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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.

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    OA02 - Novel Therapies in ROS1, HER2 and EGFR (ID 893)

    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 8
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
    • +

      OA02.01 - Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 13903)

      10:30 - 10:40  |  Presenting Author(s): Robert C. Doebele  |  Author(s): Myung-Ju Ahn, Salvatore Siena, Alexander Drilon, Matthew G Krebs, Chia-Chi Lin, Filippo G. De Braud, Thomas John, Daniel S.W. Tan, Takashi Seto, Rafal Dziadziuszko, Hendrick-Tobias Arkenau, Fabrice Barlesi, Christian Rolfo, Jürgen Wolf, Edna Chow-Maneval, Pratik S. Multani, Na Cui, Todd Riehl, Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Background

      Entrectinib is a central nervous system (CNS) active, potent, and selective inhibitor of ROS1, TRKA/B/C and ALK. Entrectinib is more potent against ROS1 than crizotinib, the only agent currently approved for the treatment of ROS1-positive NSCLC. Interim data demonstrated that entrectinib was tolerable and achieved high objective response rates (ORR) in patients with ROS1-positive, ROS1 inhibitor-naive NSCLC, including patients with baseline CNS disease (Ahn MJ WCLC 2017).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Phase 1/2 studies of entrectinib (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267) enrolled patients with locally advanced or metastatic solid tumors. The safety-evaluable population included patients who received ≥1 dose of entrectinib. The integrated efficacy analysis included ROS1-positive NSCLC patients enrolled based on identification of ROS1 fusions via nucleic acid-based diagnostic platforms. Safety was assessed by monitoring adverse events (AEs), laboratory tests, and physical examination. Tumor assessments were performed at the end of cycle 1 and every 8 weeks thereafter. All scans were submitted for blinded independent central review (BICR) using RECISTv1.1. Primary endpoints were ORR and duration of response (DOR) by BICR. Key secondary objectives were progression-free survival (PFS), overall survival (OS), and safety. Additional endpoints evaluated in patients with baseline CNS disease were intracranial ORR (defined as complete or partial responses in patients with baseline CNS lesions per BICR using RECISTv1.1), intracranial DOR, and PFS. For intracranial assessments, the CNS subgroup was derived per BICR; for systemic analyses, the CNS subgroup was derived per investigator.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 53 efficacy-evaluable patients with treatment-naïve, ROS1-positive NSCLC. BICR ORR was 77.4% (95% CI 63.8–87.7) with complete responses in three patients (5.7%); median BICR DOR was 24.6 months (95% CI 11.4–34.8). Per baseline CNS status (as determined by investigator), median BICR PFS was 26.3 months (95% CI 15.7–36.6) and 13.6 months (95% CI 4.5–NR) for patients without (n=30) and with CNS disease (n=23), respectively. Intracranial ORR was 55.0% (95% CI 31.5–76.9) and median intracranial DOR was 12.9 months (95% CI 5.6–not reached [NR]) in patients with baseline CNS disease per BICR (n=20). In the overall safety-evaluable population (n=355), most treatment-related AEs were grade 1–2. Few patients required dose reduction (27.3%) or discontinued treatment (3.9%) due to treatment-related AEs.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Entrectinib was tolerable with a manageable safety profile, and showed clinically meaningful, deep and durable systemic responses in ROS1-positive NSCLC. Clinically meaningful intracranial activity was also demonstrated in patients with baseline CNS disease.

      Study Sponsor: Ignyta, Inc., a wholly owned subsidiary of F. Hoffmann-La Roche Ltd.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA02.02 - Safety and Preliminary Clinical Activity of Ropotrectinib (TPX-0005), a ROS1/TRK/ALK Inhibitor, in Advanced ROS1 Fusion-Positive NSCLC (Now Available) (ID 14217)

      10:40 - 10:50  |  Presenting Author(s): Jessica Jiyeong Lin  |  Author(s): Dong-Wan Kim, Alexander Drilon, Robert C. Doebele, Jeeyun Lee, Viola Zhu, Myung-Ju Ahn, John Lim, Shanna Stopatschinskaja, J. Jean Cui, David M Hyman, Ross Camidge, Sai-Hong Ignatius Ou, Alice T. Shaw, Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Background

      Ropotrectinib is a potent ROS1/TRK/ALK inhibitor with a >90-fold greater ROS1 potency than crizotinib. Preclinical studies demonstrate robust activity against all known ROS1 resistance mutations, including solvent-front mutation G2032R.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this Phase 1 study (NCT03093116), TKI-naïve and TKI-refractory (≥1 TKI) pts with advanced ALK/ROS1/TRK+ solid tumors received ropotrectinib. Asymptomatic brain metastases were allowed. Primary objectives were to determine MTD and RP2D, with safety, pharmacokinetics, and preliminary antitumor efficacy as the secondary objectives. This is a safety analysis of all pts and subgroup efficacy analysis of the ROS1+ NSCLC pts on the study.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 16-April-2018, 72 pts have been treated at 6 dose levels from 40mg QD to 200mg BID. Most AEs were grade 1-2. Common (>10%) treatment-related AEs included dizziness (49%), dysgeusia (46%), paresthesias (29%), constipation (19%), fatigue (18%), nausea (11%), and anemia (11%). 4 DLTs were observed at ≥240mg/day: 1 grade 3 (Gr3) dyspnea/hypoxia, 2 Gr3 & 1 Gr2 dizziness. 31 of 72 pts had ROS1+ NSCLC by local testing (FISH, n=20; NGS, n=11) with 1 pt determined as ROS1-negative by central NGS. Antitumor activity in ROS1+ NSCLC has been observed at ROS1 dose levels 40mg QD-160mg BID per investigator assessment, with the best ORR 70% for TKI-naïve and 11% for TKI-refractory pts (17% for 1 prior TKI crizotinib, n=12) (Table). Two crizotinib-resistant pts with G2032R achieved durable cPR and cSD, respectively. Ongoing blinded independent review identified 7 evaluable pts with target CNS lesions at baseline; the intracranial best ORR was 43% (3 cPR, 1 PR*). Updated efficacy data and ctDNA biomarker analyses will be presented.

      Dose Level

      TKI Naïve (n = 10)

      TKI Refractory (n = 20)

      n

      Best Overall Response

      n

      Best Overall Response

      40 mg QD (n = 6)

      2

      2 cPR (ORR 100%)

      4

      2 cSD, 1 SD, 1 PD

      80 mg QD (n = 5)

      2

      2 cPR (ORR 100%)

      3

      1 cSD, 2 SD

      160 mg QD (n = 10)

      4

      2 cPR, 2 cSD (ORR 50%)

      6

      2 cPR, 2 cSD, 1 SD, 1 PD (ORR 33%)

      240 mg QD (n = 2)

      1

      1 cPR (ORR 100%)

      1

      1 SD

      160 mg BID (n = 7)

      1

      1 PR*

      6

      1 PR*, 1 SD*, 1 cSD, 2 SD, 1 NE

      Total (n = 30)

      10

      7 cPR, 1 PR*, 2 cSD

      20

      2 cPR, 1 PR*, 6 cSD, 1 SD*, 7 SD, 2 PD, 1 NE

      Best ORR

      70%

      11%

      Median follow-up

      8 months with 90% still on treatment

      4 months with 50% still on treatment

      cPR: confirmed partial response; SD: stable disease for 2 cycles; cSD: SD for at least 4 cycles; PR* or SD*: waiting for subsequent time point scan; PD: progressive disease; NE: inevaluable; ORR: objective response rate

      8eea62084ca7e541d918e823422bd82e Conclusion

      Ropotrectinib is well tolerated and demonstrates promising activity in pts with advanced ROS1+ NSCLC, including TKI-naïve and TKI-refractory pts. RP2D has not yet been achieved. These Phase 1 data warrant further clinical testing of ropotrectinib in ROS1+ NSCLC.

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      OA02.03 - Clinical Activity of Lorlatinib in Patients with ROS1+ Advanced Non-Small Cell Lung Cancer: Phase 2 Study Cohort EXP-6 (Now Available) (ID 12787)

      10:50 - 11:00  |  Presenting Author(s): Sai-Hong Ignatius Ou  |  Author(s): Alice T. Shaw, Gregory J Riely, Rita Chiari, Jessica R. Bauman, Jill S. Clancy, Holger Thurm, Gerson Peltz, Antonello Abbattista, Ben J Solomon

      • Abstract
      • Presentation
      • Slides

      Background

      Among patients with ROS1-positive non-small cell lung cancer (NSCLC), most achieve initial benefit from crizotinib treatment but often develop resistance, and further treatment options are limited. Lorlatinib is a potent, brain-penetrant third-generation ALK/ROS1 TKI with broad mutational coverage. It has shown compelling clinical activity in patients with ALK-positive and ROS1-positive advanced NSCLC, most of whom had CNS metastases and had received prior crizotinib.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This ongoing Phase 2 study (NCT01970865) enrolled patients with ROS1-positive advanced NSCLC ± asymptomatic CNS metastases without restriction on the type or number of prior lines of therapy (cohort EXP-6). Patients received lorlatinib 100 mg QD. Primary endpoints were overall and intracranial response by independent central review. Secondary endpoints included duration of response and progression-free survival. Safety was assessed in all treated patients (cohorts EXP-1–6); molecular profiling is ongoing.

      4c3880bb027f159e801041b1021e88e8 Result

      As of the data cut-off (02 Feb 2018), 47 patients with ROS1+ NSCLC were treated; 25 had baseline CNS metastases; 34 had received prior crizotinib and 13 were crizotinib-naïve. Treatment with lorlatinib led to rapid and durable responses in both crizotinib-naïve and crizotinib-pre-exposed patients (Table).

      ICR-assessed endpoint Crizotinib-naïve Crizotinib-pre-exposed Total EXP-6
      Overall, N 13 34 47
      ORR, % (95% CI) 61.5 (31.6, 86.1) 26.5 (12.9, 44.4) 36.2 (22.7, 51.5)
      Confirmed response, n 8 9 17

      Response lasting at least 12 months, n

      5 5 10
      Median time to tumor response, months (range) 1.4 (1.3–8.3) 2.5 (1.4–4.2) 1.4 (1.3–8.3)
      Intracranial (IC), N 6 19 25
      IC ORR, % (95% CI) 66.7 (22.3, 95.7) 52.6 (28.9, 75.6) 56.0 (34.9, 75.6)
      Confirmed IC response, n 4 10 14

      IC response lasting at least 12 months, n

      1 4 5
      Median PFS, months (95% CI)a 21.0 (4.2, 26.7) 8.5 (4.4, 18.0) 9.9 (5.5, 21.0)

      ICR, independent central review; PFS, progression-free survival.

      aPer Kaplan-Meier method.

      The most common treatment-related adverse events (TRAEs) in EXP-6, were hypercholesterolemia (83%) and hypertriglyceridemia (60%). In EXP-6, 36% and 23% of patients had TRAEs leading to dose interruptions and dose reductions, respectively. No permanent treatment discontinuations due to TRAEs or treatment-related deaths occurred.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lorlatinib showed clinically meaningful benefit in patients with ROS1-positive NSCLC, including those who had received prior crizotinib or were crizotinib-naive, as demonstrated by rapid and durable responses. These findings further suggest that the activity of lorlatinib differs depending on prior exposure to crizotinib. The safety profile of lorlatinib in ROS1 patients was comparable to that previously reported in the overall ALK/ROS1 population.

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      OA02.04 - Discussant - OA 02.01, OA 02.02, OA 02.03 (Now Available) (ID 14548)

      11:00 - 11:15  |  Presenting Author(s): Shengxiang Ren

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA02.05 - CK-101 (RX518), a Third Generation Mutant-Selective Inhibitor of EGFR in NSCLC: Results of an Ongoing Phase I/II Trial (Now Available) (ID 11982)

      11:15 - 11:25  |  Presenting Author(s): Melissa L. Johnson  |  Author(s): Janet Karlix, Howard A Burris, Suzanne F Jones, Dean Harris, Kenneth O’byrne, Virote Sriuranpong, Chaiyut Charoentum, Naiyarat Prasongsook, Wittawat Jitpewngam, Kosin Wirasorn, Judy Sing-Zan Wang, Saiama N. Waqar, James Oliviero, Leonid Gorelik, Xiangping Qian

      • Abstract
      • Presentation
      • Slides

      Background

      CK-101 (also known as RX518) is a novel, oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and resistance mutations, with minimal activity on wild-type EGFR. CK-101 is being studied in an ongoing first-in-human, multicenter, Phase I/II trial in advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations and other advanced malignancies in the US, Australia, New Zealand and Thailand (NCT02926768). Following dose escalation in which 18 pts received CK-101 in dose groups ranging from 100 mg to 1200 mg/day, a first dose-expansion cohort was enrolled at 400 mg bid.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible pts in dose escalation had a confirmed diagnosis of NSCLC or any advanced solid tumor where targeting EGFR was reasonable. Eligible pts in dose-expansion had a confirmed diagnosis of either (1) EGFR mutation-positive advanced or metastatic NSCLC without prior exposure to EGFR-TKI therapy, or (2) T790M-positive advanced or metastatic NSCLC with disease progression on previous EGFR-TKI therapy, with no limit on number of prior lines of systemic therapy.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 25 June 2018, 37 pts were treated in dose escalation and expansion and evaluable for safety; median age 59 years, 51% male, 51% Asian, 84% ECOG PS 1. No DLTs or treatment-related SAEs were reported. Most common treatment-emergent adverse events: nausea (16%), diarrhea (14%), lacrimation increased (14%) and vomiting (11%), all grade 1/2 except one grade 3 diarrhea; no grade 4. In dose-expansion, 19 pts were treated with CK-101 at a dose of 400 mg bid and evaluable for response; 8/19 (42%) pts were treatment-naïve, 6/19 (32%) pts had brain metastases; 16/19 (84%) pts remained on treatment. Disease control rate was 100% (19/19), with 16/19 pts (84%) experiencing target lesion reduction versus baseline and 8 pts achieving a partial response (7 confirmed, 1 pending confirmation). In treatment-naïve pts, 6/8 (75%) pts achieved a partial response. In pts with brain metastases, 3/6 (50%) pts achieved a partial response. Higher drug exposures were associated with higher response rate with a confirmed ORR of 55% (6/11) in pts achieving Cmax >400 ng/mL. Median duration of response and progression-free survival were not reached as of the data cutoff.

      8eea62084ca7e541d918e823422bd82e Conclusion

      CK-101 was well tolerated with a manageable safety profile. Durable anti-tumor activity was observed, particularly in treatment-naïve pts. Further study is ongoing to establish the optimal dose to maximize therapeutic effect in a planned Phase 3 study in treatment-naïve EGFR-mutant NSCLC pts.

