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Jyoti D Patel

Moderator of

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    OA11 - Decomplexifying Molecular Targets, Immunotherapy and Treatment Settings in the Real World (ID 137)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 8
    • Now Available
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      OA11.01 - Complex EGFR Mutations in Lung Adenocarcinoma (Now Available) (ID 2114)

      14:00 - 15:30  |  Presenting Author(s): Shang-Gin Wu  |  Author(s): Chong-Jen Yu, James Chih-Hsin Yang, Jin-Yuan Shih

      • Abstract
      • Presentation
      • Slides

      Background

      Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) provides a favorable treatment efficacy for EGFR-mutant lung cancer patients. Majority of EGFR mutations are a single mutation, including deletion in exon 19 (del-19) or L858R in exon 21. There is a subset of patients with complex EGFR mutations which contains two or more EGFR mutation types. It is unclear the treatment efficacy to different EGFR TKIs and survival prognosis for the complex EGFR-mutant patients due to small sample sizes of the prior studies. This study aimed to improve the understanding of the clinical characteristics and the prognosis of EGFR TKI treatment in lung adenocarcinoma patients with complex EGFR mutations.

      Method

      Between June 2005 to July 2018, patients harboring lung adenocarcinoma with complex EGFR mutations who were treated with EGFR TKIs were collected for EGFR mutation analysis by direct Sanger sequencing. Patients’ clinical characteristics, EGFR mutation status, treatment response, progression-free survival (PFS) and overall survival (OS) were analyzed. Patients harboring tumor with de novo T790M mutations were excluded for evaluation of EGFR TKI effectiveness.

      Result

      There were 175 patients (6.3%) with complex EGFR mutation from 2390 EGFR-mutant patients. Of the 175 complex EGFR-mutant patients, 122 patients who received EGFR TKIs were enrolled for evaluation of TKI effectiveness. Patients with the classical mutation pattern (del-19 or L858R) had higher treatment response rate (78.6% vs. 47.4%; p = 0.001) and PFS (8.6 months vs. 3.3 months; p = 0.006) than those without the classical mutations patterns (Fig-A). In multivariate analysis, female (p = 0.002), patients with disease relapse status, and the classical mutation patterns (p < 0.001) were associated with prolonged PFS. Compared with gefitinib and erlotinib, afatinib had a longer PFS, especially for patients without the classical mutation patterns. For OS, multivariate analysis revealed that female (p < 0.001), patients harbored classical mutation pattern (p = 0.001) (Fig-B), and patients with disease relapse status had longer OS. There were 51 patients who had re-biopsy tissue samples after acquired resistance to EGFR TKIs, 17 (33.3%) samples harbored T790M. In addition, small cell lung cancer transformation was detected in 3 (2%) patient’s re-biopsy tissue samples.

      layout 5.jpg

      Conclusion

      Female patients with complex EGFR-mutant lung adenocarcinoma and the classical mutation patterns have higher response rate, longer PFS and OS than those without the classical mutation patterns. Afatinib was active in lung adenocarcinoma harboring complex EGFR mutations, and may especially benefit patients without the classical mutation patterns due to longer PFS results.

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      OA11.02 - Changes of Brain Structure in Advanced NSCLC Patients Receiving EGFR-TKIs: Dynamic Analysis Based on Series MRI Images (Now Available) (ID 314)

      14:00 - 15:30  |  Presenting Author(s): Chunli Luo  |  Author(s): Beisheng Yang, Xiaojuan Zhou, Lin Zhou, Ying Zhou, Jiang Zhu, Meijuan Huang, Feng Peng, Yongmei Liu, Yongsheng Wang, Zhiping Li, You Lu, Su Lui, Youling Gong

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR-TKI was the standard care for metastatic NSCLC patients harboring positive EGFR mutation, which might inhibit EGF signaling pathway and consequently have effect on differentiation, maturation and rehabilitation of neural cells. For the first time, we evaluated the dynamic changes of white matter lesion (WML) and gray matter volume (GMV) among such patients based on series of MRI images.

      Method

      We retrospectively identified 778 patients with pathologically diagnosed advanced NSCLC receiving first-generation EGFR-TKIs in our hospital from 2010 to 2017, and 75 patients without brain metastasis and else comorbidity (hypertension, etc.) were analyzed. The modified Scheltens visual scale were performed to evaluate the changes of WML based on the series (baseline, 12 months' point and 24 months' point) of MRI images, and CBM (cluster-based morphometry) method based on SPM12 were adopted to identify GMV loss. The statistical methods were performed using SPSS software 22.0.

      Result

      During the 24-month EGFR-TKI treatment, the patient's WML visual scores showed a progressive worsen. Comparing to the baseline (6.683.636), the scores were significantly changed at the 12 months' point (8.650±3.857; Mean scores increasing 1.973, 95% CI 1.595-2.352, p<0.001) and changed more obviously at the 24 months' point (10.113.854; Mean scores increasing 3.427, 95% CI 2.979-3.874, p<0.001), respectively. Also, the significant GMV loss were found in subregions of the right occipital lobe (mean decrease 76.714, 95% CI 40.739-112.690), left occipital lobe (mean decrease 93.476, 95% CI 37.483-149.469) and left basal ganglia (mean decrease 37.571, 95% CI 21.576-53.567), respectively (all p<0.005, the cluster level FDR<0.05).

