) and 1,8m (95% CI, 0-4,3), respectively (p=0,0001). LIPI showed correlation with OS in patients with known PD-L1 status and also in those with no information about it. PFS was also correlated (p=0,004) with LIPI score. A LIPI score of 2 was independently associated with poorer OS (HR 4,9; 95% CI, 2,18-11,1).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results support the prognostic value of pretreatment LIPI score. dNLR >3 and LDH greater than ULN was correlated with worse outcomes for ICI, regardless of the knowledge of PD-L1 status. This is a useful tool, based on clinical criteria, that can help us in daily practice to identify which patients benefit from ICI.

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      P1.01-70 - Efficacy and Safety of Second- or Third-Line Nab-Paclitaxel + Durvalumab in Patients with Advanced NSCLC (ABOUND.2L+) (ID 13042)

      16:45 - 18:00  |  Presenting Author(s): Daniel Morgensztern  |  Author(s): Ramaswamy Govindan, Manuel Cobo, Santiago Ponce Aix, Pieter E. Postmus, Conrad Lewanski, Jaafar Bennouna, Juergen R. Fischer, Óscar Juan-Vidal, David J Stewart, Andrea Ardizzoni, Rafia Bhore, Marianne Wolfsteiner, Martin Reck, Denis Talbot, Teng Jin Ong

      • Abstract

      Background

      Cytotoxic chemotherapy may enhance the effect of immune checkpoint blockers (ICBs) through interaction with the immune system (immunostimulation) and cancer cells (increased antigenicity). The phase II ABOUND.2L+ trial investigated second-/third-line nab-paclitaxel monotherapy, nab-paclitaxel + CC-486, or nab-paclitaxel + durvalumab in patients with previously treated advanced-stage NSCLC. This report presents an updated analysis of the efficacy and safety from the nab-paclitaxel + durvalumab treatment arm.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients ≥ 18 years with advanced NSCLC and no more than 1 prior line of platinum-containing chemotherapy (ICBs in prior line, first/second, allowed) were included. Patients were treated with nab-paclitaxel on days 1 and 8 + durvalumab 1125 mg on day 15 of a 21-day cycle until unacceptable toxicity or progressive disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or immune-related RECIST v1.1. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 79 patients were assigned to nab-paclitaxel + durvalumab. The median age of patients in that arm was 63.0 years; 68.4% were male, 97.5% were white, 77.2% had ECOG performance status 1, and 69.6% had nonsquamous histology; 8 patients received prior ICBs. Median and 1-year PFS were 4.5 months (95% CI: 3.45-5.88) and 25.7% (95% CI 16.3-36.2); median PFS in those with and without prior ICB treatment was NE (95% CI 1.38-NE) and 4.4 months (95% CI 2.96-5.68) and in those with squamous and nonsquamous histology was 6.0 months (95% CI 2.99-7.75) and 4.2 months (95% CI 2.86-5.75). The ORR was 27.8%, and DCR was 70.9%. Median OS was 10.1 months (95% CI: 7.75-NE). Median percentage of per protocol dose was 87.5% for nab-paclitaxel and 82.9% for durvalumab. All patients had at least 1 treatment-emergent adverse event (TEAE), and 67.9% had at least 1 grade 3 or 4 TEAE. Common TEAEs of special interest (all grades) included peripheral neuropathy (grouped term; 37.2%), diarrhea (34.6%), anemia (30.8%), dyspnea (25.6%), nausea (24.4%), cough (24.4%), pyrexia (19.2%), and neutropenia (17.9%). TEAEs leading to dose interruption/reduction (nab-paclitaxel and/or durvalumab) were reported in 73.1% of patients, and those leading to discontinuation in 11.5%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      nab-Paclitaxel + durvalumab demonstrated promising antitumor activity and manageable toxicity in second- or third-line treatment of patients with advanced NSCLC. NCT02250326.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-71 - Co-Mutations, Natural History, and Outcomes of BRAF-Mutated Non-Small Cell Lung Cancer at a Single Academic Cancer Center (Now Available) (ID 12392)

      16:45 - 18:00  |  Presenting Author(s): Nathaniel James Myall  |  Author(s): Solomon Henry, Douglas Wood, Joel W. Neal, Heather A Wakelee

      • Abstract
      • Slides

      Background

      Mutations in the BRAF oncogene occur in 2-4% of cases of non-small cell lung cancer (NSCLC). Based on recent trials, combination therapy targeting BRAF and MEK within the MAPK pathway is now approved for BRAF V600E-mutated NSCLC. As BRAF mutations occur infrequently, however, the natural disease history of BRAF-mutated NSCLC remains an area of ongoing study. Our aim was to describe the natural history and outcomes of patients with BRAF-mutated NSCLC seen at our institution.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      An IRB-approved protocol was used to query the Stanford Cancer Registry and Stanford Cancer Institute Research Database (SCIRDB) for patients with BRAF­-mutated NSCLC presenting between January 1, 2006 and July 31, 2015. Each patient chart was then retrospectively reviewed.

      4c3880bb027f159e801041b1021e88e8 Result

      The cohort included 18 patients (median age 66.5 years, 72% male). V600E mutations were most common (72%; 13/18) while non-V600E mutations included G469A (n = 2), G466V, K601E, and V600_W604delinsR. Most patients (69%; 9/13) with V600E mutations were light or never smokers whereas most patients with non-V600E mutations (80%; 4/5) were heavy smokers (>15 pack-years). Secondary mutations occurred most commonly in TP53 (28%; 5/18). With respect to treatment, no patients received BRAF-targeted therapy upfront. Median duration of first-line platinum-based chemotherapy was 9 months (range 1.5-21.5). In the second-line setting, median duration of chemotherapy was 6 months (range 1-52) and median duration of BRAF-targeted therapy was 5.5 months (range 5.5-6.5). Median overall survival of the entire cohort was 34.8 months. Median survival from the onset of metastases (n = 16) was 26.8 months (range 2-130.5) (Table). Among patients diagnosed with stage III-IV disease, survival at 2-years was 53%, with many showing slow progression and control of oligometastatic or intrathoracic disease with systemic therapy or localized radiation.

      Stage BRAF Mutation Co-occurring Mutations Overall Survival (months) Post-Metastases Survival (months)
      1 IA V600E None 83.5+ 39.5+
      2 IIIB V600E None 8.5 7
      3 IV G469A None 37 37
      4 IIIB V600E None 40+ 26.5+
      5 IIIA G469A TP53 41 27
      6 IV V600E None 14 14
      7 IV V600E None 130.5 130.5
      8 IIA V600E None 65 NA
      9 IV V600E CTNNB1 2 2
      10 IV V600E PIK3CA 47.5 47.5
      11 IIIA G466V Multiple (incl. TP53) 39.5 32.5
      12 IA V600E TP53 32.5+ NA
      13 IV V600_W604 None 22.5 22.5
      14 IV V600E None 28 28
      15 IV V600E Multiple (incl. TP53) 13.5 13.5
      16 IV V600E None 88.5 88.5
      17 IV K601E TP53 6.5 6.5
      18 IV V600E NKX2-1 19.5 19.5

      8eea62084ca7e541d918e823422bd82e Conclusion

      BRAF-mutated NSCLC can be associated with prolonged survival in some patients. Future research should aim to identify factors predicting longer outcomes.