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      OA02.06 - A Phase II Trial of Poziotinib in EGFR and HER2 exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 14277)

      11:25 - 11:35  |  Presenting Author(s): John V Heymach  |  Author(s): Marcelo Vailati Negrao, Jacqulyne Ponville Robichaux, Brett W. Carter, Anisha Patel, Mehmet Altan, Don Lynn Gibbons, Frank Fossella, George R. Simon, Vincent K Lam, George R Blumenschein, Anne S. Tsao, Jonathan M Kurie, Frank Mott, Daveta Jenkins, Dahlia Mack, Lei Feng, Brent Roeck, Zane Yang, Vassiliki A Papadimitrakopoulou, Yasir Y Elamin

      • Abstract
      • Presentation
      • Slides

      Background

      Insertions/mutations in exon 20 of EGFR or HER2 occur in ~3% of all lung adenocarcinomas. These alterations are characterized by primary resistance to tyrosine kinase inhibitors (TKIs) with response rates of <12%. We previously showed that exon 20 insertions restrict the size of drug-binding pocket, limiting binding of most available TKIs. However, poziotinib can potentially circumvent these steric changes due to its smaller, flexible structure and is a potent inhibitor of EGFR and HER2 exon 20 mutants (Robichaux et al. Nat Med, 2018). Herein, we report the results of an investigator-initiated study of poziotinib in EGFR and HER2 exon 20 mutant NSCLC (NCT03066206).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients ≥18yrs with metastatic NSCLC bearing mutations/insertions in EGFR or HER2 exon 20 (except EGFR T790M) were eligible. Unlimited prior systemic and targeted therapies were permitted. Poziotinib 16mg PO daily was administered until progression, death, or withdrawal. The primary endpoint was objective response rate (ORR) based on RECIST v1.1. Response was evaluated every eight weeks. A Bayesian design was used with a plan to enroll patients in cohorts of 10 and to terminate the study if ORR was ≤20%. Secondary endpoints included DCR, PFS, OS and safety

      4c3880bb027f159e801041b1021e88e8 Result

      As of May 3, 2018, the planned EGFR cohort of 50 patients was fully enrolled, and 40 patients were evaluated for response. 65.1% of patients had received at least two prior lines of therapy for metastatic disease. 60% of patients had ≥grade 3 adverse events; most common were skin-rash (27.5%) and diarrhea (12.5%). 45.0% of patients required dose reduction to 12mg, while 17.5% required dose reduction to 8mg. One patient stopped treatment due to grade 3 skin rash. ORR at eight weeks was 58% (95%-CI 40.9-73.0) and the DCR was 90% (95%-CI 76.3-97.2). Among 23 patients who achieved partial response, 15 responses were confirmed with subsequent scans, five responses were unconfirmed, and three patients are pending confirmation. Responses were observed in 8/13 (62%) patients that were previously treated with TKI. Median PFS was 5.6mo (95%-CI 5.06-NA). Furthermore, 13 patients were enrolled in HER2 cohort. Toxicities were similar to EGFR cohort except one case of grade 5 pneumonitis, assessed to be possibly drug related. Twelve patients were evaluated for response with ORR of 50% (95% CI 21.1-78.9) at eight weeks and DCR of 83%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In heavily pre-treated population with EGFR and HER2 exon 20 mutant NSCLC, poziotinib demonstrated encouraging antitumor activity in both TKI-naive and -refractory patients, and manageable toxicity profile.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA02.07 - Updated Results of Phase 1 Study of DS-8201a in HER2-Expressing or –Mutated Advanced Non-Small-Cell Lung Cancer (Now Available) (ID 13325)

      11:35 - 11:45  |  Presenting Author(s): Junji Tsurutani  |  Author(s): Haeseong Park, Toshihiko Doi, Shanu Modi, Shunji Takahashi, Kazuhiko Nakagawa, Ian E. Krop, Saiama N. Waqar, Kiyotaka Yoh, Bob T. Li, Shinichiro Taira, Takahiro Jikoh, Jasmeet Singh, Masahiro Sugihara, Pasi A Jänne

      • Abstract
      • Presentation
      • Slides

      Background

      DS-8201a is a HER2-targeting antibody-drug conjugate with a novel peptide-based cleavable linker, a topoisomerase I inhibitor payload, and a high drug-to-antibody ratio (7 to 8). In preclinical studies, DS-8201a showed broad antitumor activity, in a wide range of tumors. The ongoing phase 1 trial has a dose-escalation (part 1) and -expansion (part 2) and includes subjects with advanced breast cancer, gastric cancer, and other HER2-expressing/-mutated solid tumors. Here, we present updated results for subjects with HER2-expressing or -mutated non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Subjects with HER2-expressing (defined as IHC ≥1+ or amplified) or –mutated (detected by NGS or other platforms) NSCLC were eligible to enroll. HER2 expression and mutation were assessed using archival tissue. Adverse events (AEs), objective response rate (ORR), disease control rate (DCR: CR + PR + SD), and duration of response (DOR) were assessed.

      4c3880bb027f159e801041b1021e88e8 Result

      [Results will be updated for presentation at meeting] As of Apr 18, 2018, 12 subjects with HER2-expressing and/or -mutated NSCLC received ≥1 dose of DS-8201a at 6.4 mg/kg. Median age was 58.5 y with median of 3 prior regimens. At data cutoff, 8 of 12 (66.7%) subjects remain on treatment. HER2 IHC status was available for 7 subjects. Median duration of treatment was 3.66 months (range 0.69, 14.19). Eight of 10 (80.0%) subjects with ≥1 post-baseline scan (ps) experienced tumor shrinkage (100.0% of them at 1st ps at 6 weeks). Overall, confirmed ORR and DCR in the evaluable subjects was 5 of 8 (62.5%) and 6 of 8 (75.0%), respectively. Among subjects with HER2 IHC 2+ or IHC 3+ expression, 2 of 5 (40.0%) had a PR. Overall, median DOR was 11.5 months (range 0.03+, 11.53). Three of 12 (25.0%) subjects experienced a grade ≥3 AE. Common AEs included decreased appetite 66.7% (0.0% grade ≥3), nausea 58.3% (0.0% grade ≥3), alopecia 41.7% (0.0% grade ≥3), and fatigue 41.7% (0.0% grade ≥3). One fatal case of interstitial lung disease was reported in this subgroup.

      8eea62084ca7e541d918e823422bd82e Conclusion

      DS-8201a demonstrated promising antitumor activity in heavily pretreated NSCLC subjects.

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      OA02.08 - Discussant - OA 02.05, OA 02.06, OA 02.07 (Now Available) (ID 14549)

      11:45 - 12:00  |  Presenting Author(s): Daniel B Costa

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA03 - Advances in Lung Cancer Pathology (ID 897)

    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 8
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 BD
    • +

      OA03.01 - The Immunophenotyping and Genomic Characteristics of Pulmonary Sarcomatoid Carcinoma: Pleomorphic, Spindle Cell and Giant Cell Carcinoma (Now Available) (ID 12239)

      10:30 - 10:40  |  Presenting Author(s): Chunyan Wu  |  Author(s): Likun Hou

      • Abstract
      • Presentation
      • Slides

      Background

      Pulmonary sarcomatoid carcinoma (PSC) is a poorly differentiated non-small cell lung cancer (NSCLC) and comprises a diagnostically and therapeutically challenging group of tumors. We explored the immunohistochemical characteristics and genetic profiles of PSC (except carcinosarcoma and pulmonary blastoma)

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 432 cases with surgically resected undifferentiated NSCLC (121 solid adenocarcinomas (ADC), 98 non-keratinizing squamous cell carcinomas (SQC), 118 large cell carcinomas (LCC) and 95 sarcomatoid carcinomas) were reviewed. Expression of epithelial-mesenchymal transition (EMT) markers (Cytokeratin (CK), Vimentin (Vim) and zinc-finger E-box binding homeobox 1 (ZEB1)) were studied by immunohistochemistry. 8 therapeutically-relevant genetic alterations(EGFR/BRAF/KRAS/HER2/MET exon 14 mutations and ALK/ROS1/RET fusion)of sarcomatoid carcinomas were detected by Capture-based targeted sequencing

      4c3880bb027f159e801041b1021e88e8 Result

      The expression of CK was almost positive in ADC, SQC and LCC, which of sarcomatoid component (SC) of PSC was observed positively only in 80/95(84.2%). Although vim expression was higher (88/95, 92.6%) in SC, it was also positive in ADC (37/121, 30.6%), SQC (14/98, 14.3%), LCC (12/118, 10.2%), respectively. In the contrast, SC was detected with 100% ZEB1 expression in PSC (95/95). ZEB1 expression was focal positive only in 1 cases of SQC (1/98, 1.0%). In ADC and LCC, no ZEB1 expression was found. The expression of ZEB1 had higher specificity (99%) and sensitivity (100%) than Vim expression in SC of PSC. The most frequent mutation genes were KRAS (18/58, 31.0%), EGFR (6/58, 10.3%), MET exon 14 (7/58, 12.0%) and no BRAF/HER2/ALK/ROS1/RET alteration were detected.

      8eea62084ca7e541d918e823422bd82e Conclusion

      ZEB1 was a useful differential diagnostic marker for PSC. Targeted mutations testing may be useful for classifying and managing PSC patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA03.02 - Nationwide Comparative Study Of PD-L1 IHC Assays on Lung Cancer: Initial Report Of LC-SCRUM-IBIS Project (Now Available) (ID 11321)

      10:40 - 10:50  |  Presenting Author(s): Noriko Motoi  |  Author(s): Genichirou Ishii, Yuichiro Hayashi, Koji Tsuta, Kiyotaka Yoh, Shingo Matsumoto, Koichi Goto

      • Abstract
      • Presentation
      • Slides

      Background

      Precision medicine requires accurate biomarkers for appropriate therapeutic decision. PD-L1 IHC is a predictive biomarker for immune checkpoint inhibitor (ICI), however, the complexity of PD-L1 IHC system could make interpretations confusion in practice. In this study, we compared four PD-L1 IHC systems using real-world clinical samples to reveal their properties and capability of harmonization as a part of nationwide immuno-oncology biomarker study of lung cancer (LC-SCRUM-IBIS).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Out of 1635 lung cancer patients enrolled in LC-SCRUM-Japan, four PD-L1 IHC assays (22C3, 28-8, SP263 and SP142) and whole-exome sequencing (WES) were analyzed in addition to NGS mutation screening by the Oncomine™ Comprehensive Assay (OCA). Planned accrual is 1000. IHC was evaluated by three certified lung pathologists independently. Three-tier scoring system (cutoff value of 1, 50%) applied for tumor cell (TC) in all assays, and TC+IC scoring algorism in SP142, according to the manufactural instruction. We calculated Spearman’s correlation coefficient and kappa value among TC proportion and the original protocol’s criteria of each assays. Discordant rate among assays was examined.

      4c3880bb027f159e801041b1021e88e8 Result

      486 patients (438 nonsmall, 48 small cell carcinoma) completed IHC study analysis from February to December 2017.

      Compared to 22C3, TC-score of 28-8 (kappa value 0.896) were and SP263 (0.729) showed good, and SP142 resulted slight (0.159) correlations. SP142-tc+ic score showed fair correlation with 22C3/28-8/SP263 TC-scores (kappa= 0.213/ 0.241/ 0.291, respectively).

      Our results showed substantial reproducibility of TC score among observers across different IHC assays (range of kappa: 0.675 – 0.837). Inter-observer concordance of the SP142-IC score was also acceptable (kappa 0.591-0.779). Of note, within 22C3 positive group (>1%), 4.5/15.6/67.7/55.0 % of 28-8/SP263/SP142-tc/SP142-(tc+ic) resulted in negative, respectively, indicating a risk of lower category switching for SP263 and SP142 compared to 22C3 and 28-8. A subset (8.3%) of 22C3-negative group resulted in SP142-positive and all such discrepancy was due to IC-positivity.

      There was no significant association between each PD-L1 expression and TMB by WES and OCA. Out of 77 patients treated with ICI, most responders (11/17, 65%) had PD-L1 high expression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results revealed an excellent/moderate/slight correlation between 22C3 and 28-8/SP263/SP142. SP142-positive-cases were fewer and more rigorous than the other three assays. A subset of lung cancer showed IC-only PD-L1-positivity. Inter-observer reproducibility was substantial for TC and moderate for IC. The scoring algorism affected concordance trend in a modest way. For harmonization, we should aware of each assays properties. PD-L1 IHC is not a perfect but a feasible biomarker for patients’ selection of ICI therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      • Abstract
      • Presentation
      • Slides

      Background
      PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each developed as predictive biomarker for specific anti PD1/PD-L1 immunotherapies. The Blueprint (BP) phase 1 comparability study demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells (TPS), while the SP-142 PD-L1 assay appeared to stain a lower percentage of tumor cells when compared to the other assays. The first part of BP phase 2 (BP2A) re-affirmed these findings in a larger cohort of ‘real life’ specimens scored by 24 experienced pulmonary pathologists, and also showed that the 73-10 assay developed for avelumab showed greater sensitivity than all other assays to detect PD-L1 on tumour cells. BP2A also demonstrated generally excellent inter-observer agreement for tumor cell PD-L1 scoring using both glass slides and digital images, with slightly lesser agreement for the cytology samples included in the study cohort. Inter-observer agreement for immune cell scoring on glass or digital slides was poor. Phase 2B of Blueprint (BP2B) aimed to compare PD-L1 scoring on triplet samples representing large tumor resection blocks, small biopsy samples and fine needle aspirate cell blocks prepared from the same tumor. a9ded1e5ce5d75814730bb4caaf49419 Method
      Triplet samples of large resected tumor block, small biopsy sample and fine needle aspirate cell block (the latter two taken from the resected tumour specimen) were gathered from 31 resected primary lung cancers (17 adenocarcinomas, 12 squamous cell carcinomas, and 2 large cell carcinomas). Sections from all 93 blocks were stained with the pharmDx 28-8 and 22C3, the FDA-approved SP142 and SP263, or clinical trial associated 73-10 PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. All H&E and PD-L1 IHC slides were scanned and digital images were used to score all cases by the same 24 pathologists involved in BP2A. As before, tumor cells PD-L1 staining were scored as continuous variable and into 7 cut-off-defined categories, as used in various immune checkpoint inhibitor trials. Immune cells were not scored. 4c3880bb027f159e801041b1021e88e8 Result
      The data reaffirm the relative comparability of 28-8, 22C3 and SP263 assays across the range of scores; SP142 assay scores were lower, those for 73-10 higher. Inter-observer agreement between readers ranged from moderate to near perfect (Kappa-Fleiss (K-F) scores generally >0.7); best overall agreement was on aspirates. Overall, the agreement between scores on the different sample types from the same tumor was good (most K-F scores >0.7); aspirates showed no significant difference from biopsy samples or whole surgical blocks. In contrast to biopsies and surgical blocks, scores could, however, not be rendered in about 14% of aspirate sections. 8eea62084ca7e541d918e823422bd82e Conclusion
      The results of BP2B confirms earlier results and also demonstrate comparable performance for fine needle aspirates in those cases where TPS scores were possible. 6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA03.04 - Discussant - OA 03.01, OA 03.02, OA 03.03 (Now Available) (ID 14550)

      11:00 - 11:15  |  Presenting Author(s): Julien Adam

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA03.05 - Characterization of the Immunologic Intra-Tumor Heterogeneity in Early Stages of Non-Small Cell Lung Cancer by Multiplex Immunofluorescence (Now Available) (ID 13334)

      11:15 - 11:25  |  Presenting Author(s): Alejandro Francisco Cruz  |  Author(s): Edwin Roger Parra, Mei Jiang, Junya Fujimoto, Santhoshi N. Krishnan, Souptik Barua, Arvind Rao, Chi-Wan Chow, Carmen Behrens, Neda Kalhor, Annikka Weissferdt, John V Heymach, Stephen Swisher, Boris Sepesi, Jack Lee, Cesar Moran, P. Andrew Futreal, Jianjun Zhang, Ignacio I. Wistuba

      • Abstract
      • Presentation
      • Slides

      Background

      Recurrence of non-small cell lung carcinoma (NSCLC) is associated with genetic and epigenetic intra-tumor heterogeneity (ITH). The interaction between malignant cells, stromal cells, and tumor-associated immune-cells (TAICs), such as T-cell lymphocytes (TCLs) and tumor-associated macrophages (TAMs), is important for progression of NSCLC and the characterization of the immunologic ITH might be relevant to predict recurrence in surgically treated patients at early stages of NSCLC. The aim of this study was to characterize the immunologic ITH of primary NSCLC tumors at early stages using image analysis and multiplex immunofluorescence (mIF) approaches.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eight cases of stage IA and 8 cases of stage IB surgically resected NSCLC (11 adenocarcinomas, ADCs; and 5 squamous-cell carcinomas, SCCs) with a history of early recurrence were selected for this preliminary analysis. FFPE blocks were obtained and consecutive sections were stained with two panels of mIF for immune profiling, panel 1: pan-cytokeratin (AE1/AE3), PD-L1, PD-1, CD3, CD8, and CD68; panel 2: AE1/AE3, CD3, CD8, granzyme-B (GB), CD45RO, and FOXP3. Three not adjacent, intra-tumor regions (3mm2 each) per case were randomly selected after gridding the whole tumor section. A total of 41 intra-tumor regions were scanned by Vectra multispectral-microscope and analyzed using InForm-software. TAICs were quantified in epithelial and stromal compartments from each intra-tumor region. G-Cross AUC (area under the curve) was computed for specific intervals of distances between TAICs and malignant cells. Median distance between TAICs and malignant cells within each region was calculated.