      Conclusion

      Dynamic structural analysis of series brain MRI images showed the significant worsen of the WML and GMV loss in patients with advanced NSCLC receiving EGFR-TKIs chronically. Perspective studies are warranted to verify its impact on the cognitive deficiency and hypomnesis among these patients in future.

      2019322fig1.jpg

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      OA11.03 - Survival Disparities Between Academic and Community Centers in Advanced Lung Cancer in the US: Can We Bridge the Gap? (Now Available) (ID 1731)

      14:00 - 15:30  |  Presenting Author(s): Sendilnathan Ramalingam  |  Author(s): Michaela Dinan, Jeffrey Crawford

      • Abstract
      • Presentation
      • Slides

      Background

      Lung cancer causes the most cancer deaths in the US. Our prior study found widening 2-year survival (2YS) disparity between academic and community-based centers (ACs and CCs) prior to 2010, most apparent in adenocarcinoma, suggesting a treatment-related effect. We hypothesized this disparity continued to widen in more recent years.

      Method

      Retrospective study of outcomes through 2015 within the National Cancer Database. The primary outcome was 2YS. We used multivariable regression modeling, incorporating diagnosis year, facility type, age, gender, Charlson-Deyo score, and histology to compare AC/CC. A third facility type was identified, Integrated Network Cancer Programs (IC); we did a separate analysis incorporating AC/CC/IC. We formed six cohorts by 1)facility type and 2)time period (2004 through 2008, and 2011 through 2015). Hazard ratios were computed to compare survival between these six cohorts.

      Result

      98,069 patients were included. Treatment in ACs had superior 2YS compared to treatment in CCs, increasing from 16.1% versus 10.3% for those diagnosed in 2004(+5.8%), to 23.7% versus 16.2% for those diagnosed in 2013(+7.5%). Our multivariable model found growth in 2YS disparity of 0.34%-per-year (95% CI 0.18% to 0.50%, p<0.001). This was histology-related: Difference in adenocarcinoma 2YS rose from 7% in 2004 to 9% in 2013(p=0.0023), while squamous carcinoma 2YS difference was 2.7% in 2004 and 0.8% in 2013(p=0.6). 9047 patients were treated at ICs. In the 2004-2008 cohort treatment at ICs had similar outcomes to CCs, however by 2011-2015 ICs had superior histology-related survival, suggesting treatment-related improvements in ICs over CCs (Table 1).

      Conclusion

      Survival disparities in metastatic lung cancer between academic and community-based centers in the US continued to widen through 2015. Treatment at integrated centers, a group of facilities with at least one hospital that can include community and academic centers, may help to bridge the divide. Treatment related disparities in other health systems warrant further study globally.

      table 1.png

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      OA11.04 - Discussant - OA11.01, OA11.02, OA11.03 (Now Available) (ID 3769)

      14:00 - 15:30  |  Presenting Author(s): Joel W Neal

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA11.05 - Optimizing Resources with Immunotherapy in Developing Countries: Experience in a Reference Center in Mexico (Now Available) (ID 2867)

      14:00 - 15:30  |  Presenting Author(s): Omar Eleazar Macedo-Perez  |  Author(s): Ivan Lyra Gonzalez, Leticia Bornstein, Katya Campos-Peralta, Jose Luis Aguilar-Ponce, Adan Gomez-Ponce, Angel Herrera-Gomez, Edgardo Jimenez-Fuentes

      • Abstract
      • Presentation
      • Slides

      Background

      Immunotherapy has proven clinical benefit in several tumors as a first line therapy or after standard treatment failure. Pivotal trials with immunotherapy were designed using a weight-based dose. However, recently as part of an effort to standardize the dose of the most common drugs (Nivolumab and Pembrolizumab) the Regulatory Agencies and Pharmaceutics have changed its prescription to fixed doses. In those pivotal studies, the median weight was around 70 to 80 kg. Our hypothesis estimates that a fixed dose increases the use of drug above effective thresholds increasing unnecessary expenses.

      Method

      We analyzed a cohort of patients treated with immunotherapy due to lung cancer (NSCLC) diagnosis either during first or second-line of treatment between 2016 and 2018 in the Thoracic Tumors Clinic at National Cancerology Institute in Mexico. We analyzed and estimated the median body in our population. Then, we compared treatment costs between weight-based doses (Nivolumab 3mg/Kg q.2 weeks and Pembrolizumab 2mg/Kg q.3 weeks) versus flat dose treatment (Nivolumab 240mg q.2 weeks and Pembrolizumab 200mg q.3 weeks).

      Result

      792 patients were included with and a median weight of 65 kg (SD ±13.11) was determined. Fixed dose of pembrolizumab administered during one year (17 applications) had an annual cost of $135,218 dlls. while the cost with weight-based dose was $87,913 dlls. with a net difference of $47,305 dlls. In the case of Nivolumab, an annual fixed-dose treatment (26 applications) has a cost of $114,816 dlls, while the weight-based dose has a cost of $93,392 dlls. with a net difference of $21,424 dlls (table1).