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      P1.01-72 - FIND Trial: A Phase II Study to Evaluate the Efficacy of the FGFR-Inhibitor Erdafitinib in FGFR-Mutated and -Translocated Squamous NSCLC (ID 14185)

      16:45 - 18:00  |  Presenting Author(s): Jürgen Wolf  |  Author(s): Lucia Nogova, Florian Malchers, Gregor Zadoyan, Axel Hillmer, Sabine Merkelbach-Bruse, Richard Riedel, Sebastian Michels, Behzad Kharabi Masouleh, Peter De Porre, Ademi Santiago-Walker, Matthias Scheffler, Rieke N Fischer, Diana Abdulla, Roman Thomas, Reinhard Büttner

      • Abstract

      Background

      Genomic FGFR alterations and their oncogenic driver potential are frequently observed in various cancers, including NSCLC, bladder cancer, glioblastoma, sarcoma and head and neck cancer. Initial clinical trials with selective FGFR inhibitors showed moderate responses in FGFR amplified squamous NSCLC (sqNSCLC) patients. However, in FGFR mutated or translocated tumor types (bladder cancer, glioblastoma, endometrial cancer) a response rate of above 30% was observed. Preclinical cell line and patient-derived sqNSCLC xenograft models with FGFR mutations or translocations indicate strong oncogenic activity and potential sensitivity to FGFR inhibitors. Thus, FGFR directed treatment in FGFR mutated and translocated sqNSCLC is of special interest. In particular as there is no approved targeted treatment in the squamous population representing about 25% of all NSCLC patients. Study challenges: Multiple FGFR translocations and mutations are known and approximately 3% of all sqNSCLC patients harbor somatic alterations within FGFR genes. However, only some of these mutations are shown to be oncogenic drivers in vitro and in vivo experiments or first in man trials. This is important given the many FGFR alterations with unknown biological significance and which confer potential resistance to FGFR inhibitors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Screening for FGFR mutations/translocations will be performed within the national Network of Genomic Medicine (nNGM) in 15 screening centers in Germany. SqNSCLC patients with activating FGFR genetic alterations will be treated in 11 clinical centers in Germany with the selective FGFR1-4 kinase inhibitor erdafitinib. Archival samples, fresh frozen tumor samples and blood for circulating tumor DNA (ctDNA) will be collected before treatment. Patients will be treated until disease progression or unacceptable toxicity. At progression, fresh frozen tumor biopsies and ctDNA analyses will be performed to characterize resistance mechanisms.

      The primary objective of the trial is to analyze the efficacy of erdafitinib in sqNSCLC patients with FGFR genetic driver alterations. NSCLC patient number will be based on a statistical hypothesis aiming at increasing the response rate compared to chemotherapy / immunotherapy after standard treatment. The estimated number of patients is based on a 2-stage Simon design. Patients will be recruited into 3 cohorts: Cohort 1: high confidence activating FGFR translocations (max. 15 patients); Cohort 2: high confidence activating FGFR mutations (max. 15 patients); Cohort 3: low confidence activating FGFR alteration (ca. 20 patients)

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      The study is under development and is currently targeted to start recruitment in Q2/2018.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      • Abstract
      • Slides

      Background

      Nintedanib is a multi-target small-molecule with anti-angiogenetic activity which confers longer progression free survival (PFS) and overall survival (OS) as second-line combination treatment with docetaxel versus standard-of-care, in non-squamous non-small cell lung cancer (nsNSCLC) patients, giving to rapidly progressing patients the greatest survival benefit. Considering the higher tolerability of weekly docetaxel than docetaxel q3wks in the real-life, the SENECA trial, a phase IIb, open label, Italian multicentre study, aims to evaluate whether treatment with nintedanib and docetaxel could be effective and safe as second-line option in nsNSCLC patients with the two different schedules.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients from eighteen Italian oncologic centres, with stage IIIB/IV non-oncogene addicted nsNSCLC patients, progressing after first-line chemotherapy, have been treated with docetaxel (T1: 33 mg/mq on days 1 and 8 in a 21-days cycle; T2: 75 mg/mq q3wks) plus continuous oral nintedanib, with the possibility of maintenance in case of stabilization or response. Primary endpoint was PFS (by investigator’s assessment), while secondary endpoints included OS, safety and quality-of-life. Study stratifies patients into two cohorts according to relapse-timing (within or over 3 months) from end of first-line chemotherapy.

      4c3880bb027f159e801041b1021e88e8 Result

      From January 2016 to data cut-off, on 30th March 2018, 197 patients have been evaluated: 30 were registered as screening failures, mainly for contraindications to nintedanib use. The 167 patients considered in this preliminary analysis had a median age of 63.4 years (range 35-86), were predominantly male (68.9%), smokers or former-smokers (84.4%) and with ECOG-performance status 0 (72.5%). According to investigator’s choice, 82 patients have been treated with T1 docetaxel (49.1%), 85 (50.9%) with T2 docetaxel (median docetaxel treatment 3.5 and 3.7 21-days cycles, respectively). No significant differences in median PFS have been observed between T1 and T2 (3.83 vs 4.32 months, respectively; HR 0.889 [95% IC 0.598-1.321], p-value=0.559). After a median follow-up of 7.28 months (standard deviation=5.55), a trend of similar OS has emerged in both T1 and T2 (6.63 vs 7.91 months, respectively; HR 0.770 [95% IC 0.484-1.225], p-value=0.270). Survival data of relapse-timing cohorts are not yet mature. Commonest toxicities in T1 and T2 were: fatigue (53.6% vs 65.9%, respectively), diarrhea (50.0% vs 47.0%), afebrile neutropenia (13.4% vs 52.9%) and ALT elevation (29.3% vs 20.0%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The SENECA trial is a real-life Italian experience, whose preliminary results confirm the efficacy and safety of second-line treatment with nintedanib and docetaxel for nsNSCLC patients, regardless from docetaxel schedule, suggesting higher toxicities for docetaxel q3wks.