      4c3880bb027f159e801041b1021e88e8 Result

      The median density of TCLs and TAMs were 1527 cells/mm2 and 635 cells/mm2, respectively, without significant differences between histologic subtypes. TCLs were predominantly concentered in stromal compartment (median, 2222 cells/mm2) compared with epithelial compartment (median, 332 cells/mm2). Percentage and density of TCLs and TAMs varied 4 and 8 times, respectively, between cases and regions. Non-cytotoxic T-cells and inactive cytotoxic T-cells were the most prevalent phenotypes. Higher density of TAMs and antigen-experienced TCLs were observed in stage IB than stage IA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Characterization of immunologic ITH of NSCLC is able by mIF and image analysis with FFPE tumor tissue. There is variability of TAICs densities between regions from the same tumor and different subpopulations were observed. TAMs and exhausted T-cells were more prominent in stage IB (tumor >3cm) suggesting these cells may play an important role in recurrence. Ongoing studies with a larger cohort and comparison with non-recurrent surgically treated patients are warranted. Supported by CPRITRP160668 and UTLungSPORE grants

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA03.06 - Extraction of Radiomic Values from Lung Adenocarcinoma with Near-Pure Histological Subtypes (Now Available) (ID 13840)

      11:25 - 11:35  |  Presenting Author(s): Mong-Wei Lin  |  Author(s): Shun-Mao Yang, Li-Wei Chen, Hao-Jen Wang, Leng-Rong Chen, Kuo-Lung Lor, Yi-Chang Chen, Min-Shu Hsieh, Jin-Shing Chen, Yeun-Chung Chang, Chung-Ming Chen

      • Abstract
      • Presentation
      • Slides

      Background

      Histological subtypes of lung adenocarcinomas classified by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) system have been investigated using radiomic approaches. However, the results have had limitations since of invasive lung adenocarcinomas may be heterogeneous, with two or more subtypes. To reduce the influence of heterogeneity during radiomic analysis, computed tomography (CT) images of lung adenocarcinomas with near-pure adenocarcinoma subtypes were analyzed to extract representative radiomic features of different subtypes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We enrolled 95 patients who underwent complete resection for lung adenocarcinoma and a pathological diagnosis of a “near-pure” (≥70%) IASLC/ATS/ERS histological subtype. Conventional histogram/morphological features and complex radiomic features (grey-level-based statistical features and component variance-based features) of thin-cut CT data of tumor regions were analyzed. A prediction model based on leave-one-out cross-validation (LOOCV) and logistic regression (LR) was used to classify all five subtypes and three pathologic grades (lepidic, acinar/papillary, micropapillary/solid) of adenocarcinomas. The validation was performed using 36 near-pure adenocarcinomas in a later cohort.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 31 lepidic, 14 papillary, 32 acinar, 10 micropapillary, and 8 solid adenocarcinomas were analyzed. With 21 conventional and complex radiomic features, for 5 subtypes and 3 pathological grades, the prediction models achieved accuracy rates of 84.2% (80/95) and 91.6% (87/95), respectively, while accuracy was 71.6% and 85.3%, respectively, if only conventional features were used. The accuracy rate for the validation set (n=36) was 83.3% (30/36) and 94.4% (34/36) in 5 subtypes and 3 pathological grades, respectively, using conventional and complex features, while it was 66.7% and 77.8% only using conventional features, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lung adenocarcinoma with high purity histological subtypes demonstrates strong stratification of radiomic values, which provide basic information for accurate pathological subtyping and image parcellation of tumor sub-regions.

      figure for wclc 2018.png

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA03.07 - Three-Dimensional Immunofluorescence Analysis of Dynamic Vessel Co-Option of Spread Through Air Spaces (STAS) in Lung Cancer (Now Available) (ID 14318)

      11:35 - 11:45  |  Presenting Author(s): Yukako Yagi  |  Author(s): Rania G Aly, Kazuhiro Tabata, Natasha Rekhtman, Takashi Eguchi, Joseph Montecalvo, Katia Manova, Prasad S. Adusumilli, Meera Hameed, William D Travis

      • Abstract
      • Presentation
      • Slides

      Background

      STAS was identified, by the 2015 WHO classification, as a new method of invasion in lung adenocarcinoma, with poor prognosis. Blood vessel co-option is a mechanism by which spreading intraalveolar tumor cells connect to the surrounding vasculature to survive. The aim of this study was to visualize the dynamic mechanism of blood vessel co-option using a high resolution and high-quality 3D reconstruction, and multiplex immunofluorescence (IF).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A 3D reconstruction image of a case of invasive lung adenocarcinoma with extensive STAS was performed on the formalin fixed paraffin-embedded (FFPE) block. 150 serial sections were obtained by the automated sectioning system AS410 (DNS. Ltd, Japan), and stained with H&E (100 slides), and multiplex IF (30 slides) for CD31, type IV collagen, TTF-1 and E-Cadherin to assess the relation between STAS and the surrounding lung parenchyma and vasculature. The IF stained sections were scanned with 0.33um/pixel by Panoramic P250 Flash (3D Histech Ltd, Hungary) Whole Slide Imaging Scanner (WSI). The WSIs were reconstructed into 3D exported to Imaris 8.0 (Bitplane, MA, US) for signal assessment.

      4c3880bb027f159e801041b1021e88e8 Result

      Serial 3D image analysis identifies the presence of STAS mainly in the form of micropapillary clusters. The multiplex IF staining highlighted the co-option which was determined by the spread and then attachment of STAS (TTF-1 and E-Cadherin positive) to distant alveolar wall capillaries (CD31 positive) with preservation of the alveolar wall (figure). This relation between STAS and the surrounding lung parenchyma was visualized in all serial sections of the whole FFPE block thickness. 01s1632681_ cd31a488_ecada594_col4a647_ttfa546_65.5x2.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The survival of STAS, beyond the tumor edge, in lung adenocarcinoma is a viable mechanism for tumor recurrence. The combination of the high resolution and high-quality 3D reconstruction and multiplex immunofluorescence in our study, supports the concept that dynamic blood vessel co-option is a mechanism for STAS survival.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA03.08 - Discussant - OA 03.05, OA 03.06, OA 03.07 (Now Available) (ID 14551)

      11:45 - 12:00  |  Presenting Author(s): David L. Rimm

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA04 - Improving Access and Outcomes in Lung Cancer Management (ID 898)

    • Type: Oral Abstract Session
    • Track: Nursing and Allied Professionals
    • Presentations: 8
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 201 F
    • +

      OA04.01 - What is the Cost of a Strong Evidence for the Treatment of Advanced Non-Small Cell Lung Cancer? (Now Available) (ID 14410)

      10:30 - 10:40  |  Presenting Author(s): Pedro Aguiar Jr  |  Author(s): Barbara Gutierres, Barbara Dourado, Alanda Alves, Carmelia Maria Noia Barreto, Gilberto de Lima Lopes, Auro Del Giglio

      • Abstract
      • Presentation
      • Slides

      Background

      Evidence-based medicine was developed to guide medical decisions based upon the strongest scientific evidence available in the literature. However, large randomized clinical trials are expensive. In addition, new antineoplastic drugs development is also extremely expensive. Therefore, we hypothesized that the strongest evidence available nowadays comes from studies developed by the pharmaceutical industry.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We carried out a search on network databases for studies published between 2014 and 2017. We included only experimental studies that assessed the treatment for advanced or metastatic non-small cell lung cancer. All included studies were divided into two groups: studies funded by pharmaceutical industry and studies funded by other sources. The primary end point was to compare the evidence strength of each group. Secondary end points were to compare other aspects, such as the number of patients included by each group of studies and the number of innovative drugs studied by each group of studies.

      4c3880bb027f159e801041b1021e88e8 Result

      We found 1,502 studies and included 299 studies (154 sponsored by pharmaceutical industry and 145 funded by other sources). 52,988 patients were included in all studies (36,455 in studies sponsored by industry and 16,533 in studies with other funding sources; p < 0.001). The studies funded by pharmaceutical industry had the stronger evidence compared with studies with other sources of funding (p = 0.005). Moreover, studies sponsored by pharmaceutical industry studied more innovative therapies (72.4% versus 48.9%; p < 0.001) and had a higher proportion of open access manuscript (60.8% versus 43.9%; p = 0.004). Results are summarized in the table.

      Parameter Industry Sponsored P value

      Yes

      154 (100%)

      No

      145 (100%)
      Number of patients 36,455 16,533 <0.001
      Mean N of patients 236.7 115.6
      Line First 110 (71.4%) 94 (64.8%) 0.220
      Second or more 44 (28.6%) 51 (35.2%)
      Biomarker Yes 55 (35.9%) 55 (37.9%) 0.723
      No 98 (64.1%) 90 (62.1%)
      Innovative Tx Yes 110 (72.4%) 69 (48.9%) <0.001
      No 42 (27.6%) 71 (51.1%)
      Phase I 20 (13%) 25 (17.2%) 0.409
      II 101 (65.6%) 97 (66.9%)
      III 32 (20.8%) 21 (14.5%)
      IV 1 (0.6%) 2 (1.4%)
      Evidence Level 1 0 (0%) 1 (0.7%) 0.005
      2 76 (49.4%) 52 (35.9%)
      3 78 (50.6%) 87 (60%)
      4 0 (0%) 5 (3.4%)
      Experimental Yes 35 (47.3%) 26 (50%) 0.765
      Superiority No 39 (52.7%) 26 (50%)
      Open Access Yes 93 (60.8%) 61 (43.9%) 0.004
      Article No 60 (39.2%) 78 (56.1%)

      8eea62084ca7e541d918e823422bd82e Conclusion

      Studies funded by pharmaceutical industry had stronger evidence, tested more innovative therapies, and were more accessible to the readers compared with studies developed with other sources of funding. These findings may alert oncology cooperative groups to the need of more studies with more evidence strength.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA04.02 - Demographic, Psychosocial, and Behavioral Associations with Cancer Screening Among a Homeless Population (Now Available) (ID 11252)

      10:40 - 10:50  |  Presenting Author(s): Lovoria B Williams  |  Author(s): Stephen W Looney, Thomas Joshua, Amber McCall, Martha S Tingen

      • Abstract
      • Presentation
      • Slides

      Background

      Although cancer incidence and mortality is declining, cancer remains among the leading causes of death worldwide. Research shows that cancer morbidity and mortality can be reduced by early detection. Yet, both cancer risks and screening behavior remain understudied in the United States homeless population. Lung cancer is the deadliest of cancers. Given the recent lung cancer screening guideline, it is especially important to assess population-based awareness of the screening recommendation among the homeless population, a population known to have higher cancer risk behaviors and lower cancer screening rates.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Researchers conducted a cross-sectional survey of homeless individuals (n =201) who attended a 1-day community event. Eligible study participants were English-speaking adults, aged 21 and above. Willing participants completed a 1-page 33 item paper survey. The analysis describes the demographic, psychosocial, and behavioral associations with cancer screenings and knowledge of the lung cancer screening recommendation.

      4c3880bb027f159e801041b1021e88e8 Result

      Participants’ mean age was 51.7 years (SD 13.6); the group was largely African American (77.3%) and male (67.9%). Despite higher cancer risk behaviors, knowledge of lung cancer screening and general participation rates for cancer screenings were below national benchmarks. Among women, the breast and cervical cancer screening rates were 46.5% and 85.1%. Among men, the prostate cancer screening rate was 34.2%. Among all participants, the colon cancer-screening rate was 44%. Cancer risk behaviors were higher than national rates and lung cancer screening knowledge was low (23.0%). Some cancer screening behaviors were associated with age, income, health status, obesity, tobacco use, and physical activity level.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The associations of screening with modifiable risk factors such as smoking, physical activity and obesity suggests that relevant behavior change interventions are necessary among this high-risk population. Given the barriers to screening of poverty-stricken individuals, such as lack of transportation and access, nurses must not only educate patients on lung cancer screening, they must assist with identifying payment resources and care navigation. Moreover, nurses must be educated on the ambiguity and inconsistency among evidenced-based screening guidelines and be prepared to engage patients in shared decision-making that weighs the recommendations with the patient’s individual cancer risks. To improve cancer survival among disparate populations, sustained community outreach is necessary to increase awareness of screening recommendations, identify high-risk individuals, and navigate them to resources. It is imperative that resources are provided to support relevant behavior change interventions, such as tobacco cessation in this high-risk population.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA04.03 - The Role of Comprehensive Genomic Profiling in the Community Setting  (Now Available) (ID 13559)

      10:50 - 11:00  |  Presenting Author(s): Kimberly Ann Rohan

      • Abstract
      • Presentation
      • Slides

      Background

      Comprehensive Genomic Profiling (CGP) is biomarker information to helo match patients to approved targeted therapies, immunotherapies, and clinical trials. This information can assist practitioners in caring for patients with solid tumors in decision making. Nurses play a key role in educating paitnets on how the testing is done, what information it will provide and how that information will be used in clinical practice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective analysis was done on the results of Comprehensive Genomic Profiling (Foundation One) on paitents that were tested in our practice from 2014-2017. The Edward Cancer Center is a community hospital based cancer center in the western suburbs of Chicago. The practice has 7 oncologists and 4 Advanced Practice Nurses. The practice saw approximately 650 new cases of cancer last year. It is rare that a patient presents with Comprehensive Genomic Profining (CGP). Our center ordered CGP on 46 patients with a cancer diagnosis after discussion with their primary oncologist. Each case was reviewed for number of genomic alterations identified, treatment associated with potential for clinical trial benefit, therapies associated with lack of response and the clinical decisions that were made based on the findings.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 46 charts reviewed: 263 genomic alterations were identified, 172 therapies were associated with potential clinical benefit and 11 therapies associated with lack of response. Of these patients, 6 (13%) were referred to clinical trial and 12 (26%) resulted in change in therapy. Of the lung cancer patients, 2 (6%) were referred to clinical trial and 11 (34%) resulted in change in therapy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Comprehesive Genomic Profiling is a useful tool in identifying patients in the community setting for clinical trial enrollement. 6-13% exceeds the national clinical trial enrollment. The results also assist in directing patient care and in directing change of therapy to more targeted therapies or continuation of current therapy. There were 4 (8.5%) patients that opted to stop care and enroll in hospice care based on the CGP lresults.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA04.04 - Discussant - OA 04.01, OA 04.02, OA 04.03 (Now Available) (ID 14552)

      11:00 - 11:15  |  Presenting Author(s): Jhanelle Elaine Gray

      • Abstract
      • Presentation
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      Abstract not provided

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      OA04.05 - An Early Rehabilitation Intervention for Enhancing Oxygenation From Lung Cancer Surgery (Now Available) (ID 11990)

      11:15 - 11:25  |  Presenting Author(s): Wei Ling Hsiao

      • Abstract
      • Presentation
      • Slides

      Background

      The purpose of this study is to test the effects of an early rehabilitation intervention on oxygenation, postoperative complications, and recovery from lung cancer surgery.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The study uses an experimental design. Ninety patients scheduled for lung cancer surgeries was recruited from thoracic surgery units of a medical center in Taiwan. Patients were randomly assigned to the intervention or the control group. The intervention includes a 5-day postoperative in-hospital rehabilitation from post op day 1. The main components of the rehabilitation were aerobic and strength exercises as well as breathing training by using an incentive spirometry. Peripheral capillary oxygen saturation (SpO2) was measured in the morning of the preoperative day and of the 4 consecutive days from postoperative day one to four by using the Nellcor™ OxiMax N-65 Portable Pulse Oximeter. The SpO2/FiO2 (S/F) ratio was then calculated to assess patients’ oxygenation. Data on postoperative pulmonary compilations and durations of chest tube drainage were collected from the patients’ charts.