      PEMBROLIZUMAB (2 mg/Kg) Q3W vs 200mg Q3W

      Comparison

      Total dose per cycle

      Cost per cycle

      Excess cost per cycle

      Dose difference

      Annual cost treatment (17 cycles)

      Net difference annual cost per patient

      Weight based dose

      (Median 65Kg)

      130 mg

      $5171.4

      $2,782.6

      70mg

      $87,913

      $47,305

      Fixed-dose

      200mg

      $7,954

      NA

      NA

      $135,218

      NA

      NIVOLUMAB (3mg/Kg) Q2W vs 240mg Q2W

      Comparison

      Total dose per cycle

      Cost per cycle

      Excess cost per cycle

      Dose difference

      Annual cost treatment (26 cycles)

      Weight based dose

      (Median 65Kg)

      195mg

      $3,592

      $824

      45mg

      $93,392

      $21,424

      Fixed-dose

      240mg

      $4,416

      NA

      NA

      $114,816

      NA

      Conclusion

      General population in developing countries like Mexico are experiencing serious difficulties to get access to immunotherapy due to lack of coverage through Public Health Care System based in costs. According with our study, optimization of resources with weight-base dose could allow us to increase the rate of treated patients. Then, according with our analysis, in the case of Pembrolizumab we calculated coverage of 154 treatments instead of 100 using same budget and favoring the use of weight-based dose. While, in the case of Nivolumab we could increase the number of patients treated from 100 to 126 using weight-based dose. Therefore, our results support that therapies like immunotherapy should be calculated based on body weight as an attempt to increase access and avoid unnecessary expenses in Health Care Systems with limited resources.

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      OA11.06 - Alternative Nivolumab (N) Duration and Scheduling in Advanced Non-Small Cell Lung Cancer (aNSCLC): Real-Life Data (Now Available) (ID 1921)

      14:00 - 15:30  |  Presenting Author(s): Elizabeth Dudnik  |  Author(s): Mor Tal Moskovitz, Abed Agbarya, Teodor Kuznetsov, Tzippy Shochat, Damien Urban, Mijana Wollner, Alona Zer, Ofer Rotem, Nir Peled, Jair Bar

      • Abstract
      • Presentation
      • Slides

      Background

      Little is known regarding the optimal scheduling and treatment (Tx) duration of N in aNSCLC. Stopping N after 1 year of Tx negatively affects outcomes.

      Method

      45 consecutive aNSCLC patients (pts) receiving N for ≥2 years (y) were identified in the electronic databases of 4 Israeli cancer centers. These were divided into Groups A (N continued for >2y at a dose 3mg/kg q2w/240mg q2w; n-21), B (N continued for >2y at a dose 3mg/kg q3w-q8w/480mg q4w; n-17), and C (N stopped at 2y for reason other than progressive disease or intolerable toxicity; n-7). PFS (RECIST 1.1) and safety since 2y after N initiation were assessed.

      Result

      Baseline, treatment characteristics and outcomes are presented in the Table and the Picture. Allocation to Group B and C was associated with HR for PFS-2.4 (95%CI, 0.3-18.8, p-0.4) and HR for PFS-3.3 (95%CI, 0.3-30.9, p-0.3), respectively. After 2y since N initiation, new N-related toxicity developed in 24%, 18%, and 28% of pts in Groups A, B, and C, respectively (p-NS).

      table wclc.jpgpicture wclc.jpg

      Conclusion

      A trend for worse outcomes was observed with alternative N scheduling/N quitting 2y after initiation. So far, continuing N at a standard dose until disease progression/ intolerable toxicity remains the standard treatment option.

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      OA11.07 - Chemotherapy Plus EGFR-TKI as First-Line Treatment Provides Better Survival for EGFR Mutation NSCLC Patients: Update Data for NCT02148380 (Now Available) (ID 2207)

      14:00 - 15:30  |  Presenting Author(s): Wei Zhang  |  Author(s): Jianlin Xu, Yuqing Lou, Yanwei Zhang, Baohui Han

      • Abstract
      • Presentation
      • Slides

      Background

      Previously, we did a prospective study to compare pemetrexed plus carboplatin and gefitinib to either pemetrexed plus carboplatin or gefitinib alone as first-line therapy for lung adenocarcinoma patients harboring sensitive EGFR mutations (NCT02148380). The primary endpoint PFS was met at Oct 1, 2016. However, the OS of combinational group was not mature then [Han B, et al. Int J Cancer. 2017;141:1249-1256]. In the present study, we continued the OS follow-up until Sep 28 2018.

      Method

      The survival curves for OS were estimated with the Kaplan-Meier method and were compared between combination and gefitinib groups using the log-rank test. 2-years, 3-years survival rates were compared between combination and gefitinib groups using Pearson Chi-Square.

      Result

      Baseline characteristics of the intent-to-treat (ITT) population have been reported. At last day of follow-up (Sep 28 2018), 30 (75.0%) patients in the combinational group, 35 (85.4%) patients in the gefitinib group died. 2-year survival rates of combinational and gefitinib groups were 85.0% (34/40), 56.1% (23/41) (P=0.004), respectively. 3-year survival rates of combinational and gefitinib groups were 52.5% (21/40), 24.4% (10/41) (P=0.009), respectively. The median OS was 37.9 months (95%CI: 17.3-58.6) for the combinational group, which was substantially longer than the median OS for first-line gefitinib group (25.8 months [95%CI: 19.2-32.3]). The HR of combinational group versus gefitinib group was 0.56 (95%CI:0.34-0.91, P=0.02).