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      P1.01-74 - MET Exon 14-Altered Lung Cancers: Central Nervous System (CNS) Metastases and Patterns of CNS Progression on MET Inhibition. (ID 14263)

      16:45 - 18:00  |  Presenting Author(s): Michael Offin  |  Author(s): Jordan Dienstag, Olivia Wilkins, Joshua K Sabari, Ai Ni, Daniel L. Feldman, Martine Van Voorthuysen, Ken Suzawa, Helena Yu, Gregory J Riely, Maria E Arcila, Marc Ladanyi, Mark G Kris, Charles M. Rudin, Romel Somwar, Bob T. Li, Alexander Drilon

      • Abstract
      • Slides

      Background

      MET exon 14 (METex14) alterations are targetable drivers found in 3-4% of lung cancers. The frequency of intracranial disease and patterns of central nervous system (CNS) progression on MET tyrosine kinase inhibitors (TKI) are not well characterized.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with advanced METex14-altered lung cancers identified by next-generation sequencing (MSK-IMPACT) between January 2014 and March 2018 were eligible for analysis. A retrospective review of clinical features, patterns of metastases, and CNS progression on MET-TKI was performed. The frequency of intracranial disease was compared to cohorts single-center of EGFR-mutant (n=200), ERBB2-mutant (n=98) and KRAS-mutant (n=200) lung cancers.

      4c3880bb027f159e801041b1021e88e8 Result

      82 patients with metastatic METex14-altered lung cancers were identified. The median age was 73; 56% (n=46) were female and 54% (n=44) were former smokers. The frequency of brain metastases at baseline was 11% (n=9/82). The lifetime frequency of intracranial metastases from diagnosis of metastatic disease was 34% (n=28/82). By comparison, the frequency of brain metastases was 47% (94/200, p=0.05) with EGFR-, 47% (46/98), p=0.09) with ERBB2-, and 32% (64/200, p=0.78) with KRAS-driven tumors. 6% (n=5/82) of patients developed leptomeningeal disease. The overall survival (OS) of patients who developed intracranial disease on therapy compared to those who did not develop intracranial disease was not significantly different (HR 0.66, 95% CI 0.30-1.43, p=0.29). 51 patients received crizotinib, 26 of whom developed progressive disease. The frequency of intracranial (alone), intracranial and extracranial, and extracranial (alone) progression was 8% (2/26), 19% (5/26), and 73% (19/26), respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A third of patients with METex14-altered lung cancers develop intracranial disease. This proportion is lower than that seen in EGFR- and ERBB2-mutant lung cancers and comparable to KRAS-mutant lung cancers. The frequency of CNS failure on crizotinib was lower than expected compared to historical rates in ALK-rearranged lung cancers.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-75 - Utility of cfDNA Testing for Acquired Resistance: The Memorial Sloan Kettering Experience with Plasma EGFR T790M Clinical Testing. (ID 12514)

      16:45 - 18:00  |  Presenting Author(s): Michael Offin  |  Author(s): Mackenzie Myers, Sowmya Josyula, Ronglai Shen, Laetitia Borsu, Dana Tsui, Gregory J Riely, Charles M. Rudin, Helena Yu, Bob T. Li, Maria E Arcila

      • Abstract
      • Slides

      Background

      Liquid biopsy for circulating tumor DNA (ctDNA) has been increasingly adopted for the detection of oncogenic drivers and drug resistance mechanisms. Practice guidelines for liquid biopsy are lacking and biologic factors influencing ctDNA detection and shedding are poorly understood. We evaluated factors influencing ctDNA detection, using EGFR-T790M as a case-study, in patients with acquired resistance to first/second-generation EGFR tyrosine kinase inhibitors (EGFR-TKI).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This single-center study included metastatic sensitizing EGFR-mutant lung cancer patients (exon 19 deletions, L858R, G719) who underwent plasma EGFR-T790M testing after acquired resistance to erlotinib, gefitinib, or afatinib between January 2016 and August 2017. Plasma T790M was performed by digital PCR. Variant allele fraction (VAF) was calculated as mutant/(wildtype+mutant) allele. Concordance between plasma and tissue testing was examined if tissue analysis (MSK-IMPACT and/or targeted PCR) occurred within 90 days of blood draw. Turnaround time (TAT) was measured from date of blood draw and/or biopsy to result. ctDNA results were correlated with metastatic site and the number of organs involved.

      4c3880bb027f159e801041b1021e88e8 Result

      177 patients underwent plasma T790M testing; 65% female, 47% current/former smokers. Plasma T790M was positive in 32% (56/177) of patients, tissue testing was T790M-positive in 46% (45/97), and overall T790M-positivity by either platform was 49% (86/177). The median TAT was shorter for plasma T790M compared to tissue PCR (9 vs 15 days, p<0.0001), and led to osimertinib use in 84% (47/56) of positive patients. Concordance between plasma and tissue T790M was 80% (32/40). 15 patients with positive plasma had matched tissue, 87% (13/15) were concordant on tissue. 76% (19/25) of the patients that were T790M-negative on plasma also tested negative on tissue. Median plasma T790M-VAF was 0.98% (range 0.1–49.5%), lower than tissue T790M-VAF (12.8%, range 2.58–27.8, p<0.0001). Plasma T790M-VAF did not correlate with time on osimertinib (p=0.72). Plasma T790M status correlated with a higher number of metastatic sites (4 vs 3, p<0.0001). Plasma T790M detection by organ sites were: pleura (58% with metastases vs 34% without metastases, p=0.14), bone (80% vs 21%, p=0.0002), hepatic (61% vs 41%, p=0.28), nodal (61% vs 33%, p=0.07), adrenal (64% vs 44%, p=0.60), brain (71% vs 38%, p=0.08), and bone/hepatic concurrently (94% vs 98%, p=0.04).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Using plasma T790M as an archetypal example, cfDNA testing showed concordance and a shorter turnaround compared to tissue testing. cfDNA was more likely to result positive in patients with more metastatic sites, or osseous and hepatic metastases possibly driven by increased ctDNA shedding.

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      P1.01-76 - A Phase II Trial of Albumin-Bound Paclitaxel and Gemcitabine in Patients with Newly Diagnosed Stage IV Squamous Cell Lung Cancers (ID 13324)

      16:45 - 18:00  |  Presenting Author(s): Paul K. Paik  |  Author(s): Rachel Kim, Linda Ahn, Andrew Plodkowski, Kenneth Ng, Daniel McFarland, Afsheen Iqbal, Juliana Eng, Charles M. Rudin

      • Abstract

      Background

      Therapeutic options for SQCLC patients are limited. The efficacy of platinum-based doublets, long the standard first-line treatments, has plateaued, with ORR=30%. Anti-tumor synergy between gemcitabine and albumin-bound paclitaxel (ABP) was demonstrated by Frese et al. who showed that ABP downregulates cytidine deaminase, leading to increased intratumoral gemcitabine (Cancer Disc 2012). Based on these data, we sought to assess the efficacy of ABP + gemcitabine in patients with SQCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This was a Simon two-stage phase 2 study of ABP + gemcitabine in chemotherapy-naïve, PD-L1 low/unknown advanced SQCLC patients (NCT02525653). Primary endpoint: best ORR. H0=25% (≥6/17 responses) and HA=45% (≥16/41 responses). ABP (100mg/m2) + gemcitabine (1000mg/m2) was initially given on D1, D8, D15 of an every 4 week cycle for up to 6 cycles (A1). After clearing H0, the study was amended to a 3 week cycle (D1, D8 treatment) and to allow maintenance ABP after C4 (A2). All patients underwent NGS by MSK-IMPACT.