      4c3880bb027f159e801041b1021e88e8 Result

      The patients’ demographics and baseline measures were equivalent between groups. Results of GEE showed a significant group by time interaction effect on S/F ratio. As for the parameter estimates, from postoperative day 1 to day 4, the S/F ratio improvement in the intervention group was 74.49 (Wald X2 = 46.42, p<0.001) more than in the control group. Result of Chi-square test showed that the number of postoperative lung complications in the intervention group (n =1) was significantly less (X2 = 8.39, p = 0.004) than it in the control group (n =10). Result of t- test showed that the duration of chest tube drainage in the intervention group (2.00±1.00 days) was significantly shorter (t =-2.32, p = 0.022) than it in the control group (2.56±1.25 days).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The study results support the effects of the early rehabilitation intervention on enhancing oxygenation, preventing complications, and promoting recovery from lung cancer surgery as indicated by shortened the duration of chest tube drainage. Surgery to remove the cancer is one of the primary treatment options for non-small cell lung cancer. However, lung cancer surgery may result in decreasing lung capacity and expansion; therefore, increase risks for postoperative pulmonary complications. Pulmonary rehabilitation designed to enhance lung expansion and ventilation may help to reduce postoperative lung complications and promote patients’ recovery from lung cancer surgery.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA04.06 - Perceptions of Non-Participation in a Rehabilitation Intervention After Surgery for Non-Small Cell Lung Cancer (Now Available) (ID 12058)

      11:25 - 11:35  |  Presenting Author(s): Mai Nanna Schoenau  |  Author(s): Malene Missel

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with non-small lung cancer (NSCLC) are difficult to engage in clinical trials. Few studies have examined in-depth why these patients refuse to participate. In a Danish randomized clinical trial; ’Postoperative rehabilitation in operable lung cancer patients (PROLUCA)’ only 32% of eligible participants consented to participate in the trial. The purpose of this qualitative study was therefore to explore perceptions, considerations and barriers of non-participation in PROLUCA.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This study was inspired by Reflective Life Research as developed by Dahlberg et al. as a descriptive and interpretive phenomenological research approach. Participants are patients who declined to participate in PROLUCA (non-participants). They were purposefully sampled and recruited from the group of patients who were found to be eligible for the exercise intervention but who declined to participate. Data were collected though telephone interviews. Openness, curiosity and sensitivity played an important role in carrying out the interviews. Analysis was performed according to Reflective Life Research.

      4c3880bb027f159e801041b1021e88e8 Result

      Fifteen non-participants consented to participate in qualitative interviews. Nine men and six women with a mean age of 68 years (range 48-84) were included. Mean time since surgery was 21 month (range 12-28). Five patients were working and ten were retired, eleven patients lived with a partner.

      The analysis revealed three essential themes referred to the patients’ experiences of being ‘Between healthy life and good life’, ‘Under the influence of society’ and their experiences of ‘Health and rehabilitation as a personal responsibility’. Perceptions of non-participation in rehabilitation after surgery for lung cancer are moderated between freedom and necessity. Patients experience ambivalence between a wish to participate in rehabilitation and not having the energy to participate. Patients refused to participate due to daily life priorities and lack of motivation which furthermore is related to social and interpersonal relationships. The patients exercise history is also essential in declining participation. Additionally the patients are under influence of norms and health perceptions from the society.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients’ perception of "the good life" was fundamental for accepting or declining participation in a rehabilitation intervention study. Consideration and barriers of non-participation was influenced by norms from the society, motivation, priorities, exercise history, social and interpersonal relations.

      This study has contributed with a sensitive awareness of why patients following lung cancer surgery might refuse participating in rehabilitation. This knowledge can be taken into consideration in the planning of future clinical trials with lung cancer patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA04.07 - Early Initiated Postoperative Rehabilitation Reduces Fatigue in Patients with Operable Lung Cancer: A Randomized Trial (Now Available) (ID 13733)

      11:35 - 11:45  |  Presenting Author(s): Morten Quist  |  Author(s): Maja Schick Sommer, Jette Vibe-Petersen, Maja Stærkind Bohlbro, Seppo W Langer, Klaus Richter Larsen, Karen Trier, Merete Christensen, Paul Frost Clementsen, Malene Missel, Carsten Henriksen, Kristina Poulsen, Henning Langberg, Jesper Holst Pedersen

      • Abstract
      • Presentation
      • Slides

      Background

      Surgical tolerability and perioperative risk of complications are correlated with high age, smoking history, comorbidities, low cardiorespiratory fitness (VO2peak) and low functional capacity, which paradoxically are characteristics describing the average patient with lung cancer. Little is known about the optimal amount and timing of exercise strain in concern of the operation wound and with regard improvement of physical function and quality of life (QOL). On this background, we decided to investigate the effect of early vs. late initiated postoperative rehabilitation in patients with operable lung cancer on exercise capacity, functional capacity, muscle strength, and QOL.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The study was designed as a two-armed randomized controlled trial with randomization to either early initiated postoperative rehabilitation (14 days after surgery (ERG)) or a control arm with late initiated postoperative rehabilitation (14 weeks after surgery (LRG)). The primary endpoint was a change in maximum oxygen consumption (VO2peak) from baseline to post intervention 26 weeks following lung resection. Fatigue was measured with EORTC QLQ C30 LC13.

      4c3880bb027f159e801041b1021e88e8 Result

      From April 2013 to June 2016, 582 patients with operable NSCLC were screened for eligibility. With 119 patients randomized in the early rehabilitation group (ERG) (68 females, 51 males; median age 65), and 116 randomized to late rehabilitation group (LRG) (62 females, 54 males; median age 65) the recruitment rate was 52.6%. There was a non-significant decrease in VO2peak in both ERG and LRG from baseline to 26 weeks and no significant difference between ERG and LRG (p=0.9269). There was a significant decrease from baseline to 14 weeks in both ERG (p=0.027) and LRG (p<0.001) and a significant difference between groups (p=0.0018). There was a non-significant increase from 14 weeks to 26 weeks in ERG (p=0.464) and a significant increase from 14 weeks to 26 weeks in LRG (p<0.001) and a significant difference between the two groups (p=0.0003). We found no significant differences in QOL but we found a significant difference between ERG and LRG from baseline to 14 weeks in fatigue level in favour of ERG.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the first randomized controlled trial to investigate the effects of early vs. late initiated postoperative rehabilitation in patients with lung cancer. There is no difference in the commencement (early vs. late) of a postoperative exercise program for patients with lung cancer on exercise capacity. But to reduce fatigue patients should be recommended to initiate early exercise programs.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA04.08 - Discussant - OA 04.05, OA 04.06, OA 04.07 (Now Available) (ID 14553)

      11:45 - 12:00  |  Presenting Author(s): Pippa Labuc

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    PC01 - Controversies in Mesothelioma (ID 840)

    • Type: Pro-Con Session
    • Track: Mesothelioma
    • Presentations: 6
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 AC
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    ES01 - Advances in Lung Cancer Screening Through Imaging (ID 769)

    • Type: Educational Session
    • Track: Screening and Early Detection
    • Presentations: 3
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 F
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      ES01.01 - Image Quality Characteristics and Nodule Growth Measurement, Medical Physics and Machine Parameters (ID 11351)

      13:30 - 13:50  |  Presenting Author(s): Ricardo S Avila

      • Abstract

      Abstract not provided

    • +

      ES01.02 - Image Interpretation and Advances from the Perspective of the Radiologist (Now Available) (ID 11352)

      13:50 - 14:10  |  Presenting Author(s): David F Yankelevitz

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES01.03 - Deep Machine Learning for Screening LDCT (Now Available) (ID 11353)

      14:10 - 14:30  |  Presenting Author(s): Bram Van Ginneken

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES01.04 - Multi-Phasic Screening - Can We Address Competing Causes of Morbidity * Mortality Such as Coronary Artery Disease and COPD (Now Available) (ID 11355)

      14:30 - 14:50  |  Presenting Author(s): Rozemarijn Vliegenthart

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA04 - Novel Approaches with IO (ID 900)

    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 11
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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      MA04.01 - Cemiplimab, a Human Monoclonal Anti-PD-1, Alone or in Combination with Radiotherapy: Phase 1 NSCLC Expansion Cohorts (ID 13177)

      13:30 - 13:35  |  Presenting Author(s): Victor Moreno  |  Author(s): Marta Gil-Martin, Melissa L. Johnson, Raid Aljumaily, Maria Pilar Lopez-Criado, Donald W Northfelt, Marka Crittenden, Salma Jabbour, Lee Rosen, Emiliano Calvo, Kyriakos P Papadopoulos, Pilar Garrido, Asuncion Hervás Morón, Petra Rietschel, Kosalai Mohan, Jingjin Li, Elizabeth Stankevich, Minjie Feng, Israel Lowy, Matthew Fury

      • Abstract

      Background

      Cemiplimab (REGN2810), a human monoclonal anti-PD-1, has exhibited substantial antitumor activities in patients with advanced malignancies in a first-in-human study. We report interim results of the Phase 1 expansion cohorts (ECs 1 and 2) of cemiplimab, alone or plus radiotherapy, in advanced NSCLC (NCT02383212).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with advanced NSCLC who had relapsed after, or were refractory to, at least, first-line therapy received cemiplimab 200 mg Q2W in EC 1, or cemiplimab 3 mg/kg Q2W plus radiotherapy (9 Gy × 3 times/week 1 week after first dose of cemiplimab) to a single lesion in EC 2. For EC 2, patients were required to have NSCLC for which palliative radiation therapy was indicated. Planned treatment duration was up to 48 weeks in both ECs. The co-primary objectives were to evaluate the safety, tolerability, and efficacy of cemiplimab, alone or plus radiotherapy. Tumor measurements (of non-irradiated lesions) were performed by RECIST 1.1 Q8W.

      4c3880bb027f159e801041b1021e88e8 Result

      As of Sept 1, 2017, 20 patients (13 M/ 7 F; median age 64.0 years [range, 50–82]) and 33 patients (22 M/ 11 F; median age 67.0 years [range, 47–82]) were enrolled in EC 1 and EC 2, respectively. ECOG performance status 1 versus 0 was 80.0% versus 20.0% and 66.7% versus 30.3%, respectively, for ECs 1 and 2, and missing in one in EC 2; 75.0% (EC 1) and 48.5% (EC 2) had received prior radiotherapy. Investigator-assessed overall response rate (ORR; complete response [CR] + partial response [PR]) was 40.0% (1 CR and 7 PRs) and 18.2% (6 PRs) in EC 1 and EC 2, respectively. Disease control rate (ORR + stable disease [SD]) was 60.0% (1 CR + 7 PRs + 4 SDs) and 72.7% (6 PRs + 18 SDs) in EC 1 and EC 2, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade were arthralgia, asthenia, cough, and dyspnea (each 20.0%) in EC 1, and decreased appetite (30.3%), fatigue (27.3%), cough (24.2%), asthenia and back pain (each 21.2%) in EC 2. Grade ≥3 TEAEs occurring in ≥2 patients were pneumonia (10.0%) in EC 1; and anemia (12.1%), hypophosphatemia and urinary tract infection (each 6.1%) in EC 2. One patient in EC 2 experienced TEAE of pneumonitis with an outcome of death, considered related to study drug.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Cemiplimab monotherapy demonstrated substantial antitumor activity in pretreated NSCLC patients. The safety profiles were comparable with other anti-PD-1 agents and radiotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA04.02 - Responses and Durability in NSCLC Treated With Pegilodecakin and Anti-PD-1 (Now Available) (ID 13986)

      13:35 - 13:40  |  Presenting Author(s): Edward B Garon  |  Author(s): Deborah J. Wong, Jeffrey G. Schneider, Raid Aljumaily, W. Michael Korn, Jeffrey R. Infante, Manish Patel, Karen A. Autio, Kyriakos P Papadopoulos, Aung Naing, Nashat Y. Gabrail, Pamela N. Munster, Jonathan W. Goldman, Annie Hung, Peter Van Vlasselaer, Joseph Leveque, Martin Oft, David R. Spigel

      • Abstract
      • Presentation
      • Slides

      Background

      Responses in NSCLC to agents targeting the PD-1/PD-L1 axis are correlated with PD-L1 expression by immunohistochemistry (IHC), tumor mutational burden (TMB), interferon-associated mRNA expression profile (GEP), and the absence of liver metastases. Anti-PD-1 impedes the inhibition of T cells while pegilodecakin (AM0010) stimulates the survival and expansion of intratumoral, antigen-activated CD8+ T cells (Mumm et al, 2010). This provides a rationale for combining anti-PD-1 agents with pegilodecakin.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Pretreated NSCLC subjects (N = 34) received pegilodecakin (10-20 µg/kg QD, SC) with pembrolizumab (2 mg/kg, Q3W, IV; n = 5) or nivolumab (3 mg/kg, Q2W, IV; n = 29). Median follow-up is 31.2 months (range, 28.3-33+ months) and 17.5 months (range, 8.3- 25.9+ months), respectively. Responses were assessed by irRC. Twenty subjects had sufficient tissue for PD-L1 testing with the 22C3 IHC assay (CLIA) and 10 subjects had sufficient tissue for TMB evaluation by whole exome sequencing (WES) and pretreatment GEP by NanoString.

      4c3880bb027f159e801041b1021e88e8 Result

      In 26 subjects evaluable for response, the ORR was 41% (11 PRs). Another 12 subjects (46%) had SD as best response. As investigators were asked to preferentially enroll PD-L1–negative patients, PD-L1 expression was <1% in 12 of 20 PD-L1–evaluable subjects with 4 achieving a PR. Ten subjects had sufficient tissue for TMB and GEP, including 6 PRs. Five of the 8 who tested low to intermediate for TMB (<243 mut) had a PR as did 2 of 6 GEP-negative subjects. In addition, 5 of 8 subjects with liver metastasis had a PR. The mPFS and mOS of the 5 NSCLC subjects (4/4 tested PD-L1 <1%) treated with pegilodecakin + pembrolizumab was 10.9 and 32.2 months, respectively. The mPFS and mOS for the pegilodecakin + nivolumab cohort (8/16 tested PD-L1 <1%) has not been reached.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pegilodecakin, when added to anti-PD-1 therapy in advanced NSCLC patients, was associated with response rates and durability of benefit greater than has been seen with anti-PD-1 alone. Responses were seen in settings in which anti-PD-1 therapy has demonstrated limited benefit, such as absent PD-L1 expression, low TMB, and/or the presence of liver metastasis. These preliminary findings support further studies of pegilodecakin with anti-PD-1 therapies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      • Abstract
      • Presentation
      • Slides

      Background

      Prospective data on immunotherapy for NSCLC with oncogenic driver mutations are limited. We recently reported first results from the global IMMUNOTARGET registry (Mazières, ASCO 2018). Here, we present new data for PD-L1 and mutation subgroups.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In 2017, we started an international retrospective registry study ("IMMUNOTARGET") for patients with advanced NSCLC, known driver mutations (KRAS, EGFR, ALK, ROS1, BRAF, HER2, MET and RET) and PD-L1 immune checkpoint inhibitor therapy. The registry is approved by University of Toulouse and Swissethics, and funded by University of Toulouse and Cantonal Hospital of Lucerne. Anonymized real-world data submitted to the coordinating center include: patient and tumor characteristics, mutation test methods and results, systemic therapy lines, immune related adverse events, best response by RECIST, survival, and tumor PD-L1 expression (optional). Statistical calculations including best response, median PFS and OS are done at University of Toulouse.