      19del: The median OS was 51.0 months (95%CI: 36.6-65.5) for the combinational group, which was substantially longer than the median OS for first-line gefitinib group (29.8 months [95%CI: 26.7-32.9]). The HR of combinational group versus gefitinib group was 0.61 (95%CI:0.30-1.25, P=0.18).

      21L858R: The median OS was 32.3 months (95%CI: 27.8-36.7) for the combinational group, which was substantially longer than the median OS for first-line gefitinib group (22.8 months [95%CI: 13.1-32.5]). The HR of combinational group versus gefitinib group was 0.50 (95%CI:0.25-1.00, P=0.05).

      Totally, 15 patients had baseline central nervous system (CNS) metastases. The median OS of patients who had baseline CNS metastases was 25.6 months (95%CI: 15.1-36.1); the median OS of patients who had no baseline CNS metastases was 31.7 months (95%CI: 28.2-35.2). The HR of CNS metastases group versus no CNS metastases group was 2.80 (95%CI:1.51-5.18, P=0.001). Among the combinational group, 20% (8/40) percent of patients had baseline CNS metastases. 17.1% (7/41) percent of patients in the gefitinib group had baseline CNS metastases.

      CNS: The median OS was 27.0 months, (95%CI: 21.8-32.3) for the combinational group, which was substantially longer than the median OS for first-line gefitinib group (15.5 months, 95%CI: 6.8-24.3). The HR of combinational group versus gefitinib group was 0.17 (95%CI:0.04-0.68, P=0.013).

      No CNS: The median OS was 47.4 months, 95%CI: 27.2-67.7 for the combinational group, which was substantially longer than the median OS for first-line gefitinib group (27.4 months, 95%CI: 23.0-33.7). The HR of combinational group versus gefitinib group was 0.57 (95%CI:0.32-0.99, P=0.044).

      Conclusion

      The current study on lung adenocarcinoma patients harboring sensitive EGFR mutations showed that the combined treatment with pemetrexed plus carboplatin with gefitinib provide better survival benefits than gefitinib alone.

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      OA11.08 - Discussant - OA11.05, OA11.06, OA11.07 (Now Available) (ID 3770)

      14:00 - 15:30  |  Presenting Author(s): Ullas Batra

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MA06 - Challenges in the Treatment of Early Stage NSCLC (ID 124)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      MA06.07 - E1505: Adjuvant Chemotherapy +/- Bevacizumab for Early Stage NSCLC: Updated Chemotherapy Subset Analysis (Now Available) (ID 2885)

      13:30 - 15:00  |  Author(s): Jyoti D Patel

      • Abstract
      • Presentation
      • Slides

      Background

      Adjuvant chemotherapy (chemo) for resected early stage NSCLC provides modest survival benefit with limited comparison data between regimens. From this trial we previously reported that adding bevacizumab (B) to adjuvant chemo failed to improve either disease free survival (DFS) or overall survival (OS). Here we update outcomes by chemotherapy regimen with an additional 30 months of follow-up.

      Method

      Enrolled patients with resected early stage NSCLC, stratified by stage, histology, sex, and chemo option, were randomized 1:1 to chemo alone or with B (15 mg/kg every 3 weeks for up to 1 year). Chemo consisted of a planned 4 cycles of every 3 week cisplatin with either vinorelbine (V), docetaxel (D), gemcitabine (G) or pemetrexed (P).

      Result

      From July 2007 to September 2013, 1501 patients were enrolled with this distribution of chemo: V 25.0%, D 22.9%, G 18.9% and P 33.2%. P was added in 2009 and restricted to non-squamous (NSq) pts. Chemo regimen was chosen (not randomized). Arms were well balanced for known prognostic factors; 28% had Sq histology. Median f/up per chemo group is: V 83.5 months(m); D 89.9m; G 87.8m; P 71.9m. In pooled analysis DFS differed by histology ranging from 29.9m(G)-43.5m(V) for NSq and 59.4m(V)-77.3m(G) for Sq. OS also differed by histology ranging from 80m(D)-98.8m(P) for NSq and 98m(G)-119m(V) for Sq. A non-significant decline in both DFS and OS was seen when B was added to D or V regimens, regardless of histology. Conversely, the addition of B to P improved both DFS (HR 0.74, p= .00994) and OS (HR 0.65, p= .00368). We thus compared outcomes across non-B regimens and though numerical differences were seen in median DFS and OS, these failed to reach statistical significance. Toxicity details were presented previously.

      Conclusion

      B did not improve OS when added to adjuvant chemo for patients with surgically resected early stage NSCLC, though variable DFS and OS outcomes by chemotherapy regimen have emerged with longer-term follow-up. These include a significant positive improvement in DFS and OS with B combined with P and trends of worse outcomes when B was added to other regimens. Ongoing molecular analysis of samples will hopefully elucidate the etiology of these differences.