      4c3880bb027f159e801041b1021e88e8 Result

      N=27 patients were evaluable for the primary endpoint. Median age=70, age ≥70=60%, female=30%, median KPS=80%, smokers=93%. 46% of patients had PD-L1 IHC <50% (0-20%). 54% were PD-L1 unknown. Grade ≥3 related AEs included: fatigue-13%, neuropathy-4%; diarrhea-4%; lung infection-4%, anemia-9%; decreased platelet count-4%, and decreased neutrophils (4%). Four patients (17%) experienced related SAEs including, separately, G3 febrile neutropenia, G3 WBC decrease, G3 thrombocytopenia, and G3 anemia.

      ORR for the entire cohort was 63% (Figure 1). ORR in A2= 71% (10/14). 8 patients in A1 had dose modifications resulting in equivalency to the A2 schedule. ORR in the A2+A1 dose modified cohort=73% (16/22), meeting the primary endpoint early. Median PFS=8mo; OS not yet mature.

      15-054 waterfall.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      ABP + gemcitabine is an effective and well-tolerated regimen in patients with untreated advanced SQCLC with a response rate exceeding that associated with platinum regimens and first-line immunotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-77 - Osimertinib in the First-Line Treatment of Non-Small Cell Lung Cancer Harboring Activating EGFR Mutation from Circulating Tumor DNA (ID 13686)

      16:45 - 18:00  |  Presenting Author(s): Cheol-Kyu Park  |  Author(s): Hyun-Ju Cho, Yoo Duk Choi, In-Jae Oh, Young-Chul Kim

      • Abstract
      • Slides

      Background

      Osimertinib is a potent, irreversible third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for both EGFR activating and T790M resistant mutation. In this trial, the treatment efficacy of osimertinib was assessed in previously untreated patients with advanced or metastatic non-small cell lung carcinoma (NSCLC) harboring the EGFR activating mutation, which was detected from circulating tumor DNA (ctDNA) combined with tumor genotyping.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Venous blood sampling was performed from the patients with EGFR activating mutation confirmed by tissue genotyping. To extract ctDNA from the plasma, 15 mL of peripheral blood was withdrawn and centrifuged, immediately before storage. CobasTM v2 and PANA MutyperTM were used for ctDNA genotyping. Patients with the EGFR activating mutation, detected from ctDNA, were enrolled and received a once-daily administration of osimertinib, 80 mg. The primary endpoint was objective response rate (ORR), and secondary endpoints were ctDNA test sensitivity, progression-free survival (PFS), duration of response (DoR), and safety of osimertinib treatment (ClinicalTrials.gov, Identifier: NCT02769286).

      4c3880bb027f159e801041b1021e88e8 Result

      Thirty-nine patients with activating EGFR mutations in tumor genotyping were screened from February 2017, and the enrollment of the last patient was completed in March 2018. The ctDNA of 29 patients was positive for activating EGFR mutation, and 19 patients were enrolled (exon 19 deletion, n=11; L858R or L861Q, n=7; G719A, n=1). Median age was 70 years (range 32-84) and the majority of patients had brain metastasis (15/19, 78.9%). In the response-evaluable population (n=17), ORR was 64.7% (11/17) and DCR was 94.1% (16/17). According to EGFR mutation type of tumor genotyping, patients with exon 19 deletion showed more favorable ORR (8/9, 88.9%) than patients with exon 21 L858R/L861Q (3/7, 42.9%). In patients evaluable for CNS response (n=14), DCR of brain metastasis was 100.0% (14/14). The sensitivity of the ctDNA tests for activating EGFR mutation was 74.4% when using both tests, and 61.5% (Mutyper) or 64.1% (Cobas V2) with either test. Only one patient experienced drug-related interstitial pneumonia of grades ≥3 and resulted in drug discontinuation. Survival data including PFS was not matured (2/19, 10.5%) and the analysis will be followed.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Osimertinib had favorable efficacy in first-line treatment of NSCLC harboring the EGFR activating mutation, detected from ctDNA combined with tumor genotyping, even though in patients with old age and brain metastasis.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-78 - The Incidence of Brain Metastases in ROS1-Rearranged Non-Small Cell Lung Cancer at Diagnosis and Following Progression on Crizotinib (Now Available) (ID 14164)

      16:45 - 18:00  |  Presenting Author(s): Tejas Patil  |  Author(s): Derek E Smith, Paul A. Bunn, Jr., Dara L. Aisner, Anh T Le, Mark Hancock, William T Purcell, Daniel W Bowles, Ross Camidge, Robert C. Doebele

      • Abstract
      • Slides

      Background

      Central nervous system (CNS) metastases in lung cancer are a frequent cause of morbidity and mortality. There are conflicting data on the incidence of CNS metastases in ROS1+ NSCLC at diagnosis and rate of CNS progression on crizotinib.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective review of 579 patients with stage IV NSCLC between June 2008 to December 2017 was performed. We captured presence of brain metastases and oncogene status. We measured progression free survival (PFS) and time to CNS progression in ROS1+ and ALK+ patients on crizotinib.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 33 ROS1+ and 115 ALK+ patients with advanced NSCLC. The incidence of brain metastases for treatment-naïve ROS1+ and ALK+ NSCLC was 36% (12/33) and 34% (39/115) respectively. There were no statistically significant differences in incidence of brain metastases across all oncogene sub-groups. Complete survival data was available for 19 ROS1+ and 83 ALK+ patients. Median PFS for the ROS1+ and ALK+ cohort was 11 and 8 months (p = 0.304). The CNS was the first site of progression for 52% (10/19) ROS1+ NSCLC and 43% (36/83) ALK+ NSCLC with no significant differences between the groups (p = 0.610). Among patients without CNS metastases prior to crizotinib therapy, 50% of ROS1+ and ALK+ patients developed CNS metastases as only site of progression at 24 and 21 months respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Brain metastases are common in treatment-naïve stage IV ROS1+ NSCLC, though incidence does not differ from other oncogene cohorts. The CNS is a common first site of progression in patients with ROS1+ NSCLC on crizotinib. This study reinforces the need to develop CNS-penetrant TKIs for patients with ROS1+ NSCLC, similar to ALK+ NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-79 - CheckMate 817: Safety of Flat-Dose Nivolumab Plus Weight-Based Ipilimumab for the First-line (1L) Treatment of Advanced NSCLC (ID 12004)

      16:45 - 18:00  |  Presenting Author(s): Luis Paz-Ares  |  Author(s): Laszlo Urban, Clarisse Audigier-Valette, Francesco Grossi, Kevin Jao, Jean-Sebastien Aucoin, Helena Linardou, Elena Vladimirovna Poddubskaya, Juergen R. Fischer, Alessandra Curioni Fontecedro, Harry J.M. Groen, Karim Vermaelen, Maryam Bourhaba, Dariusz Kowalski, Rathi N Pillai, David R. Spigel, Samreen Ahmed, Wenhua Hu, Donna Vickery, Joseph Fiore, Neal E. Ready