      4c3880bb027f159e801041b1021e88e8 Result

      In April 2018, the registry included 551 pts from Europe, USA, Israel and Australia. Patients were 50% male/female, 28% current smokers, median age 60 years (range 28-83), 85% had PS0/1. Most (73%) tumors were stage IV at diagnosis, almost all (96%) were adenocarcinomas. Molecular classification by dominant driver mutation: KRAS=271 (49%), EGFR=125 (23%), BRAF=43 (8%), MET=36 (7%), HER2=29 (5%), ALK=23 (4%), RET=16 (3%), ROS1=7 (1%), 1 (0.2%) not classified (ALK+RET+MET). Most pts received nivolumab (466) or pembrolizumab (48) and were treated with immunotherapy in second or third line (67%). The median number of cycles was 5 (range 1-68). Fifty (11%) pts had grade 3-5 toxicity. Median OS from start of immunotherapy was 13.3 months, median PFS was 2.8 months. Best response was PR/CR in: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, ALK=0%. Percentage of PD-L1 positive cells was available for 177 pts: 0%=71 (40%), 1-49%=46 (26%), 50-100%=60 (34%). Median % of positive cells was highest for ROS1 (90%), BRAF (50%), MET (30%) and RET (26%) mutant tumors. PD-L1 positivity was predictive for improved PFS in KRAS and EGFR mutant tumors. PD-L1 status was known in 18 tumors with ALK, ROS1 or RET rearrangements: 5 had 0%, 4 had 1-49% and 9 had 50%-100%. No tumor remissions were observed in this subgroup. The registry remains open, updated results will be presented at the conference.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although response rates were lower than in KRAS mutant NSCLC, individual tumors with other driver mutations responded to immunotherapy. PD-L1 expression may not accurately predict clinical benefit from immunotherapy in some molecular subgroups, better markers are needed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA04.04 - Discussant - MA 04.01, MA 04.02, MA 04.03 (Now Available) (ID 14585)

      13:45 - 14:00  |  Presenting Author(s): Jose Pacheco

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA04.05 - Outcomes in NSCLC Patients Treated with First-Line Pembrolizumab and a PD-L1 TPS of 50-74% vs 75-100% or 50-89% vs 90-100% (Now Available) (ID 14358)

      14:00 - 14:05  |  Presenting Author(s): Mark M. Awad  |  Author(s): Elizabeth Jimenez Alguilar, Justin F Gainor, Sasha Kravets, Sara Khosrowjerdi, Christine A Lydon, Anika Adeni, Safiya Subegdjo, Hira Rizvi, Matthew D. Hellmann

      • Abstract
      • Presentation
      • Slides

      Background

      Among patients with NSCLC and a PD-L1 tumor proportion score (TPS) ≥50%, the response rate to the PD-1 inhibitor pembrolizumab is ~45%. Whether certain subsets of patients with a PD-L1 TPS ≥50% are more likely to benefit from treatment with a PD-1 inhibitor is currently unknown. We compared outcomes among NSCLC patients treated with first-line pembrolizumab and different PD-L1 TPS groupings: 50-74% vs 75-100% or 50-89% vs 90-100%.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed patients who received commercial pembrolizumab as first-line treatment for NSCLC with a PD-L1 TPS of ≥50% from the Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, and Massachusetts General Hospital. Clinicopathologic characteristics and clinical outcomes were compared among patients with a PD-L1 TPS of 50-74% vs 75-100% or 50-89% vs 90-100%. Event-time distributions were estimated using Kaplan-Meier and compared with the log-rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      172 patients were identified for inclusion in this study. In the entire cohort, the overall response rate (ORR) to pembrolizumab was 33.9%, median progression-free survival (mPFS) was 4.8 months, and median overall survival (mOS) was 20.6 months. Compared to patients with TPS 50-74% (N=68, 39.5%), patients with TPS 75-100% (N=104, 60.5%) had a significantly higher ORR (45.2% vs 20.6%, P=0.001), a significantly longer mPFS (5.3 vs 2.5 mo, HR=0.61 [95% CI: 0.41-0.90], P=0.008), and a trend towards improved mOS (33.6 vs 20.6 mo, HR=0.60 [95% CI: 0.34-1.04], P=0.056). Compared to patients with TPS 50-89% (N=99, 57.6%), patients with TPS 90-100% (N=73, 42.4%) had a significantly higher ORR (50.7% vs 24.2%, P<0.001), a significantly longer mPFS (6.4 vs 2.8 mo, HR=0.52 [95% CI: 0.36-0.76], P<0.001), and a significantly longer mOS (33.6 vs 18.0 mo, HR=0.46 [95% CI: 0.27-0.79], P=0.008). There were no significant differences in smoking history, histology, sex, and age between patients in each TPS cutoff group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Among NSCLCs with a PD-L1 TPS ≥50% treated with first-line pembrolizumab, higher PD-L1 TPS levels above 75% and 90% are associated with improved clinical outcomes compared to NSCLCs with lower PD-L1 levels.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA04.06 - PD-1 Blockade Promotes Hyperprogressive Disease in NSCLC Through Macrophages Activation via Antibody-Fc/FcR Interaction (Now Available) (ID 12334)

      14:05 - 14:10  |  Presenting Author(s): Gabriella Sozzi  |  Author(s): Michele Sommariva, Massimo Moro, Claudia Proto, Diego Signorelli, Monica Ganzinelli, Sabina Sangaletti, Mattia Boeri, Giuseppe Lo Russo, Simona Ferro, Elena Tassi, Veronica Huber, Lucia Sfondrini, Massimo Milione, Claudio Tripodo, Mario Colombo, Andrea Anichini, Andrea Balsari, Licia Rivoltini, Marina Chiara Garassino

      • Abstract
      • Presentation
      • Slides

      Background

      In a subset of patients, named hyperprogressors (HPs), immunotherapy seems to paradoxically boost tumor growth. However, neither pathological and clinical features nor the underlying biological mechanism have been identified. We dissected the role of tumor-myeloid cells crosstalk as possible players.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      HPs were defined on the basis of clinical and radiological features. Baseline histological samples from patients treated with immune checkpoints inhibitors (ICI) were evaluated by immunohistochemistry for myeloid and lymphoid markers. We tested the effect on tumor growth of murine and human ICI in T-cell deficient mice injected with human lung cancer cell lines and PDXs bearing different genotypes (EGFR+, KRAS+, STK11+ and wt). Innate immune microenvironment was evaluated by FACS analysis and immunohistochemistry. In vitro studies of ICI binding functional modulation were performed in human myeloid cells from patients and healthy donors.

      4c3880bb027f159e801041b1021e88e8 Result

      In a clinical series of 187 patients treated with ICI, hyperprogression was observed in 40 (26.3%) cases. All available HP pre-treatment tissue samples (11 cases) showed CD163+CD33+PD-L1+Arginase-A1+ clustered epithelioid macrophages infiltrating the tumor foci also expressing FcRs including CD32b. No differences in T cell compartment were observed. Murine and human PD1 blocking mAbs induced a boost of tumor growth in H460 xenografs in imunocompromised mice. A similar effect was observed in EGFR+ but not in KRAS+ and wt PDXs treated with human anti-PD1. Notably, no hyperprogression was observed after treatment with murine and human anti PD-1 F(ab)2. Hyperprogressive tumors were enriched in arginase+ myeloid-macrophage cells and fibrotic features. ICI bind in vitro to human macrophages and monocytes via Fc/FcR interactions, likely involving CD32b (FcgRIIb) and triggering functional polarization.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results provide evidence that FcR triggering on macrophages by ICI delivers a signaling cascade promoting a functional reprogramming of these cells toward a more aggressive pro-tumorigenic behavior eventually inducing hyperprogression in a subset of patients with distinctive immune and genetic profile. A validation prospective study in ongoing.

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      MA04.07 - MicroRNA-Based Liquid Biopsy Combines with PD-L1 Tumor Expression to Predict Response to Immunotherapy in Advance NSCLC Patients (Now Available) (ID 12566)

      14:10 - 14:15  |  Presenting Author(s): Mattia Boeri  |  Author(s): Massimo Milione, Diego Signorelli, Claudia Proto, Giuseppe Lo Russo, Carlotta Galeone, Giovanni Centonze, Ugo Pastorino, Marina Chiara Garassino, Gabriella Sozzi

      • Abstract
      • Presentation
      • Slides

      Background

      The advent of the new immune checkpoint inhibitors (ICIs) targeting the PD-1/L1 axis drastically improves survival of advance non-small-cell lung cancer (NSCLC) patients. However, only a limited subset of patients actually benefits of ICIs treatment and PD-L1 as predictive biomarker has a limited efficacy. We have previously identified a plasma microRNA-signature classifier (MSC) reflecting a circulating tumor-host interaction with diagnostic and prognostic value in low-dose computed tomography (LDCT) lung cancer screening trials.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The tumor immune contexture of 40 LDCT-screening detected lung tumors was characterized by the “cell-type identification by estimating relative subsets of RNA transcripts” (CIBERSORT) software. In a consecutive series of 84 advanced lung cancer patients treated with ICIs, both plasma and tissue samples were collected and prospectively analyzed. Both 2-years progression free (PFS) and overall survival (OS) in strata of plasma MSC risk level alone or combined with tumor PD-L1 expression were evaluated in univariate and multivariate analysis by log-rank test and Cox proportional hazards models.

      4c3880bb027f159e801041b1021e88e8 Result

      A pro-tumorigenic immune contexture was identified in tumors of MSC high risk patients. Lower levels of cytotoxic CD8+ and CD4+ T cells and increased levels of Tregs, γδ T Cells, M2 macrophages characterized these tumors. In addition, genes differentially expressed according to MSC risk level (high vs. intermediate and low) were associated with 5-years OS in the screening series (p-values=0.02), as well as in additional 1000 cases from The Cancer Genome Atlas database (p-values<0.01). In the 84 advanced NSCLC patients treated with ICIs, the PFS hazard ratio ranged from 0.44 (95%CI: 0.25-0.75) of PD-L1 (adjusted p-value=0.005) and 0.38 (95%CI:0.2-0.73) of MSC (adjusted p-value=0.004) alone, to 0.25 (95%CI: 0.14-0.45) if combined (adjusted p-value<0.0001). In the subgroup of 45 patients with both plasma and tumor tissue available, the combination of MSC and PD-L1 stratified patients in three groups with 2-years PFS ranging from 25%to 10% and 0% (p-value=0.01) according to the presence of 2, 1 or 0 favorable markers, respectively. Similar results were obtained when considering OS, where the median survival time for patients with no favorable markers was 5.6 months (p-value<0.0001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Overall, these findings suggest that a circulating microRNA-based risk level, reflecting an altered tumor immune contexture, could implement PD-L1 tumor tissue expression as predictive biomarkers of response to immunotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA04.08 - Discussant - MA 04.05, MA 04.06, MA 04.07 (Now Available) (ID 14589)

      14:15 - 14:30  |  Presenting Author(s): Patrick M Forde

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA04.09 - Neoadjuvant Atezolizumab in Resectable Non-Small Cell Lung Cancer (NSCLC): Updated Results from a Multicenter Study (LCMC3) (Now Available) (ID 12941)

      14:30 - 14:35  |  Presenting Author(s): Valerie W Rusch  |  Author(s): Jamie E Chaft, Bruce E Johnson, Ignacio I. Wistuba, Mark G Kris, Jay M Lee, Paul A. Bunn, Jr., David J Kwiatkowski, Karen L. Reckamp, David J. Finley, Eric B. Haura, Saiama N. Waqar, Robert C. Doebele, Edward B Garon, Justin Blasberg, Alan Nicholas, Katja Schulze, See Phan, Mayank Gandhi, David P Carbone

      • Abstract
      • Presentation
      • Slides

      Background

      Cisplatin-based chemotherapy, before or after surgery, provides only a 5% benefit in 5yr. OS in resectable NSCLC. A 20 patient study (NEJM April 2018) showed that preoperative immune checkpoint inhibitor therapy yielded a clinically meaningful major pathologic response rate (MPR ≤10% residual viable tumor cells) and did not delay or complicate surgery. This large multicenter trial measures MPR and biomarkers of benefit using neoadjuvant atezolizumab (atezo) [NCT02927301].

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We planned 2 cycles of atezo (1200mg, days 1, 22) in patients with stages IB -selected IIIB resectable NSCLC prior to surgical resection (day 40 +/- 10). Chest CT, PET were planned pre-atezo and presurgery to assess response. Primary tumor +/- node biopsies and blood samples were obtained before atezo and presurgery for biomarker studies. The primary endpoint was MPR. Secondary endpoints included safety, response by PD-L1, OS, and DFS.

      4c3880bb027f159e801041b1021e88e8 Result

      For this updated efficacy and safety analysis (Feb’18 datacut), we report first 54 of 180 planned pts: 29 males, median age 65 yr, all ECOG 0-1; 17 current, 33 former smokers; 35 non-squamous NSCLC; clinical stages Ib/IIa/IIb/IIIa/IIIb = 5/11/13/20/5. Two pts received one dose of atezo due to treatment related AE (Gr 1 pyrexia, Gr 2 dyspnea) but underwent uncomplicated resection with MPR assessment. There was 1 unrelated Gr 5 AE (sudden cardiac death post surgical resection), 16 Gr 3-4 AEs (3 treatment related). Surgery was delayed in 1 pt due to Gr3 pneumonitis. By RECIST, 3 pts had PR, and 49 had SD. 50 pts underwent surgery and 47 pts had MPR assessment: 2 pts discontinued study preop due to radiographic PD and 2 discontinued due to other reasons; 3 pts had unresectable disease. MPR rate was 10/50 (20%, 95% CI 10-34%) including 3 pts who had pCR (no viable tumor cells) in the primary tumor. Excluding 5 pts who had known driver mutations (4 EGFR+, 1 ALK+), MPR rate was 10/45 (22%, 95% CI 11-37%). PD-L1 status was evaluable in 44/54 pts; 8/10 pts with MPR had PD-L1+ status and 2 had unknown PD-L1 status; 8/28 PDL-1 (+) patients had MPR (29%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In a multicenter study, neoadjuvant atezo was well tolerated. MPR rate is encouraging. Clinical and pathological responses are often discordant. Correlative analyses on pre- and post atezo tissues are ongoing. Preliminary correlative analyses in blood samples are included in a separate abstract.