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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA09.07 - Activity of Larotrectinib in TRK Fusion Lung Cancer (Now Available) (ID 1600)

      15:15 - 16:45  |  Author(s): Jyoti D Patel

      • Abstract
      • Presentation
      • Slides

      Background

      Tropomyosin receptor kinase (TRK) fusions involving NTRK1, NTRK2, and NTRK3 occur in a range of tumor types. Larotrectinib, the first FDA-approved highly selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% by independent central review across a broad spectrum of tumors that harbor NTRK gene fusions (Drilon et al., NEJM 2018;378:731–9). Here, we report updated data on the patients with lung cancer who have been treated with larotrectinib.

      Method

      Patients with non-small cell lung cancer (NSCLC) in two clinical trials (NCT02122913 and NCT02576431) with TRK fusion cancer were included in this analysis. Larotrectinib (100 mg BID) was administered on a continuous 28-day schedule until withdrawal, unacceptable toxicity, or disease progression. Response was assessed by investigator (INV) and independent review committee (IRC) per RECIST v1.1.

      Result

      As of July 30, 2018, 11 patients with metastatic lung adenocarcinoma were enrolled. Median age was 52 years (range 25–76 years). Eight patients had fusions involving NTRK1 and diverse fusion partners: EPS15 (n=2), TPM3 (n=2), IRF2BP2 (n=2), TPR (n=1), and SQSTM1 (n=1). Three patients had fusions involving NTRK3 (fusion partner: SQSTM1 [n=2] and ETV6 [n=1]). Ten patients had prior systemic therapy (five patients had three or more prior therapies) with best responses on last prior therapy being one partial response, four with stable disease, three progressive disease, and three unknown or unevaluable. Seven patients were evaluable for response to larotrectinib. INV and IRC assessment were in agreement, with one complete response, four partial responses (including one patient with central nervous system [CNS] metastases), and two with stable disease (ORR 71%). Results from four patients not evaluable at the July 30, 2018 data cut-off due to insufficient follow-up are expected in April 2019 and will be presented at the meeting. The median time to response was 1.8 months. One patient with brain metastases had an intracranial near complete response (–95% reduction) to larotrectinib, as well as an extracranial response. The duration of response by IRC ranged from 7.4+ months to 25.8+ months; the median duration of response was not reached. One patient continued receiving treatment post-progression. Two patients discontinued treatment due to disease progression and one withdrew without cause. Larotrectinib was well tolerated, with treatment-related adverse events being predominantly grade 1–2.

      Conclusion

      Larotrectinib is highly active in advanced lung cancer patients harboring NTRK gene fusions, including those with CNS metastases, with a favorable safety profile. These results support the use of larotrectinib in NTRK fusion NSCLC.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 3
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-109 - Phase II Trial of Pemetrexed/Carboplatin/Bevacizumab +/- Atezolizumab in NSCLC Patients That Are EGFR Mutated or Never Smoked (Now Available) (ID 1456)

      09:45 - 18:00  |  Author(s): Jyoti D Patel

      • Abstract
      • Slides

      Background

      Patients with advanced NSCLC who harbor an EGFR mutation or are never smokers do not benefit from single-agent immunotherapy. Retrospective subgroup analyses from recent phase III trials suggest that immunotherapy-chemotherapy +/- VEGF inhibition may overcome the resistance to immunotherapy seen in these patients, though further prospective research is needed and no checkpoint inhibitor to date is approved in the first-line for EGFR patients after TKI failure. This trial will exclusively examine a population of patients with stage IV non-squamous disease who either have an EGFR exon 19 or 21 mutation or are never smoker wild-types to determine whether the PD-L1 inhibitor atezolizumab in combination with pemetrexed/carboplatin and bevacizumab can improve outcomes.

      Method

      This is a phase II double-arm, multi-center, open-label trial to assess pemetrexed/carboplatin and bevacizumab +/- atezolizumab in 117 subjects with stage IV non-squamous NSCLC. Randomization will be 2:1 with twice the number in the + atezolizumab arm, and randomization will be stratified by EGFR mutation status (i.e. EGFR exon 19 or 21 vs. never smoker wild-type) to ensure equal distribution in each arm. Never smoker wild-type is defined as smoking < 100 cigarettes in a lifetime and without any EGFR mutation or ALK or ROS1 rearrangement. Patients with EGFR exon 19 or 21 mutations must have progression or intolerance of treatment with prior TKI therapy. All patients must be chemotherapy, immunotherapy, and VEGF inhibitor therapy naïve. Primary endpoint will be progression-free survival (PFS). Secondary endpoints will include overall survival (OS), overall response rate, duration to response, and time to response. Primary objective is to compare PFS between arms. Secondary objectives include a safety analysis in all treated subjects, and comparisons of PFS and OS between arms for the subset of patients with tumors with EGFR exon 19 or 21 mutations. Correlative studies will include evaluation of biomarkers of the signaling network and tumor microenvironment, and characterizing the potential contribution of estrogen metabolites. Enrollment for this trial will open in August of this year and accrual will continue for 31 months.

      Result

      Section not applicable - Trial in progress

      Conclusion

      Section not applicable - Trial in progress

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      P1.01-127 - Antitumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 in NSCLC with EGFR Exon 20 Insertions (ID 1302)

      09:45 - 18:00  |  Author(s): Jyoti D Patel

      • Abstract
      • Slides

      Background

      We report results of a phase 1/2 open-label, multicenter study of TAK-788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor.