      • Abstract
      • Slides

      Background

      CheckMate 227 demonstrated significant, clinically meaningful progression-free survival benefit with 1L nivolumab 3 mg/kg every 2 weeks (Q2W) plus low-dose ipilimumab 1 mg/kg Q6W vs chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and tumor mutational burden (TMB) ≥10 mutations/megabase. The dose and schedule for this combination regimen were optimized for 1L NSCLC in CheckMate 012 and further validated in CheckMate 568 and CheckMate 227. Flat dosing of nivolumab (240 mg Q2W) may simplify treatment while providing comparable exposure, and was recently approved for previously treated NSCLC. CheckMate 817 (NCT02869789) is a multi-cohort, open-label phase 3b/4 study evaluating the safety and efficacy of flat-dose nivolumab plus weight-based low-dose ipilimumab in recurrent/metastatic NSCLC. We report safety results from Cohort A, which evaluated this regimen in the 1L setting; updated results will be presented.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with ECOG PS ≤1 and previously untreated NSCLC were eligible, regardless of tumor programmed death ligand 1 (PD-L1) expression and TMB. Nivolumab 240 mg Q2W plus ipilimumab 1 mg/kg Q6W were administered for 2 years or until disease progression/unacceptable toxicity. The primary endpoint was safety assessed by the incidence of grade ≥3 select treatment-related adverse events (TRAEs; defined as AEs of potential immunologic causes).

      4c3880bb027f159e801041b1021e88e8 Result

      Enrollment occurred between October 2016 and August 2017, with 391 patients initiating treatment at 68 academic and community-based centers in Europe and North America. Median age was 65 years and 27.9% of patients had squamous histology. PD-L1 expression was evaluable in 91% of patients; of these, 50% had ≥1% tumor PD-L1 expression. At database lock (March 1, 2018), minimum follow-up was 5.4 months and 34.5% of patients remained on treatment. The median (range) number of nivolumab and ipilimumab doses received were 9 (1–28) and 3 (1–10), respectively. Any grade and grade 3–4 TRAEs occurred in 74.4% and 27.6% of patients, respectively; 14.1% of patients discontinued treatment due to TRAEs. Rates of any grade select TRAEs by category ranged from 1.3% (renal) to 28.4% (skin). The most common grade 3–4 select TRAEs by category were hepatic (4.6%), pulmonary (3.1%), and gastrointestinal (3.1%). Two treatment-related deaths were reported; one due to Guillain-Barré syndrome and one due to rhabdomyolysis leading to heart failure.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The safety profile of flat-dose nivolumab plus low-dose ipilimumab was consistent with previous reports of weight-based nivolumab plus low-dose ipilimumab optimized for NSCLC. Toxicities were manageable with no new safety signals identified.

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      P1.01-80 - ELIOS: A Multicenter, Open-Label, Molecular Profiling Study of Patients with EGFRm and NSCLC Treated with Osimertinib (ID 13198)

      16:45 - 18:00  |  Presenting Author(s): Zofia Piotrowska  |  Author(s): Juliann Chmielecki, Diana Cripps, Miguel F Miranda

      • Abstract
      • Slides

      Background

      Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard-of-care for locally advanced/metastatic non-small cell lung cancer (NSCLC) harbouring EGFR sensitizing mutations (EGFRm). Osimertinib, a third-generation, CNS-active EGFR-TKI potently and selectively inhibits both L858R and exon19del sensitizing EGFRm and T790M mutations, is now approved for first-line treatment of EGFRm-NSCLC. Studies of osimertinib resistance have focused on patients previously treated with first-/second-generation EGFR-TKIs; however, resistance mechanisms to first-line osimertinib are not well-described.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      ELIOS (NCT03239340) is a phase 2, open-label, single-arm study designed to prospectively characterize the molecular profile of patients who progress on first-line osimertinib. The study will enroll patients (n=100) with locally advanced/metastatic non-squamous EGFRm-NSCLC nonamenable to curative surgery/chemoradiation, WHO performance status 0-1, and life expectancy ≥12 weeks. Patients must have EGFRm known to be associated with EGFR-TKI sensitivity, must be EGFR-TKI treatment-naïve, and be eligible to receive first-line osimertinib therapy. Patients with clinically significant toxicities, history of interstitial lung disease, and EGFR exon 20 insertion will be excluded. All patients will receive 80 mg osimertinib orally once daily and will continue treatment beyond progression if they show continued clinical benefit. Mandatory tumor biopsies will be obtained prior to treatment initiation and following investigator-assessed disease progression. An optional biopsy may be obtained following 2-3 weeks of treatment. Longitudinal plasma samples will be collected for plasma-derived circulating tumor DNA (ctDNA) analysis. Tumor- and plasma-derived specimens will be analyzed by next-generation sequencing; additional exploratory analyses are also planned. The primary endpoint is the proportion of patients with a given genetic/proteomic marker at disease progression (investigator-assessed, RECIST v1.1). Relevant genetic and proteomic markers will be selected based on the profile comparison at disease progression to baseline. Relevant markers of resistance to first-line osimertinib may include, but are not limited to, EGFR resistance mutations (including C797S) and cMET/HER2 amplification; this analysis may reveal other, potentially novel, resistance mechanisms. Secondary endpoints include progression-free survival, objective response rate, duration of response, disease control rate, assessment of osimertinib efficacy post-progression using time to treatment discontinuation, and time to first subsequent therapy. Efficacy analyses based on predefined subgroups (according to the patient molecular profiles) including presence of baseline T790M mutation, EGFR Ex19del or L858R mutations, and EGFR Ex19del or L858R detectable in ctDNA, will be assessed. Safety will also be assessed. Primary analysis will be performed when ≥50 patients have paired biopsies upon progression. Recruitment is in process (May 1, 2018).