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      MA04.10 - Comprehensive Peripheral Blood Immunophenotyping and T-Cell Clonal Analysis During Neoadjuvant Immunotherapy with Atezolizumab in NSCLC (Now Available) (ID 13118)

      14:35 - 14:40  |  Presenting Author(s): Filiz Oezkan  |  Author(s): Kai He, Dwight Hall Owen, Maciej Pietrzak, Rhonda Kitzler, Rebecca Pearson, Alan Nicholas, Paul A. Bunn, Jr., Mark G Kris, David J. Kwiatkowski, Bruce E Johnson, Fred R. Hirsch, Ignacio I. Wistuba, Valerie W Rusch, Jay M. Lee, Mayank Gandhi, Katja Schulze, David S. Shames, Gerard Lozanski, David P Carbone

      • Abstract
      • Presentation
      • Slides

      Background

      Immune-checkpoint blockade targeting PD-L1/PD-1 to activate anti-tumor immunity is associated with improved response rates and survival compared to chemotherapy in selected metastatic NSCLC patients. Evaluation of the pre-therapeutic immune profile and its treatment-related evolution associated with clinical benefit will guide future immunotherapy development and support clinical decision-making. Here, we present an analysis of peripheral blood (PB) immunophenotyping and T-cell-receptor (TCR) clonality before and after immunotherapy from an ongoing 180-patient phase II study of atezolizumab as neoadjuvant therapy with stage IB-IIIB resectable NSCLC (NCT02927301; LCMC3).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      As of February 5th datacut, the first 54 enrolled and dosed patients are presented. The biomarker evaluable population (BEP) further subset to patients with paired PB samples analyzed within 72 hours after collection and a major pathological response (MPR) assessment. Comprehensive immune cell phenotyping (10-color flow cytometry, IMMUNOME) and TCR-Vß-analysis by flow cytometry were performed. Immunoprofile analyses were correlated with atezolizumab treatment, pathological response and PD-L1 expression.

      4c3880bb027f159e801041b1021e88e8 Result

      In this ongoing analysis, BEP included 31 patients. 5 patients (16%, 95% CI (5%, 34%)) had a MPR; all of which stained positive for PD-L1 by IHC using 22C3 (TPS≥1%) and SP142 (PD-L1 expression on ≥1% tumor cells (TC) and/or tumor infiltrating immune cells (IC)) at baseline. We observed significant increases in natural killer (NK) cells (p=0.005) and CD8+ T-cells (p=0.031) and a Th1-response related dendritic cell (DC) subpopulation (p=0.031) and significant decreases in B-cells (p=0.015) after treatment.

      Patients who achieved MPR show lower baseline levels of degranulated CD8+ T-cells (p=0.015), late-activated NK-cells (p=0.043), memory CD4+ (p=0.048) and memory CD8+ T-cells (p=0.032); changes in PB NK-cells (p=0.041), a decrease in M-MDSCs and a Th-2 and Th-17-response related DC subpopulation (p=0.043) in response to treatment were noted in patients with MPR versus non-MPR.

      Among the 16 patients with TC/IC 1/2/3 (> 1% PD-L1 expression) the following significant differences were observed compared to TC0/IC0 (7 patients): higher levels of late-activated CD4+ T-cells (p=0.025) and mid-activated CD8+ T-cells (p=0.044) at baseline, decrease of senescent T-cells (p=0.041), monocytic myeloid-suppressor cell subpopulations (M-MDSCs) and an increase in a Th1-response related DC subpopulation (p=0.026) after treatment.

      TCR clonality analysis showed expansions in Vß-subtypes after atezolizumab treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Immunophenotyping and TCR-Vß-repertoire analysis in peripheral blood samples from NSCLC patients treated with neoadjuvant atezolizumab show differences in immune cell subsets in baseline samples and changes after treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA04.11 - Neoantigen Targeting and T Cell Reshaping in Resectable NSCLC Patients Treated with Neoadjuvant PD-1 Blockade (Now Available) (ID 12605)

      14:40 - 14:45  |  Presenting Author(s): Kellie Nicole Smith  |  Author(s): Margueritta El Asmar, Jiajia Zhang, Justina X Caushi, Zhicheng Ji, Valsamo Anagnostou, Tricia R Cottrell, Hok Yee Chan, Prerna Suri, Haidan Guo, Kristen A. Marrone, Jarushka Naidoo, Taha Merghoub, Jamie E Chaft, Matthew D. Hellmann, Janis M Taube, Julie R. Brahmer, Patrick M Forde, Victor Velculescu, Drew M Pardoll, Hongkai Ji

      • Abstract
      • Presentation
      • Slides

      Background

      PD-1 blockade is now standard treatment for advanced non-small cell lung cancer (NSCLC) and has recently shown impressive efficacy in promoting major pathologic response (MPR) and delaying relapse in the neoadjuvant setting. The role of tumor mutational burden, and specifically T cells targeting neoantigens derived from these mutations, in facilitating tumor clearance has been demonstrated in advanced NSCLC. However, it is unknown how neoadjuvant PD-1 blockade impacts the frequency and function of tumor specific T cells and their ability to promote major pathologic response, or how these factors may synergize to prevent or delay relapse after surgical resection.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Whole exome sequencing and neoantigen prediction was performed on pre-treatment tumor biopsies and matched normal tissue from 11 patients with resectable NSCLC treated with neoadjuvant nivolumab as part of a clinical trial (NCT02259621). T cell recognition of peptides representing candidate neoantigens was evaluated using the MANAFEST assay, which identifies T cell receptor clonotypes corresponding to antigen specificities. T cell receptor sequencing was additionally performed on serial peripheral blood T cells, pre-treatment tumor biopsies, and resected post-treatment tissues. A bioinformatic platform was developed to evaluate the dynamics of intratumoral T cell clonotypes, and more specifically neoantigen-specific clonotypes detected before, during, and after treatment and during long-term follow-up.

      4c3880bb027f159e801041b1021e88e8 Result

      High-magnitude, polyclonal neoantigen-specific T cell responses were detected in the peripheral blood and persisted for many months after surgical resection and cessation of treatment. Binding to and stability with cognate HLA I molecules was validated for reactive neoantigens. Significant treatment-induced systemic perturbations in the tumor-specific T cell repertoire and an influx of peripheral T cell clonotypes into tumor tissue and lymph nodes was observed in patients regardless of pathologic response, whereas peripheral clonotypic reshaping of the anti-tumor repertoire and intratumoral T cell clonality were associated with MPR status.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We show significant and systemic alterations in the peripheral anti-tumor T cell repertoire in NSCLC patients treated with neoadjuvant anti-PD-1 regardless of MPR status. Notwithstanding, the impaired restructuring of the anti-tumor T cell repertoire in patients without MPR highlights a potential immunological deficiency to overcome in future therapeutic approaches aiming to increase the MPR rate in NSCLC patients treated with neoadjuvant PD-1 blockade.

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      MA04.12 - Discussant - MA 04.09, MA 04.10, MA 04.11 (Now Available) (ID 14588)

      14:45 - 15:00  |  Presenting Author(s): Alex Adjei

      • Abstract
      • Presentation
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      Abstract not provided

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    MA05 - Improving Outcomes in Locoregional NSCLC II (ID 901)

    • Type: Mini Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 105
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      MA05.01 - E6508: Phase II Study of Immunotherapy with Tecemotide and Bevacizumab after Chemoradiation in Unresectable Stage III NS-NSCLC (Now Available) (ID 13853)

      13:30 - 13:35  |  Presenting Author(s): Jyoti Patel  |  Author(s): Ju-Whei Lee, Henry Wagner Jr, David P Carbone, Anil Shanker, Leora Horn, Melissa L. Johnson, David E Gerber, Jane Jijun Liu, Millie S Das, Mohammad Ali Al-Nsour, Christopher S R Dakhil, Suresh S. Ramalingam, Joan Schiller

      • Abstract
      • Presentation
      • Slides

      Background

      Chemoradiation (CRT) is standard of care for unresectable stage III NSCLC. Tecemotide is a MUC1 antigen-specific cancer immunotherapy. Bevacizumab is considered to have a significant role in immune modulation. Immunotherapy in combination with VEGF blockade was tested in this phase II trial combining tecemotide and bevacizumab in patients with stage III NS- NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Subjects with stage III NS- NSCLC suitable for definitive CRT received carboplatin(C) AUC 2 + paclitaxel(P) 45 mg/m2 weekly + 66 Gy/33fx/6.5wk and consolidation C AUC 6 + P 225 mg/m2 q21 days x 2. Patients with CR/PR/SD were then registered onto Step 2 (S2). S2 was 6 weekly tecemotide injections followed by q6 weekly injections and bevacizumab 15 mg/kg q3 weeks for up to 34 doses. The primary endpoint was safety of tecemotide and bevacizumab after CRT and consolidation. The proportion of circulating dendritic cells and their expression of CD40, HLA-DR and CD123 (IL-3R) were analyzed by flow cytometry at various time points.

      4c3880bb027f159e801041b1021e88e8 Result

      70 patients were enrolled from Dec 2010 to Oct 2014; 68 started therapy, and 39 completed CRT and consolidation therapy. Reasons for discontinuation included progression (11) and toxicity (10). 33 patients were registered to S2. The median number of S2 cycles was 12 (range 2-34). S2 toxicity: gr 3 N=9 (6 hypertension), gr 4 N=1, gr 5 N=1. Among the treated and eligible patients (n=31), from study entry, the median PFS was 14.3 (95% CI 11.0-22.2), OS was 40.1 (95% CI 21.7-NA) months. A correlative trend of increased expression of CD40 and HLA-DR on CD11c+ cells was observed at cycle 7 (week 21) of S2.

      e6508.patel.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      This cooperative group trial met its endpoint, demonstrating tolerability of tecemotide and bevacizumab after CRT and consolidation in NS-NSCLC pts. In this select group of patients, therapy with tecemotide and bevacizumab was associated with encouraging PFS and OS.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.02 - PACIFIC Subgroup Analysis: Pneumonitis in Stage III, Unresectable NSCLC Patients Treated with Durvalumab vs. Placebo After CRT (Now Available) (ID 13876)

      13:35 - 13:40  |  Presenting Author(s): Johan F. Vansteenkiste  |  Author(s): Jarushka Naidoo, Corinne Faivre-Finn, Mustafa Özgüroğlu, Augusto Villegas, Davey Daniel, Shuji Murakami, Rina Hui, Ki Hyeong Lee, Byoung Chul Cho, Kaoru Kubota, Lynne Poole, Catherine Wadsworth, Phillip A. Dennis, Scott J Antonia

      • Abstract
      • Presentation
      • Slides

      Background

      In the Phase 3 PACIFIC study of durvalumab versus placebo in patients with stage III, unresectable non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (cCRT), on-treatment pneumonitis or radiation pneumonitis (‘pneumonitis’) occurred in both arms with similar rates of grade 3/4 pneumonitis (durvalumab, 3.4%; placebo, 2.6%). We performed exploratory analyses to further characterize time to onset and duration of pneumonitis and examine its relationship with underlying risk factors, including patient characteristics and prior CRT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PACIFIC (NCT02125461) was a randomized, double-blind study of patients with WHO PS 0/1 without progression after ≥2 cycles of platinum-based cCRT. Patients were stratified by age, sex, and smoking history and randomized (2:1) 1–42 days after completing cCRT to durvalumab 10 mg/kg IV Q2W or placebo up to 12 months. Potential associations between the presence of the AE pneumonitis (investigator assessed with review/adjudication by study sponsor) and baseline characteristics or patient disposition were investigated.

      4c3880bb027f159e801041b1021e88e8 Result

      As of Feb 13, 2017, 709 patients had received treatment; 33.6% on durvalumab and 24.9% on placebo had any-grade pneumonitis. Treatment exposure was similar in patients with or without pneumonitis across both arms. Median time to onset of pneumonitis from treatment start was the same for both durvalumab and placebo, 55.0 days (73.0 and 76.5 days from RT completion). Pneumonitis was self-limited, with median durations of 64.0 and 57.0 days, respectively. Patients with pneumonitis were more likely to be Asian (47.9% vs 17.6%) or have EGFR mutations (11.0% vs 3.8%); however, the proportions of patients with pneumonitis and these risk factors were numerically lower with durvalumab than with placebo (Asian: 44.4% [71/160] vs 57.6% [34/59]; EGFRm: 10.6% [17/160] vs 11.9% [7/59]), suggesting no apparent interaction with treatment. There were no apparent associations of pneumonitis with baseline respiratory disorders, prior RT dose, or prior cisplatin or carboplatin use. Previous induction CT was more commonly associated with the absence of pneumonitis in both treatment arms (durvalumab: 30.1% vs 17.5%; placebo: 31.5% vs 20.3%). The presence of pneumonitis was associated with greater discontinuation due to AEs (durvalumab: 25.6% vs 10.2%; placebo: 18.6% vs 6.8%) regardless of treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Rates of pneumonitis were higher in Asian patients and those with EGFRm, as previously reported. Durvalumab did not increase pneumonitis in patients with these risk factors. There were no differences in treatment exposure in patients based on the presence/absence of pneumonitis. Multivariate analyses may further assist in the discernment of etiologic risks.

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      MA05.03 - Immune Microenvironment and its Association with Adjuvant Chemotherapy Benefit in Locoregionally Advanced Lung Adenocarcinoma (Now Available) (ID 12999)

      13:40 - 13:45  |  Presenting Author(s): Raj Ghanshyam Vaghjiani  |  Author(s): Takashi Eguchi, Navin Chintala, Xiaoyu Li, Rania G Aly, Katsura Emoto, Kay See Tan, David R. Jones, Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      The impact of the tumor immune microenvironment on the effectiveness of platinum-based adjuvant chemotherapy (ACT) in locoregionally advanced (stage II-III) lung adenocarcinoma (ADC) is unknown. We performed an analysis of the cellular components of the tumoral and tumor-associated stromal immune environment in stage II-III lung ADC and examined their association with ACT benefit.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue microarrays (6 tumor and 3 stromal cores from each tumor) were constructed using resected tissue from patients with pT2-T4N1 lung ADC (n=500, 2000-2012) who did (n=225) and did not (n=214) receive ACT. Multiplex immunofluorescence was used to determine the quantity, localization, and colocalization of 21 types of immune cells and markers (including PD-1, PD-L1, CD3, CD20, CD68, CD163, MPO, and PanCK). The association between immune cell infiltration and recurrence free probability (RFP) was compared using Kaplan-Meier methods, and benefit from ACT by unsupervised hierarchical cluster modeling.

      4c3880bb027f159e801041b1021e88e8 Result

      Overall, increased tumoral infiltration of CD20+ B-cells and CD3+ and CD4+ T-cells was associated with an improvement in 5-yr RFP (CD20+ low vs high: 37% vs 49%, p=.03; CD3+: 39% vs 48%, p=.003; and CD4+: 39% vs 47%, p=.02, respectively) whereas increased stromal MPO+ neutrophil infiltration was associated with a worse 5-yr RFP (low vs high: 50% vs 38%, p=.003). Among patients who received ACT, cluster modeling revealed 5 risk groups (Groups A-E; Figure) with immune signatures including tumoral B-cells and CD163+PD-1+ macrophages as well as stromal CD57+ NK-cells and CD163+PD-L1+ macrophages that provided a progressive stratification of RFP following adjuvant treatment.

      vaghjiani.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Immune infiltration analysis can predict benefit from ACT and thereby provide a rationale to select patients for either chemotherapy, immunotherapy, or combination therapy following surgical resection.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.04 - Discussant - MA 05.01, MA 05.02, MA 05.03 (Now Available) (ID 14590)

      13:45 - 14:00  |  Presenting Author(s): Scott N. Gettinger

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA05.05 - Photon-Based Cardiac Sparing Via Volumetric Modulated Arc Therapy in Thoracic Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer (Now Available) (ID 13419)

      14:00 - 14:05  |  Presenting Author(s): Matthew J Ferris  |  Author(s): Katherine Sykes, Oluwatosin A Kayode, Jonathan Wolf, Robert H Press, Jeffrey M Switchenko, Walter John Curran, Jr., Kristin A Higgins

      • Abstract
      • Presentation
      • Slides

      Background

      Increasing radiation dose to the heart is associated with worse survival in stage III non-small cell lung cancer. Techniques to reduce the dose to the heart, including proton beam therapy (PBT), are being evaluated in ongoing clinical trials. However, advanced technologies such as PBT are not readily accessible for most patients. We therefore sought to evaluate the efficacy of volumetric modulated arc therapy (VMAT), a readily available technology in the United States, to spare cardiac substructures and determine how a cardiac optimization treatment planning algorithm influences dose distribution to other thoracic organs at risk (OARs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We selected stage III non-small cell lung cancer patients who were treated at our institution with VMAT to 60 Gy in 2 Gy fractions. Cardiac substructures were retrospectively contoured, and included: valves, atrioventricular node (AVN), coronary arteries (CA), chambers, and great vessels. New radiation treatment plans were created to spare these structures while preserving planning target volume (PTV) coverage and maintaining standard dose constraints to OARs. Dosimetry variables—maximum dose (Dmax), mean dose (Dmean), and common clinically relevant dose-volume relationships—for the new cardiac-sparing radiation treatment plans were compared via paired t-test to the original radiation treatment plans.