      Method

      Patients with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for patients with EGFR exon 20 insertions who received TAK-788 160 mg QD. Safety is reported for all patients across all doses and at 160 mg. To improve gastrointestinal tolerability, food intake instructions in this ongoing study were amended to allow for administration with or without a low-fat meal based on emerging clinical pharmacokinetic data in a healthy volunteer study (data on file).

      Result

      As of 14 Sep 2018, 101 patients (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5–180 mg QD. RP2D was determined to be 160 mg QD. 28 patients with EGFR exon 20 insertions were treated with 160 mg QD during dose escalation or in expansion cohort 1 (3.6 months on treatment; 3.8 treatment cycles [medians]); 24 patients remain on treatment. At data cutoff, best response (RECIST v1.1) among 26 patients with ≥1 disease assessment was PR, n=14; SD, n=9; and PD, n=1 (objective response rate, 54%; 95% CI: 33.4%–73.4%); 2 patients were unevaluable. 7/14 objective responses (all PR) were confirmed (6 awaiting confirmation; 1 unconfirmed PR at 160 mg QD); median time to response in these 14 patients was 56 days. 23/26 patients (89%; 95% CI: 69.9%–97.6%) achieved disease control. 23/24 evaluable patients with EGFR exon 20 insertions treated at 160 mg QD had decreased target lesion measurements (median best percent change, -32.6% [-79.1%–3.8%]). Most common TEAEs (≥20%) in patients treated with 160 mg QD: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), stomatitis (22%); grade ≥3 TEAEs (≥5%): diarrhea (26%); hypokalemia, nausea, stomatitis (7% each). Among patients treated with 160 mg QD, median dose intensity was 93%, rate of dose reduction due to AEs was 21.7%, and rate of treatment discontinuation due to AEs was 10.9%. There was no clear trend that response to TAK-788 was enriched in any single EGFR exon 20 insertion variant.

      Conclusion

      In NSCLC patients with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and a safety profile consistent with other EGFR TKIs.

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      P1.01-67 - Ph I/II Carboplatin, Nab-Paclitaxel and Pembrolizumab for Advanced NSCLC (HCRN LUN13-175): Outcomes by Nab-Paclitaxel Dose (ID 530)

      09:45 - 18:00  |  Author(s): Jyoti D Patel

      • Abstract
      • Slides

      Background

      Combination chemotherapy and immunotherapy have significantly improved survival for patients with treatment-naïve advanced non-small cell lung cancer (NSCLC). We sought to evaluate the safety and efficacy of adding pembrolizumab to a standard regimen at the time of study development, nab-paclitaxel and carboplatin. Safety data from phase I have been reported, and phase II commenced with the same chemotherapy doses and flat dosing of pembrolizumab at 200 mg.

      Method

      Patients with treatment-naïve, stage IIIB/IV NSCLC AJCC 7 (all histology), any PDL1, no EGFR or ALK, ECOG 0-1, received carboplatin AUC 6 day 1, nab-paclitaxel 100 mg/m2 days 1, 8, 15, and pembrolizumab 200 mg day 1 q21 days for 4 cycles followed by maintenance pembrolizumab q3wks. Co-primary endpoints were progression-free survival (PFS) and response rate (RR). PDL1 was assessed prior to treatment and from biopsies obtained after cycle 4.

      Result

      46 patients enrolled, 14 on phase I and 32 in phase II, from June 2015–July 2018. Accrual stopped after data was presented from similar phase III trials. 43 were evaluable for the primary endpoints. Median age was 65 years, 48% female, 45% adenocarcinoma, 94% current/former smokers, 9% brain metastases. PDL1 expression (TPS) by <1%, 1-49%, and ≥ 50% cutoffs was 44%, 28%, and 28%, respectively. ORR was 28%. Median PFS was 5.6 months (CI, 4.2-10.5 mo). Median OS was 15.7 mo (CI 11.1-22.3 mo). There was no statistical differences in PFS or OS outcomes by PDL1 status. Paired PDL1 results from pre- and post-treatment biopsies were available in 8 patients. PDL1 status changed categories in 4/8 samples (n=3, 0% to positive; n=1, 99% to 0%). The most common grade 3-4 adverse events (AEs) were neutropenia (64%), anemia (31%), thrombocytopenia (24%), leukopenia (16%) and fatigue (11%). Other notable AEs included rash (58%), diarrhea (47%), neuropathy (22%), arthralgia (18%), transaminitis (13%), and myalgia (11%). 18% discontinued treatment due to AEs. In an exploratory analysis, there was no difference in median PFS for those receiving total nab-paclitaxel dose of 400–799 mg/m2 compared to ≥800 mg/m2 (6.2 mo vs. 8.2 mo, p=0.62).