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-81 - Phase 3 Study of Pemetrexed-Platinum with or without Pembrolizumab for TKI-Resistant/EGFR-Mutated Advanced NSCLC: KEYNOTE-789 (ID 14192)

      16:45 - 18:00  |  Presenting Author(s): Gregory J Riely  |  Author(s): Rina Hui, David P Carbone, Keunchil Park, Marion Carrigan, Xia Xu, Thao Dang, James Chih-Hsin Yang

      • Abstract
      • Slides

      Background

      In the phase 3 KEYNOTE-189 study, pembrolizumab plus pemetrexed-platinum improved OS and PFS over chemotherapy plus placebo in first-line, metastatic NSCLC without targetable EGFR mutations (Gandhi et al. NEJM 2018). The phase 3 KEYNOTE-789 (ClinicalTrials.gov, NCT03515837) study evaluates pemetrexed-platinum combined with pembrolizumab vs placebo in EGFR-TKI–resistant, EGFR-mutated, metastatic nonsquamous NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligibility for this multicenter, randomized, double-blind, placebo-controlled study requires age ≥18 years; EGFR-TKI–resistant EGFR-mutated (exon 19 deletion or L858R mutation), histologically/cytologically confirmed stage IV, nonsquamous NSCLC; measurable disease per RECIST version 1.1; ECOG PS 0/1; and archival/newly obtained pretreatment tumor sample to evaluate PD-L1 expression. If progression on prior EGFR-TKI occurred with first- or second-generation TKIs (eg, erlotinib, afatinib, gefitinib) and T790M mutation is present, patients must have had subsequent progression on osimertinib; patients with progression on first-line osimertinib are eligible regardless of EGFR T790M mutation status. Patients are randomized 1:1 to pembrolizumab 200 mg or placebo, each in combination with pemetrexed 500 mg/m2 plus platinum chemotherapy (carboplatin AUC 5 or cisplatin 75 mg/m2; investigator’s choice) Q3W for 4 cycles. Patients continue allocated treatment (pembrolizumab or placebo) plus pemetrexed for up to 35 cycles, followed by pemetrexed maintenance therapy until documented disease progression or intolerable toxicity. Randomization is stratified by PD-L1 tumor proportion score ≥50% vs <50%, prior osimertinib vs no prior osimertinib, and geographic region of East Asia vs non-East Asia. Tumor response is assessed radiographically at baseline, week-6, then every 9 weeks through week-54 and every 12 weeks thereafter, per RECIST version 1.1 by blinded, independent central review. Treatment decisions are based on iRECIST criteria by investigator review. PFS and OS are dual primary endpoints, which will be tested with one-sided alphas of 0.001 and 0.02, respectively. Secondary endpoints are ORR; duration of response; change from baseline global health status and quality-of-life scores on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Core 30; time to true deterioration in composite endpoint of cough, chest pain, or dyspnea on EORTC QLQ-Lung Cancer Module 13; and safety and tolerability. Severity of AEs will be graded per NCI CTCAE version 4.0. Approximately 480 patients will be enrolled beginning June 1, 2018.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-82 - Risk of Not Receiving 2nd Line Therapy is High in EGFR mt+ pts: Real World Data of Certified Lung Cancer Centers on Treatment Sequence in EGFR mt+ pts (Now Available) (ID 13238)

      16:45 - 18:00  |  Presenting Author(s): Julia Roeper  |  Author(s): Markus Falk, Stefanie Schatz, Markus Tiemann, Sandra Sackmann, Dieter Ukena, Claas Wesseler, Gunther Wiest, Lukas Heukamp, Frank Griesinger

      • Abstract
      • Slides

      Background

      Recently FLAURA study demonstrated significant PFS and numeric OS benefit for Osimertinib 1st line vs. 1st generation TKI’s Erlotinib/Gefitinib. The number of patients switching from 1st generation to 3rd gen. TKI (30%) appeared to be low and it is questionable whether these data represent real world sequencing treatment patterns. Therefore, we investigated the sequence pattern, i.e. the percentage of 2nd line therapy in EGFR mt+ patients in 3 certified lung cancer centers in Germany.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data of 912 of 1477 patients tested for EGFR mutations (treated in Oldenburg, Bremen, Hamburg) were analyzed between 2009-2017. 140/144 patients with an activating EGFR mutation (16%) and treated with systemic therapy (4 patients received no therapy) were identified and their treatments were captured as well as their outcome. 36 patients were treated before accessibility to 3rd generation TKI and 104 patients after accessibility to 3rd generation TKI.

      4c3880bb027f159e801041b1021e88e8 Result

      130/140 patients were treated with 1st line TKI and 10 received 1st line chemotherapy. 17 patients are still on 1st line TKI, 8 patients were lost to follow-up, 3 patients died while on 1st line TKI. 112 patients were candidates for 2nd line therapy. 34/112 (30%) of these patients did not receive 2nd line therapy. Causes for not receiving 2nd line therapy were patients refusal (n=2), bad PS (n=26) frequently due to CNS metastases, fast progression and death (n=6). After accessibility of 3rd generation TKI, 20 of 66 (30%) patients did not receive 2nd line therapy. Median OS of the overall cohort was 27 months (n=140), median OS of patients receiving 2nd line (n=78) vs. no 2nd line (n=62) was 36 vs. 14 months (p<0.0001). After accessibility of 3rd generation TKI 30/104 patients (29%) receive a 3rd generation TKI after 1st line or 2nd line therapy. Median OS of patients receiving (n=30) and not receiving 3rd generation TKI (n=110) was 55 months vs. 22 months (p<0.0001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In real world, a significant number of patients treated with 1st or 2nd generation TKI do not reach 2nd line therapy even when 3rd generation TKI were accessible. Reasons for not receiving 2nd line therapy are in most cases deterioration of PS and lack of possibility to test for T790M in the minority of cases (n=28/66, 42% were not tested). These data, although favorable for the small and very selected cohort of patients treated with Osimertinib, might argue for the most effective therapy in 1st line for patients with EGFR mt+ tumors.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-83 - IMpower150: Impact of Chemotherapy Cycles in 1L Metastatic NSCLC in Patients Treated With Atezolizumab + Bevacizumab (ID 12180)

      16:45 - 18:00  |  Presenting Author(s): Jeffrey Rothenstein  |  Author(s): Alexander Spira, Vamsidhar Velcheti, Ronald B Natale, Mark F Kozloff, Michael Kosty, Jerome Goldschmidt Jr., Julien Mazieres, Santiago Ponce Aix, Wei Yu, Mayank Gandhi, Anthony Lee, Geetha Shankar, Wei Lin, Christian A. Thomas

      • Abstract
      • Slides

      Background

      In the randomized Phase III IMpower150 study, atezolizumab (anti–programmed death-ligand 1 [PD-L1]) + bevacizumab + chemotherapy (Arm B) showed statistically significant and clinically meaningful improvement in both progression-free survival (PFS) and overall survival (OS) over bevacizumab + chemotherapy (Arm C) in patients with first-line (1L) nonsquamous non-small cell lung cancer (NSCLC). The study protocol allowed investigator choice of 4 or 6 chemotherapy cycles. The objective of this exploratory analysis was to assess the impact of chemotherapy cycles on safety and efficacy outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients were categorized based on actual chemotherapy cycles received in Arm B. Landmark analysis of PFS was performed to assess the benefit of 4 vs 6 chemotherapy cycles. Sensitivity analyses were performed to adjust the numerically imbalanced baseline factors.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 356 patients were randomized in Arm B; 188 patients (53%) were planned to receive 4 cycles, and 168 patients (47%) were planned to receive 6 cycles of chemotherapy. Within these 2 groups, 143 (76%) and 98 patients (58%) completed 4 and 6 chemotherapy cycles, respectively. The demographic and baseline disease characteristics were balanced, except for race (Asian vs other), smoking status, and PD-L1 status (TC3 or IC3 vs other). The landmark PFS analysis showed no difference between patients who completed 4 vs 6 cycles (HR 0.83 [95% CI: 0.59, 1.17). The sensitivity analyses, which adjusted for race, smoking status, or PD-L1, showed comparable results (adjusted HRs of 0.80, 0.85, or 0.91, respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In the atezolizumab + bevacizumab + chemotherapy arm, patients who received 4 cycles of chemotherapy appeared to have similar PFS benefit as those who received 6 cycles of chemotherapy. Detailed analyses of varying chemotherapy cycles, safety analyses, and impact on OS will be presented.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-84 - High Basal Serum EGF Levels Predicts Response to CIMAvax-EGF, a Therapeutic Vaccine for Advanced NSCLC (Now Available) (ID 14045)