      4c3880bb027f159e801041b1021e88e8 Result

      Twenty-six patients, treated from July 2013 to September 2017, were included. Statistically significant improvements were demonstrated for all cardiac structures for the new cardiac-sparing plans compared to the original plans, while maintaining appropriate lung, esophagus, and spinal cord constraints, and PTV coverage goals, as demonstrated in Table 1 (significant P-values in bold).

      Table 1

      Dosimetry variable

      Cardiac-sparing plan (mean)

      Original plan (mean)

      P-value*

      Cardiac parameters

      Heart Dmax

      64.9 Gy

      63.6 Gy

      0.928

      Heart Dmean

      12.3

      16.1

      < 0.001

      Heart V5Gy

      55.4

      64.1

      0.003

      Heart V30Gy

      12.5

      18.7

      < 0.001

      Heart V40Gy

      7.9

      11.5

      < 0.001

      Heart V45Gy

      6.5

      11.5

      < 0.001

      Heart V60Gy

      2.7

      3.4

      0.001

      Aortic valve Dmax

      22.9

      31.7

      < 0.001

      Aortic valve Dmean

      11.4

      31.7

      < 0.001

      Mitral valve Dmax

      24.6

      29.4

      0.002

      Mitral valve Dmean

      11.2

      16.7

      < 0.001

      Pulmonic valve Dmax

      26.8

      35.4

      < 0.001

      Pulmonic valve Dmean

      14.1

      25.1

      < 0.001

      Tricuspid valve Dmax

      9.7

      16.6

      < 0.001

      Tricuspid valve Dmean

      5.6

      10.3

      < 0.001

      AVN Dmax

      13.4

      20.4

      < 0.001

      AVN Dmean

      8.1

      14.0

      < 0.001

      Left main CA Dmax

      26.4

      38.8

      < 0.001

      Left main CA Dmean

      16.4

      30.2

      < 0.001

      Left anterior descending CA Dmax

      27.4

      34.8

      < 0.001

      Left anterior descending CA Dmean

      14.4

      22.6

      < 0.001

      Left circumflex CA Dmean

      32.6

      36.8

      0.001

      Left circumflex CA Dmean

      19.3

      26.9

      < 0.001

      Right CA Dmax

      18.1

      26.1

      < 0.001

      Right CA Dmean

      9.4

      15.7

      < 0.001

      Left atrium Dmax

      51.8

      54.8

      0.091

      Left atrium Dmean

      17.5

      21.0

      < 0.001

      Left ventricle Dmax

      35.7

      40.1

      < 0.001

      Left ventricle Dmean

      8.3

      11.3

      < 0.001

      Right atrium Dmax

      31.4

      36.1

      0.004

      Right atrium Dmean

      11.1

      13.9

      < 0.001

      Right ventricle Dmax

      23.7

      33.2

      < 0.001

      Right ventricle Dmean

      6.9

      12.2

      < 0.001

      Aorta Dmax

      50.8

      55.3

      0.001

      Aorta Dmean

      20.4

      27.9

      < 0.001

      Pulmonary artery Dmax

      65.2

      65.1

      0.895

      Pulmonary artery Dmean

      32.3

      37.9

      < 0.001

      Superior vena cava Dmax

      47.4

      51.7

      0.002

      Superior vena cava Dmean

      29.4

      33.1

      0.006

      Other OAR parameters

      Lungs V5Gy

      56.5

      58.2

      0.121

      Lungs V20

      22.4

      23.3

      0.083

      Lungs Dmean

      13.6

      14.8

      0.012

      Spinal cord Dmax

      28.0

      31.1

      0.013

      Esophagus Dmean

      21.2

      22.1

      0.023

      PTV coverage parameters

      PTV Dmax

      65.5

      67.2

      0.189

      PTV minimum dose

      51.2

      52.7

      0.019

      PTV V100%

      95.2%

      95.4%

      0.195

      8eea62084ca7e541d918e823422bd82e Conclusion

      Dose to the heart and cardiac substructures can be substantially lowered using a cardiac-sparing optimization algorithm with VMAT, without increasing radiation dose other thoracic OARs or compromising PTV coverage. Though time-consuming, delineation of the full complement of cardiac substructures provides an effective means of improving the quality of radiation treatment plans with readily available technologies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.06 - Locally Advanced Lung Cancer Radiotherapy in Deep Inspiration Breath Hold: Dosimetric Benefits from a Prospective Trial (Now Available) (ID 12465)

      14:05 - 14:10  |  Presenting Author(s): Mirjana Josipovic  |  Author(s): Marianne C Aznar, Jonas Scherman Rydhög, Jakob Borup Thomsen, Sidsel Marie Skov Damkjaer, Lotte Nygård, Mette Pøhl, Seppo W Langer, Lena Specht, Gitte Fredberg Persson

      • Abstract
      • Presentation
      • Slides

      Background

      Radiotherapy for locally advanced non-small cell lung (NSCLC) cancer is often complicated by treatment-related toxicity. A toxicity-reducing technique is deep inspiration breath hold (DIBH), where the lungs inflate and the heart is pushed downwards. DIBH is widely applied in breast radiotherapy, but only sporadically in NSCLC. We initiated the INHALE trial, investigating compliance and benefits of DIBH for NSCLC at a single academic institution.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients referred for definitive radiotherapy of locally advanced NSCLC (66Gy/33 fractions) were included from May 2015-Dec 2017. All patients underwent respiratory coaching for voluntary visually guided DIBH and were imaged with PET/CT, 4D-CT and DIBH-CT. Target volumes were defined according to national guidelines. PTV margins were patient- and modality-specific. For all patients, FB and DIBH plans were made with volumetric modulated arc therapy, with equal PTV coverage. The plan with the lowest lung and/or heart dose was chosen for treatment. Normal tissue complication probability for pneumonitis was calculated retrospectively based on a logistic dose response model.

      4c3880bb027f159e801041b1021e88e8 Result

      The treatment intent was maintained in 69 of included 88 patients (2 were downstaged, 12 upstaged, 2 withdrew consent, other causes in 3). 62/69 were DIBH compliant and in 61 patients a FB and a DIBH plan were made (in one patient, 4DCT image quality was not sufficient). In 54/61 patients, the DIBH plan was chosen for treatment. 3/54 patients lost DIBH compliance within the first few fractions.

      All data is presented as median (range), with p<0.001 (Wilcoxon signed rank). Lung volume increased in DIBH by 55% (20-168%). Compared to FB, DIBH reduced mean lung dose from 14.4Gy (1.2-25.3Gy) to 11.8Gy (1.0-20.4Gy), and lung V20 from 23.7% (1.5-47.8%) to 20.8% (1.2-39.7%). Reduced lung dose translated to reduced pneumonitis risk: from 8.6% (2.3-23.3%) to 6.5% (2.2-14.4%). Lung dose constraints were violated in 5/62 patients in FB and 1/62 patients in DIBH.

      Mean heart dose was reduced from 3.6Gy (0.1-25.8Gy) in FB to 2.4Gy (0.1-25.3Gy) in DIBH. DIBH reduced mean heart dose in 44/61 patients. The differences between FB and DIBH varied between – 6.6Gy and 8.9Gy, stressing the influence of tumour location on the potential of reducing heart dose with DIBH.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Benefits of changed anatomy with DIBH were reduced dose to lungs and, for most patients, to the heart. Curative treatment intent could be maintained in more patients. Risk of developing radiation pneumonitis was reduced. Continuous follow up of INHALE patients will reveal how the reduced risk is manifested clinically.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.07 - Dose Escalated Chemo-RT to 84 Gy in Stage III NSCLC Appears Excessively Toxic: Results from a Randomized Phase II Trial (Now Available) (ID 11966)

      14:10 - 14:15  |  Presenting Author(s): Jan Nyman  |  Author(s): Stefan Bergström, Hedvig Björkestrand, Anna-Maja Svärd, Simon Ekman, Erik Lundin, Erik Holmberg, Mikael Johansson, Signe Friesland, Andreas Hallqvist

      • Abstract
      • Presentation
      • Slides

      Background

      Concurrent chemoradiotherapy is the mainstay treatment for NSCLC stage III disease, however, with a rather high probability of locoregional and metastatic recurrence further treatment optimization is warranted. Based on previous one-armed trials with dose escalated radiotherapy, showing feasibility, the Swedish Lung Cancer Study Group aimed to investigate whether dose escalation based on individual normal tissue constraints could improve outcome in this randomized phase II trial.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      NSCLC patients with stage III disease, good performance status (0-1), adequate lung function (FEV1 > 1.0 L and CO diff. > 40%) received three cycles of cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 day 1 and 8) every third week. The radiotherapy started concurrently with the second cycle, with either 2 Gy daily, 5 days a week, to a total dose of 68 Gy (standard arm A) or escalated therapy (B) based on constraints to the spinal cord, esophagus and lungs up to 84 Gy by adding an extra fraction of 2 Gy per week while keeping the total treatment time constant at seven weeks with the same dose to involved nodes and primary tumor.

      4c3880bb027f159e801041b1021e88e8 Result

      A pre-planned safety analysis revealed excessive toxicity and decreased survival in the escalated arm, and the study was stopped. Thirty-six patients were included during 2011-2013 (56% male, 78% with adenocarcinoma, 64% with PS 0 and 53% with stage IIIB). The median progression-free survival (PFS) and overall survival (OS) were 11 and 17 months in the dose escalated group compared to 28 and 45 months in the standard group. The 1-, 3- and 5-year survival rates were 56%, 33% and 17% in the escalated arm and 72%, 61% and 34% in the standard arm. There were four toxicity-related deaths due to esophageal perforations (one in arm A and three in arm B) and three deaths due to pneumonitis (one in arm A and two in arm B).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Dose-escalated concurrent chemoradiotherapy to 84 Gy to primary tumor and nodal disease is hazardous, with a high risk of excessive toxicity, whereas modern standard dose chemoradiotherapy with proper staging given in the control arm shows a promising outcome with a median survival of 45 months and a 5-year survival of 34%. A possible step forward will be to improve systemic therapy, but future approaches with escalated radiotherapy may include boost techniques to remaining PET positive areas or different escalation schedules to the primary tumor and mediastinal nodes.

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      MA05.08 - Discussant - MA 05.05, MA 05.06, MA 05.07 (Now Available) (ID 14591)

      14:15 - 14:30  |  Presenting Author(s): Benjamin H Lok

      • Abstract
      • Presentation
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      Abstract not provided

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      MA05.09 - PFS and Cardiac-Toxicity-Adjusted-PFS As Predictors of OS in Locally Advanced NSCLC Treated with Concurrent Chemoradiation (Now Available) (ID 12391)

      14:30 - 14:35  |  Presenting Author(s): Chen Hu  |  Author(s): Mitchell Machtay, James Dignam, Rebecca Paulus, Jeffrey Bradley

      • Abstract
      • Presentation
      • Slides

      Background

      Overall survival (OS) is the gold standard for LA-NSCLC with chemoradiation (CCRT), while the complex relationships among RT dosimetry, systemic therapies, cardiopulmonary toxicity, progression (PD) and OS are also of increasing scientific and clinical interest.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      NRG Oncology RTOG 0617 (NCT00533949) was a randomized phase 3 trial comparing standard (SD, 60 Gy) versus high-dose (HD, 74 Gy) CCRT +/- cetuximab from 11/07-06/11. This secondary analysis includes 469 patients (pts) given ≥50 Gy. A PFS event was defined as the first occurrence of local, regional, distant PD or death w/o documented PD. A CTA-PFS event was the first occurrence of grade 2+ treatment-related cardiac toxicity event or a PFS event. Landmark analyses at 6mo and 12mo were used to minimize the immortal time bias. Cox model with PD or CT/PD as a time-dependent covariate was used to evaluate their predictive roles. Median f/u time for surviving pts was 5.1 years.

      4c3880bb027f159e801041b1021e88e8 Result

      As previously reported, pts treated with HD had significantly lower OS rates (HR=1.28, 95%CI: 1.04-1.58, p=0.018) and CTA-PFS rates (HR=1.24, 95%CI: 1.02-1.51, p=0.035), and marginally lower PFS rates (HR=1.21, 95%CI: 0.99-1.47, p=0.06) than pts treated with SD. Median survival time (MST) among pts having PD within 6mo versus not were 13.4mo (95%CI: 10.0-19.0mo) and 30.7mo (95%CI: 28.0-37.0mo) (p<0.001). MST for pts having PD within 12mo versus not were 20.6mo (95%CI: 18.8-25.0mo) and 60mo (95%CI: 47.6-74.5mo)(p<0.001). Results are similar when using CTA-PFS with 6mo or 12mo cutoff (p<0.001). RT dose was no longer significantly associated with OS (p=0.08 or p=0.15) when PD or CT/PD was included in multivariable analysis (p<0.001), suggesting OS differences in HD/SD may be partially captured by PFS or CTA-PFS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Long-term survival results from RTOG 0617 suggest that PFS (or CTA-PFS) status at 6mo or 12mo predicts long-term OS, and may potentially be considered as a surrogate endpoint of OS in clinical trials. Pts who were progression-free at 12mo had a MST of 5 years. Further validation on external datasets and in the modern era of immunotherapy are needed.

      Funding: This project was supported by grants NCORP (UG1CA189867), NRG Operations (U10CA180868), NRG SDMC (U10CA180822), IROC (U24CA180803), and CTEP from the National Cancer Institute (NCI).

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.10 - The Pathologic Response of Locally Advanced NSCLC Treated with Concomitant Chemoradiation to 60 Gy in Image Guided Radiation Therapy (IGRT) (Now Available) (ID 13758)

      14:35 - 14:40  |  Presenting Author(s): Sarit Appel  |  Author(s): Jair Bar, Damien Urban, Amir Onn, Marina Perelman, Yaacov Richard Lawrence, Alon Ben-Nun, Ory Haisraely, Zvi Symon, Tatiana Rabin El Ezra, Edith Marom, Sivan Liberman, Efrat Ofek

      • Abstract
      • Presentation
      • Slides

      Background

      Neoadjuvant concomitant chemoradiation (NACCRT) was historically limited to 45 Gy. We recently published data on the safety of a higher radiation dose in this setting. Here we evaluate the pathologic response of locally advanced non small cell lung cancer (LANSCLC) treated with 60Gy NACCRT combined with modern IGRT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Our cohort comprised patients that underwent NACCRT followed by surgery during August 2012-December 2017 at our institution. We retrospectively collected the demographic, stage, histology, and treatment details. Radiation was planned using eclipse system to deliver 2 Gy per fraction to a total of 60 Gy

      Treatment effect was determined from the pathologic specimen in accordance with College of American Pathologists recommendations, based on the modified tumor regression grading: Favorable pathologic responses included major tumor regression (MTR); we also evaluated the average percent of the residual tumor cells seen in the specimen. Statistical analysis was performed to analyze treatment effect on the pathologic response using spearman correlation and Kruskal-Wallis test with SPSS software v.24.