      Conclusion

      Although the study did not meet its pre-specified endpoints of PFS 9 months and RR of 50%, results were similar to previously reported phase III Keynote 407 (squamous histology). Despite hematologic toxicity, the combination could safely be administered, and outcomes were similar for those receiving moderate doses of nab-paclitaxel compared to those with an average of at least 200 mg/m2 per cycle.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-17 - Phase I/II Study of Nivolumab and Vorolanib in Patients with Refractory Thoracic Tumors (ID 2443)

      09:45 - 18:00  |  Author(s): Jyoti D Patel

      • Abstract

      Background

      Single-agent nivolumab has limited efficacy in thoracic tumors. The antitumor activity of VEGF TKIs is typically attributed to their effect on angiogenesis; however, emerging data suggest these agents can modulate the immune system, especially in the immune suppressive microenvironment. Preliminary results in multiple solid tumors demonstrated clinical benefit when nivolumab was added to anti-angiogenic agents albeit with increased toxicities. Vorolanib was designed to improve the safety profile without compromising efficacy. No dose-limiting toxicities (DLTs) from vorolanib were reported in multiple single-agent phase I trials.

      Method

      NCT03583086 is an ongoing multi-institutional, phase I/II study of nivolumab and vorolanib in patients with thoracic tumors who have failed at least one prior line of therapy. A standard 3+3 dose escalation design was planned with three doses of vorolanib (200, 300, and 400 mg once-daily) and 240 mg nivolumab every two weeks to determine the maximum tolerated dose. Phase II will evaluate the response rate in five cohorts: PD-1/PD-L1 naïve non-small cell lung cancer (NSCLC), PD-1/PD-L1 primary refractory (defined as progression on PD-1/PD-L1 therapy within 12 weeks), NSCLC patients with acquired resistance (achieved at least stable disease and then progressed) to PD-1/PD-L1, thymic carcinoma, and small cell lung cancer patients who have progressed on prior platinum-based chemotherapy. Exploratory correlatives will assess changes in the innate and adaptive immune responses after treatment.

      Result

      Phase I enrolled 10 patients (eight NSCLC and two thymic cancers); one patient was not evaluable for DLT and replaced. No DLTs were observed in three patients at the first dose level of 200 mg. Vorolanib was escalated to 300 mg, and elevated ALT (Grade 3) occurred in two of six patients just beyond the DLT period but deemed clinically significant; thus, 200 mg vorolanib with 240 mg nivolumab is being evaluated in expansion cohorts. The most common adverse events were elevated ALT, AST, and lipase, diarrhea, and fatigue; most were Grade 1/2. Grade 4 hyperglycemia and elevated lipase and Grade 3 elevated serum amylase occurred in one patient each. In seven efficacy-evaluable patients (2 immunotherapy naïve NSCLC; 3 NSCLC with prior immunotherapy; 2 thymic cancer), two partial responses were observed (1 PD-1/PD-L1 naive NSCLC and 1 thymic cancer patient); the NSCLC patient was also PD-L1 negative. Three NSCLC patients with prior PD-1/PD-L1 inhibitors had tumor regression; two of these had acquired resistance and the other was primary refractory to prior immunotherapy.

      Conclusion

      The combination of 200 mg vorolanib and 240 mg nivolumab was generally well tolerated. Clinical activity was observed in both PD-1/PD-L1 naïve patients and those treated with prior immunotherapy. Final phase I results and available phase II data will be presented.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-12 - Ph I Trial of Concurrent or Sequential Ipilimumab, Nivolumab, and SBRT to Multiple Sites in Patients with Stage IV NSCLC  (ID 2903)

      10:15 - 18:15  |  Presenting Author(s): Jyoti D Patel

      • Abstract

      Background

      Despite the promise of immunotherapy for the treatment of advanced NSCLC, only a fraction of patients experience significant benefit from immunotherapy alone. Previous studies have shown that SBRT can stimulate innate and adaptive immunity to potentially augment immunotherapy. In addition, SBRT is used in patients with limited metastatic disease as consolidative approach, showing an improvement overall survival when compared to systemic treatment alone. Combining immunotherapy with ablative therapy is being studied by a number of investigators. While many of these pre-clinical and clinical studies are promising, timing of immunotherapy with SBRT has not be formally studied. Further, few of these studies have addressed treatment of multiple sites of disease and little is known about what molecular changes occur in the tumor microenvironment immediately after ablative therapy. This trial is designed to evaluate the safety and efficacy of the combination of nivolumab (N) and ipilimumab (I) plus sequential(S) or concurrent(C) SBRT in patients with stage IV NSCLC.

      Method

      This is a single-center phase I, open-label, two-arm, randomized platform trial. Eligible patients include those with stage IV NSCLC with >2 metastatic lesions that meet criteria for SBRT (0.2 cc to 65 cc of viable tumor, larger tumors able to be partially treated up to 65 cc). Eligible patients are simultaneously accrued on arm I (S) and arm II (C) in a 1:1 ratio. Participants in arm I complete SBRT to 2-4 sites followed by initiation of N/I 1-7 days after completion of SBRT. Participants in arm II are treated with N/I within 24-48 hours of SBRT with required SBRT completion to 2-4 sites within two weeks (prior to the second dose of N). Protocol therapy consists of treatment with N 3mg/kg every 2 weeks and I 1mg/kg every 6 weeks for a maximum of 24 months. The primary endpoint is dose-limiting toxicity defined as a >33% rate of grade ≥3 toxicity. DLT is defined as any grade ≥3 toxicity possibly, likely, or definitely related to SBRT plus N/I (the combination and not the individual components). 
Secondary endpoints include response rate and progression free survival at 6 months, control rate of treated lesions and non-treated lesions, and comparison of efficacy and toxicity between the arms. Biopsies and blood draws performed pre- and post-SBRT will facilitate molecular correlative studies including investigation of changes in the immune microenvironment induced by the two approaches.