      16:45 - 18:00  |  Presenting Author(s): Orestes Santos Morales  |  Author(s): Patricia Luaces, Tania Crombet, Camilo Rodríguez, Elia Neninger

      • Abstract
      • Slides

      Background

      CIMAvax-EGF is a therapeutic vaccine for the treament of advanced NSCLC. The rationale of its use is to create an immune response against circulating plasmatic EGF and by doing this prevent its binding to EGFR. Previous early stage trials have shown its safety and efficacy. Recently a randomized controlled phase III pivotal trial have confirmed its efficacy and safety in open population when used according to stablished protocols. Exploratory results from this study suggested EGF could function as prognostic and predictive biomarker. In this study we aim to evaluate whether basal EGF plasmatic levels can predict patients response to this immunotherapeutic product.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To know the effect of biomarker status on CIMAvax-effect we pooled data from two previously published controlled trials that used the product in a population of advanced non small cell lung cancer after First Line platinum based chemotherapy. Low doses of cyclophosphamide (200mg/m2) were administered IV three days before the first administration of the vaccine. 2.4 mg/dose of the product were administered during induction phase and then monthly for maintenance treatment. Both studies used Best Support Care as Control Arm. The main outcome was Overall Survival.

      4c3880bb027f159e801041b1021e88e8 Result

      Out of 485 patients included in both studies, 229 were screening for EGF levels (56.5%), (120 and 109 in the high and low level subgroup, respectively). All patients were considered in the analyses. A significant biomarker/treatment effect was found (p=0.000). Hazard ratio (CIMAvax-EGF vs BSC) in the high egf subgroup favoured CIMAvax-EGF (0.44, p=0.000).

      abstract 14045.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Basal level of plasmatic EGF predicts clinical benefit from CIMAvax-EGF therapeutic cancer vaccine in advanced NSCLC after First Line of Treatment based on Platinum. Vaccinated patients in the subgroup of high EGF levels significantly benefit from CIMAvax-EGF.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-85 - The Prevalence of Different EGFR exon20 Mutations in 12,833 Chinese Lung Cancer Patients (Now Available) (ID 14141)

      16:45 - 18:00  |  Presenting Author(s): Yang W. Shao  |  Author(s): Xiaoling Tong, Xiaonan Wang, Fufeng Wang, Xue Wu

      • Abstract
      • Slides

      Background

      Mutations in EGFR exon20 are relatively rare in lung cancers compared to L858R/exon19 mutations, some of which have shown sensitivity to EGFR tyrosine kinase inhibitors (TKIs), and have been actively tested in clinical trials. However, due to the high-variety of EGFR exon20 alterations, it becomes increasingly difficult for their functional studies in related to clinical practice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively screened 12,833 Chinese lung cancer patients that have underwent genotyping on their tumor and/or liquid biopsy samples using targeted next-generation sequencing between 2014 and 2017 for EGFR exon20 mutations as well as other concurrent EGFR mutations in the same patient.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 442 patients (3.4%) were found harboring 493 different EGFR exon20 variations, among which 49 patients (11%) carried more than one exon20 mutations. The frequencies of the most prevalent alterations were summarized in Table 1. 18% of these mutations have concurrent TKI-sensitive mutations L858R or exon19 deletion. In-frame deletion/insertions (delins or ins) and missense mutations were identified at a frequency of 53% and 47%, respectively. The short delins/ins occurred between 763~773 residues, while missense mutations dwelled at 768~820 residues, suggesting that these two types of alterations have their own manners for regulating EGFR kinase domain function. The most prevalent insertion is p.M766delinsMASV, occurred in 15.2% of all patients. Meanwhile, the diversity of inserted peptides at p.D770 and p.D771 positions is much higher than other positions with a total of 17 and 19 different insertion peptides composed of 1-5 amino acids, respectively. Missense mutations at S768 were detected in 20.4% of patients, but 60% of them were accompanied by mutations at G719. table 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the largest cohort of Chinese lung cancers for studying EGFR exon 20 mutations, which should be informative for functional studies, the design of targeted drugs, and the testing for existing therapies.

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      P1.01-86 - BTCRC-LUN15-017: Phase-Ib Study of Imprime PGG and Pembrolizumab in Stage IV NSCLC after Progression on Platinum Based Therapy (ID 12794)

      16:45 - 18:00  |  Presenting Author(s): Ardaman Shergill  |  Author(s): Muhammad Furqan, Jyoti Malhotra, Li Liu, Nandita Bose, Chandra Belani, Lawrence Eric Feldman

      • Abstract
      • Slides

      Background

      Imprime PGG (Imprime) is a β-glucan isolated from a proprietary strain of Saccharomyces cerevisiae. It acts as pathogen associated molecular pattern, creating ‘non-self’ signals, enhancing innate immune cell killing, and possibly T-cell cross-talk, thereby enhancing efficacy of checkpoint inhibitor therapy like pembrolizumab. Clinical use of Imprime in combination with chemotherapy and monoclonal-antibodies has been reported, however no studies to date have evaluated its use with anti-PD-1 therapy. We aimed to evaluate safety and tolerability of Imprime with pembrolizumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a single-arm, phase-1b, open-label, dose-escalation trial for patients with stage IV NSCLC after progression on platinum-based chemotherapy. Key eligibility included measurable disease, adequate organ function and ECOG performance status of 0-2. Patients received 2 mg/kg or 4 mg/kg IV Imprime on day 1, 8, 15, and 200mg IV pembrolizumab on day 1, every 21 days. “3+3” design was used to establish highest tolerated dose. The dose with toxicity rate of <33% in first cycle would be considered the recommended phase-II dose i.e.≤1 out of 6 patients experience dose limiting toxicity (DLT). Primary endpoint was to establish highest tolerated dose of Imprime for recommendation for phase-II study. Secondary objectives were to define safety and tolerability, and to correlate clinical benefit with biomarkers on immune cells, soluble PD-L1 levels, anti-β-glucan antibody and FcγRIIa polymorphism. This trial is registered with ClinicalTrials.gov, NCT03003468.