      Result

      Current enrollment includes 27 of the 40-80 participants: 15 patients are enrolled on arm 1 (sequential) and 12 patients are enrolled on arm 2 (concurrent). SBRT safety cohorts, to which patients can contribute to more than one, include the following: central lung (n=20), peripheral lung (n=7), abdominal (n=5), osseous (n=9), and liver (n=5). All patients have paired pretreatment and posttreatment biopsies of at least one irradiated lesion. 79% of post-ablative biopsies are suitable for DNA/RNA sequencing.

      Conclusion

      Section not applicable

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-12 - Tyrosine Kinase Inhibitor Resistance Mechanisms in EGFR T790M-Positive Lung Cancer: The University of Chicago Experience (ID 2709)

      10:15 - 18:15  |  Author(s): Jyoti D Patel

      • Abstract
      • Slides

      Background

      Acquired resistance to osimertinib in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is a poorly understood phenomenon and presents an ongoing challenge. Previously described mechanisms include emergence of mutations at EGFR C797S, MET amplification, transformation to small cell lung cancer, and BRAF mutation. Next-generation sequencing (NGS) of tumors at progression through osimertinib may help to illuminate novel mechanisms of resistance to osimertinib.

      Method

      We surveyed University of Chicago Medicine case records for osimertinib-treated NSCLC patients treated who progressed through therapy. Panels utilized for NGS included, among others, the University of Chicago’s validated panel (the UCM-OncoPlus, surveying greater than 1,100 genes) and Guardant (Guardant Health; Redwood City, CA). Patients were stratified according to presence of EGFR T790M mutation at the initiation of osimertinib therapy.

      Result

      28 patients were identified to have progressed through osimertinib. 23 patients (82.1%) had next-generation performed at the time of progression. Among osimertinib-resistant patients who had NGS, 17 (73.9%) demonstrated at least one resistance mechanism, of which 8 (34.8% of tested patients) were subsequently treated with tyrosine kinase inhibitor-containing regimens or clinical trial of targeted therapy. Mutational profile at progression through osimertinib included: 2 patients (11.8%) with EGFR C797 mutation, 2 patients (11.8%) with MET amplification, 2 patients (11.8%) with RET fusion protein, 2 patients (11.8%) with MET point mutation, 1 patient (5.9%) with EGFR amplification, and 1 patient (5.9%) with small cell transformation. Newly identified resistance mechanisms (n = 1 for each) included mutation to EGFR G724 and L718 residues, ROS1 fusion protein, and in the same patient CBLB Q371* and SMAD4 loss. Of the 23 patients undergoing NGS at progression, 11 (47.8%) harbored EGFR T790M mutations prior to treatment, 3 (27.3%) of whom demonstrated resistance mutations susceptible to additional tyrosine kinase inhibitor therapy.

      Conclusion

      On the basis of these data, we confirm many previously described mechanisms of osimertinib resistance, including EGFR amplification, MET amplification, fusions involving RET, and transformation to small cell lung cancer, as well as novel resistance mechanisms including ROS1 fusion protein. We demonstrate the utility of NGS at the time of progression through osimertinib in our practice, regardless of the patient’s EGFR T790M status. We conclude that re-biopsy and utilization of NGS identifies a significant subset of osimertinib-resistant patients in whom well-tolerated tyrosine kinase inhibitor therapies remain an option and, in the interests of both patient well-being and clinical trial enrollment, should be considered standard practice at progression.

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    PC03 - Adjuvant Therapy for Resected NSCLC Harboring EGFR Mutation, Chemotherapy or Targeted Therapy (ID 85)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      PC03.02 - CONs (Now Available) (ID 3568)

      15:45 - 17:15  |  Presenting Author(s): Jyoti D Patel

      • Abstract
      • Presentation
      • Slides

      Abstract

      Surgery remains the cornerstone of treatment for early-stage non-small cell lung cancer (NSCLC). However, despite undergoing potentially curative surgery, patients with stage I, II, or IIIA NSCLC are at substantial risk for recurrence and death from lung cancer. Adjuvant cisplatin-based systemic therapy has conclusively been proven to decrease the risk of recurrence and improve overall survival outcomes. EGFR tyrosine kinase inhibitors have been proven to be the superior first-line treatment for EGFR-mutant advanced NSCLC. Several trials have shown superior progression-free survival and fewer side effects compared with doublet chemotherapy in advanced disease. Given that EGFR-TKIs are more active than platinum-based doublet chemotherapy in patients with advanced EGFR mutant lung cancer, there has been substantial interest in bringing these agents to earlier disease states.There are several clinical trials evaluating the effect of EGFR-TKIs as adjuvant treatment. Despite improvements in disease free survival, to date, none have demonstrated statistically significant improvements in overall survival. Moreover, multiple questions regarding duration of therapy and appropriate TKI remain unanswered. More survival data are needed before one can recommend adjuvant TKIs for all.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)

      08:00 - 10:15  |  Author(s): Jyoti D Patel

      • Abstract
      • Presentation
      • Slides

      Background

      No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.

      Method

      This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.

      Result

      As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.

      Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.

      The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

      Conclusion

      LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

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