      4c3880bb027f159e801041b1021e88e8 Result

      Between 07/2017-02/2018, nine patients were enrolled: three patients received 2 mg/kg and six received 4 mg/kg dose of Imprime. Eight out of nine patients had one line of treatment prior to participation, and one had two lines. Two patients received eleven cycles with 4 mg/kg Imprime. To date, no DLTs have been recorded and the highest dose of Imprime was well tolerated. Five patients stopped treatment due to progression. Four patients are continuing treatment. No patients stopped treatment due to toxicity. Most common adverse event (AE) at 2 mg/kg was grade 1 sore throat in two patients. One Grade 3 diarrhea and one grade 3 neutropenia were reported. Most common AE in the 4 mg/kg group was grade 1 headache in three patients. One episode of grade 3 diarrhea was reported. There were no grade 4 or 5 toxicities. The results of the immunopharmacodynamic analysis will be reported when available.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Imprime in combination with pembrolizumab is well tolerated in outpatient settings and the role of this combination in treatment of NSCLC warrants further investigation. Phase-II enrollment of this trial is ongoing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-87 - A Phase 1b Study of TRC105 In Combination with Paclitaxel/Carboplatin and Bevacizumab in Patients with Stage 4 Non-Squamous Cell Lung Cancer  (Now Available) (ID 12978)

      16:45 - 18:00  |  Presenting Author(s): Garrett Sherwood  |  Author(s): Francisco Robert, Mary Jerome, Debi Miley, Michael Harris, Brian Simpson, Bonne Adams, Charles Theuer

      • Abstract
      • Slides

      Background

      Endoglin plays a critical role in angiogenesis and is implicated in resistance to VEGF inhibition. TRC105, an endoglin antibody, has been shown to potentiate the anti-angiogenic effect of bevacizumab (B) in pre-clinical models of human angiogenesis. Given the critical role of anti-angiogenic therapy in the treatment of advanced NSCLC and the tendency of the tumor to develop escape pathways of angiogenesis following treatment with anti-VEGF agent, investigation of dual anti-angiogenic therapy in advanced NSCLC is indicated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A standard (3+3) dose-escalation design of TRC105 with15 mg/kg bevacizumab (B), 200 mg/m2 paclitaxel (P) and 6 AUC carboplatin (C) given IV on day 1 of each 21-day cycle was employed, followed by an expanded cohort to further assess the safety and tolerability of the recommended phase 2 dose (RPTD) of TRC105. Patients completed induction therapy with TRC105 + B, P and C for a maximum of 6 cycles with those demonstrating no evidence of disease progression transitioned to a maintenance phase of TRC105 + B. Secondary endpoints: ORR, PFS, OS, PK, immunogenicity and angiogenic biomarkers. Key inclusion criteria: chemotherapy-naïve stage 4 NSQ-NSCLC, ECOG < 1, measurable disease and no significant cardiovascular comorbidities.

      4c3880bb027f159e801041b1021e88e8 Result

      Fifteen pts have been enrolled; three were unevaluable for efficacy due to DLT of Grade 3 rash and unrelated SAE’s of Grade 3 weakness and Grade 3 hypoxia. Four of 12 evaluable pts achieved PR, one with 81% tumor reduction. Median PFS was 6.54 months. Common adverse events regardless of relationship included epistaxis, fatigue, telangiectasia, diarrhea, headache and nausea. Common TRC105 related AEs included epistaxis, telangiectasia, fatigue and headache. One patient experienced Grade 5 neutropenic sepsis considered unrelated to TRC105 or B. Analysis of the angiogenic biomarkers will be presented.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Induction treatment for six 3-week cycles withTRC105 + B, P, and C, followed by maintenance therapy with TRC105 + B until disease progression was tolerable and did not potentiate the toxicity of B, P or C. The combination of TRC105 + B, P and C demonstrated signs of activity including PR in 4 of 12 evaluable pts.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-88 - Osimertinib Maintenance After Definitive Chemoradiation in Patients with Unresectable EGFRm-Positive Stage III NSCLC (LAURA) (ID 13684)

      16:45 - 18:00  |  Presenting Author(s): Lu Shun  |  Author(s): Tony Nash, Matilde Saggese, Helen Mann, Suresh S. Ramalingam

      • Abstract
      • Slides

      Background

      The standard of care for patients with stage III unresectable NSCLC is definitive platinum-based chemoradiation, regardless of epidermal growth factor receptor mutation (EGFRm) status. There is evidence that following chemoradiation, patients with EGFRm-positive NSCLC have superior local control but inferior distant control, including an increased incidence of CNS metastases, compared with patients with EGFR wild type (EGFRwt)-NSCLC. This supports the rationale for evaluation of EGFR tyrosine kinase inhibitor (TKI) maintenance in EGFRm-positive patients without disease progression following chemoradiation. Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both sensitizing EGFR and T790M mutations. It has shown superior progression-free survival (PFS) vs. standard EGFR-TKIs in first-line treatment of patients with EGFRm-positive advanced NSCLC, including patients with or without CNS metastases at trial entry.1 These data further support the rationale for evaluation of osimertinib in the even earlier disease setting of EGFR-TKI-naïve stage III NSCLC following definitive chemoradiation where it has the potential to prevent/delay progression, including in the CNS, and improve survival compared with chemoradiation alone.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      LAURA is a double-blind, randomized, placebo-controlled, multicenter, phase 3 study designed to assess efficacy and safety of osimertinib as maintenance therapy in patients with locally advanced, unresectable, EGFRm-positive, stage III NSCLC without disease progression following definitive platinum-based chemoradiation therapy. All patients will have tumors bearing exon 19 deletion or L858R mutation (centrally or locally confirmed by cobas®EGFR Mutation Test v2), age >18 years, and a WHO performance status of 0-1. Patients will have received prior concurrent (CCRT) or sequential (SCRT) chemoradiation treatment (including ≥2 cycles of platinum-based chemotherapy and radiation of 60 Gy ±10% [54-66 Gy]). Key exclusion criteria include a history of interstitial lung disease, symptomatic pneumonitis following chemoradiation, other unresolved toxicity >Grade 2, cardiac abnormalities, and inadequate organ function. Approximately 200 patients will be randomized 2:1 to osimertinib 80 mg oral once daily or placebo, within 6 weeks of completion of chemoradiation, until disease progression. Stratification factors are prior chemoradiation strategy (CCRT vs SCRT), tumor stage (IIIA vs IIIB/IIIC), and China vs non-China. The primary endpoint is RECIST 1.1 assessed PFS based on blinded independent central review (BICR). Key secondary endpoints include time to CNS PFS, overall survival, objective response rate, disease-related symptoms and health-related QoL, safety and tolerability, and pharmacokinetics. Study enrollment will commence from July 2018.

      1Soria et al N Engl J Med 2018; 378:113-125

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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