      4c3880bb027f159e801041b1021e88e8 Result

      Our cohort included 70 patients. Mean age was 63 years (range 45–79.7), men n=49 (70%), smoking status: never smokers n=11 (16.2%), past smokers n=10 (14.7%), current smokers n=47 (69.1%). Histology consisted adenocarcinoma n=42 (60%), squamous n=21 (30%) and other n=7 (10). Stage 2 were n=65 (78.3%) and stage 3 n=15 (21.4%). Chemotherapy consisted of platinum-doublet administered to 69 patients (98.5%). A mean radiation dose of 59 Gy (range 46-72 Gy) was delivered with IGRT prior to each fraction. Five patients received lower radiation doses due to toxicity or dose constraints. Surgery comprised of lobectomy n=50 (71.4%), chest wall resection n=9 (12.9%) or pneumonectomy n=11 (15.7%). Negative surgical margins were achieved in n=63 (90%) and positive margins in n=7 (10%). 30-day mortality was n=2 (2.8%) both cases after Right-sided pneumonectomy.

      MTR was observed in 45 cases (64.3%) including a pathological complete response in 25 (35.7%) and < 10% residual tumor in 20 cases (28.5%). The mean percent of residual tumor cells was 16% and the median 6.5%. Percent of residual tumor cells did not correlate to radiation dose (Rs=0.092), and not to the histology (p= 0.165), and not to type of chemotherapy (p=0.35).

      8eea62084ca7e541d918e823422bd82e Conclusion

      NACCRT delivered to 60 Gy with modern image-guided radiation therapy is safe. Two thirds of such patients achieve major tumor regression.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.11 - Radiomics Analysis Using SVM Predicts Mediastinal Lymph Nodes Status of Squamous Cell Lung Cancer by Pre-Treatment Chest CT Scan (Now Available) (ID 12033)

      14:40 - 14:45  |  Presenting Author(s): Xing Wang, Wu Nan  |  Author(s): Shi Yan, Quanzheng Li, Ning Guo, Zhe Guo

      • Abstract
      • Presentation
      • Slides

      Background

      Assessment of mediastinal lymph nodes (N2 station) is essential in staging patients with Non-small-cell lung cancer (NSCLC), for patients with preoperative confirmed N2 status should follow neoadjuvant therapy before surgery, and occult N2 status should be avoided. There are several invasive and non-invasive exams available for preoperative N staging, like EBUS-TBNA and PET-CT scan. Chest CT scan was the basic examination of every patient, while only the length of minor axis could be used to predict lymph node involvement, and the potential value of CT might be underestimated. In this study we aimed to explore the value of radiomics analysis with machine learning in differentiating N2 from N1/N0 subjects using pre-treatment chest CT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Ninety-three patients with squamous cell lung cancer, who underwent pre-treatment CT scans were included in this study. By use of Laplacian of Gaussian (LoG) filter and matrix based radiomics models (e.g. gray-level co-occurrence matrix), comprehensive radiomics features were extracted from the regions of interest which were manually delineated on primary tumors. We performed radiomics analysis using support vector machine (SVM) to test texture and heterogeneity features derived from pre-treatment CT images as indicators for the staging of lymph node metastasis, especially N2. The gold standard of N staging is confirmed pathologically after systematic mediastinal lymphadenectomy (N2 subjects=31).

      4c3880bb027f159e801041b1021e88e8 Result

      For the performance evaluation of single image feature, there are 16 features able to differentiate N2 subjects from others (N0 and N1) with p value <0.05. Furthermore, SVM training and classification were performed using 5-feature combinations as inputs. With feature selection, the best performance of N2 prediction is 83% accuracy with 87% sensitivity and 81% specificity.

      figure.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Radiomics analysis using SVM training can successfully predict N staging by pre-treatment chest CT scan for NSCLC patients, which could diminish the odds of occult N2 status and provide unique information preoperatively for treatment planning.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.12 - Discussant - MA 05.09, MA 05.10, MA 05.11 (Now Available) (ID 14592)

      14:45 - 15:00  |  Presenting Author(s): Matthew Hatton

      • Abstract
      • Presentation
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      Abstract not provided

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    MA06 - PDL1, TMB and DNA Repair (ID 903)

    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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      MA06.01 - The Intrinsic PD-L1 Promotes Cellular Invasiveness Via their PD-1 Receptor in Lung Adenocarcinoma Cells (Now Available) (ID 13356)

      13:30 - 13:35  |  Presenting Author(s): Wen-Pin Su  |  Author(s): Hung-Chang Wu, Shuen-Ru Yang, Jheng-Cheng Huang, Jing-Jou Yan, Wan-Chen Kao, Li-Chan Chang, Wu-Chou Su

      • Abstract
      • Presentation
      • Slides

      Background

      Lung cancer is the most frequent cause of cancer death. Programmed death 1 (PD-1) in T cells and its ligand PD-L1 in tumor cells play a key role in immune checkpoint therapy and had applied to advanced stage lung cancer. Migration and invasion of tumor cells is a prerequisite for tumor cell metastasis. Since intrinsic PD-1 receptor functions promote tumor growth was reported, we will investigate the interaction between PD-1 and PD-L1 in lung adenocarcinoma cell lines, the impact on chemosensitivity, and clinical outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In vitro experiments, lung adenocarcinoma CL1-5 cells, derived from CL1-0 cells. We prepared PD-L1-overexpression human lung adenocarcinoma cell line, derived from CL1-0 cells (CL1-0-PD1). Migration and invasion ability were assessed by transwell assay; EMT marker and regulator were evaluated by Western blotting. We also observed the morphology of cells. To explore interaction between PD1 and PD-L1, we added anti-PD-1 antibody into CL1-0, CL1-5, and CL1-0-PDL1 cells, and then test migration, invasion and cellular morphology. We also suppressed PD-1 by siRNA to test whether PD-1/PDL-1 interaction contributed to the EMT change. Further, we evaluated cellular proliferation and chemosensitivity by MTT assay and colony formation assay. We will correlate PD-L1 expression in lung cancer cells with clinical outcome by IHC stain clinically.

      4c3880bb027f159e801041b1021e88e8 Result

      In CL1-5 cells, derived from CL1-0 cells, with high PD-L1 expression possessed higher cellular migration ability than the parental CL1-0 cells with less PD-L1 expression. CL1-0 cells with PD-L1 overexpression had more expression of EMT (epithelial mesenchymal transition) regulator and mesenchymal marker. We also observed that CL1-5 and CL1-0-PDL1, which had more PD-L1 expression, are shaped like spindles; while CL1-0 cells are more rounded. Therefore, PD-L1 up-regulated cell migration and invasiveness in human lung adenocarcinoma cells and promotes EMT.

      After adding anti-PD1 antibody in CL1-5, CL1-0, and CL1-0-PDL1 cells, migration and invasion ability decreased. These result indicated anti-PD-1 antibody block the link between PD-1 and PD-L1 in cancer cells. The phenomenon was confirmed by PD-1 siRNA. Therefore, PD-1/PD-L1 axis regulated cancer cells migration and invasiveness. PD-L1 expression also decreased cellular proliferation and had little influence on chemsensitivity. Finally, we found that higher PD-L1 expression was correlated with lymph node metastasis in clinical specimen.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lung adenocarcinoma cells with higher PD-L1 expression promote cell migration, invasiveness, EMT, and little chemoresistance. PD-L1 expression lowers proliferation rate. PD-1 and PD-L1 interaction on lung adenocarcinoma cells contribute cellular migration and invasiveness.

      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.

      • Abstract
      • Presentation
      • Slides

      Background

      Our previous work has demonstrated that higher level of genomic complexity is associated with more heterogeneous neoantigen repertoire, suppressed T cell repertoire and postsurgical relapse in localized non-small cell lung cancers (NSCLC) highlighting the complex interaction of tumor molecular and immune landscape and their impact on cancer biology and patient survival. We launched the ICON Project (Immune Genomic Profiling of NSCLC) to prospectively delineate the molecular and immune landscape of early stage NSCLC and their impact on patient survival through a multidisciplinary approach. Here we report the updated genomic and immune analyses.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Surgical specimens from stage I-III NSCLC were subjected to whole-exome and RNA sequencing for mutational analysis, in silico neoantigen prediction and gene expression analysis as well as T cell receptor sequencing, cytometry by time-of-flight and multiplex immunofluorescence staining.

      4c3880bb027f159e801041b1021e88e8 Result

      From 2016-2018, 127 patients were accrued and 50 surgical samples have undergone WES, RNAseq, TCR sequencing and immune phenotyping. Median age is 66 yrs (range: 39-86), 52% (26/50) were female and 76% (38/50) former smokers. 76% (38/50) are non-squamous carcinomas and 24% (12/50) squamous cell carcinomas. 34% have stage I disease (17/50), 30% stage II (15/50), 34% stage III (17/50) and 2% stage IV (1/50). The majority of patients had upfront surgery (45/50; 90%). With median follow-up of 19 months, 15 patients have relapsed. Median tumor mutational burden is 7.8mut/Mb and predicted neoantigen burden was 10/sample (range: 0-250). Predicted neoantigen burden is significantly correlated with tumor mutational burden (r=0.41, p=0.002). The most commonly mutated genes are TP53, KRAS, CDKN2A, PIK3CA, EGFR, BRAF, GRIN2A and ATM. C->A transversions and C->T transitions were the most common mutational subtypes. PD-1 expression and regulatory T-cell (CD4+/FoxP3+) infiltration are significantly increased in tumor tissue compared to normal tissue (p=0.003 and p=0.02 respectively), while CD3, CD8, granzyme B and CD45RO are decreased in tumor tissue compared to normal lung.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NSCLC tumors have an immunosuppressive microenvironment compared to tumor adjacent normal lung tissues. Clinical data will be adequate to conduct genomic and immune profiling comparisons across different clinical subgroups. Mutational and neoantigen profiling are consistent with previously reported studies and correlations between molecular and immune landscapes and its impact on patient survival are ongoing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA06.03 - PD-1 and Id-1 Combined Blockade Impacts Tumor Growth and Survival Through PD-L1 Expression and Tumor Infiltration by Immune-Related Cells  (Now Available) (ID 14033)

      13:40 - 13:45  |  Presenting Author(s): Ignacio Gil-Bazo  |  Author(s): Iosune Baraibar, Marta Roman Moreno, Ines Lopez, Jesus Corral, Juan Jose Lasarte, Alfonso Calvo, Silve Vicent, Daniel Ajona

      • Abstract
      • Presentation
      • Slides

      Background

      PD-1/PDL-1 inhibitors are approved in advanced non-small cell lung cancer (NSCLC). Long-term survival rates associated to PD-1/PDL-1 blockade have changed treatment paradigm. However, many patients do not benefit from PD-1/PDL-1 blockade. New therapeutic combinations are under investigation. Id1 is involved in proliferation, angiogenesis and immunosuppression. We described Id1 as an independent prognostic factor in NSCLC (Ponz-Sarvise, Clin Cancer Res 2011) and more recently showed Id1’s role in lung cancer metastasis (Castanon, Cancer Letters 2017). Here we test a combined therapeutic strategy targeting PD-1 and Id1 in a murine lung cancer model.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Three in vivo studies evaluated the impact of Id1 inhibition in tumor cells, tumor microenvironment and in both, on tumor volumes and mice survival. A syngeneic tumor model using C57BL/6 and Id1-/- Id3+/- mice was created by subcutaneous injection of Lewis Lung Carcinoma (3LL) cells and Id1 silenced 3LL (Id1Sh) cells. After injection, mice were treated with an anti-PD-1 (RMP-1-14) monoclonal antibody or PBS. Tumor volumes according to mice strain, Id1 status in tumor cells and treatment were quantified. Mice's survival was calculated in those groups. Tumor CD8+ and CD3+ TILs and CD68+ cells were quantified by specific immunostainings.

      4c3880bb027f159e801041b1021e88e8 Result

      Id1 inhibition in the tumor environment and the injected tumor cells, combined with anti-PD-1 treatment, induced a significant tumor growth impairment (p < 0.0001) and increased survival (p = 0.0051). CD3+ and CD8+ TILs and tumor CD68 + cells were significantly higher in tumors from mice with the combined Id1-PD-1 blockade treated with the anti-PD-1 inhibitor compared to control animals suggesting that tumor increased immune-related cells infiltration exerts the effector phase of the antitumor immune response. Additionally, PD-L1 expression seemed to be higher when Id1 expression was absent in the immune microenvironment (p = 0.04). Additional data based on multiplexed immunohistochemistry results will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Id1 and PD-1 combined blockade in our syngeneic murine lung cancer model significantly impaired tumor growth and increased survival. Increased tumor PD-L1 expression and CD3+ and CD8+ TILs and CD68+ cells may explain these findings.

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      MA06.04 - Discussant - MA 06.01, MA 06.02, MA 06.03 (Now Available) (ID 14593)

      13:45 - 14:00  |  Presenting Author(s): Akihiko Yoshida

      • Abstract
      • Presentation
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      Abstract not provided

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      MA06.05 - The Micro-Environmental Cross Talk Between Mast Cells and Lung Cancer Cells Through Cell-to-Cell Contact (Now Available) (ID 11140)

      14:00 - 14:05  |  Presenting Author(s): Rachel Shemesh  |  Author(s): Yaara Gorzalczany, Smadar Geva, Laila C. Roisman, Ronit Sagi-Eisenberg, Nir Peled

      • Abstract
      • Presentation
      • Slides

      Background

      Mast cells (MCs) are key effectors in allergic reactions, but are also involved in tissue remodeling, wound healing and protection against pathogens. MCs infiltrate tumors and their number within the tumor microenvironment in certain cancer types, such as lung cancer, have been correlated with poor prognosis. The nature of crosstalk between lung cancer and MCs remain poorly resolved. In this study, we investigated the activation patterns within the MCs following cell-to-cell contact with lung cancer cells showing CD73 involvement and implying metabolic changes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Human MCs (HMC-1 and LAD-2) were exposed to Human lung cancer cells (H1299), derived membranes to recapitulate cell contact mediated activation. Lysates of MCs were tested for protein expression and posttranslational modifications (i.e. phosphorylation) by targeted western blotting. We unraveled the intracellular signaling molecules that are necessary for this signaling pathway by a pharmacological approach using several inhibitors. Each condition was repeated at least twice.

      4c3880bb027f159e801041b1021e88e8 Result

      H1299 membrane exposure activated the ERK 1/2 MAP kinases in HMC-1 and in LAD-2 cells. AKT signaling was also activated in LAD-2 cells as a result of this contact. CD73 dephosphorylates AMP to adenosine within the MCs. Interestingly enough, this ERK 1/2 activation was inhibited by CD73 inhibitor and A3 receptor antagonists in HMC-1 cells. ERK 1/2 activation was inhibited by A3 receptor antagonists and PI3K in LAD-2 cells. Furthermore, we discovered that protein kinase C (PKC) inhibitor augments the activation of ERK 1/2 in LAD-2 cells. In contrast, PKC inhibitor inhibits the activation of ERK 1/2 in HMC-1 cells. In addition, we discovered that the AKT activation was inhibited by A3 receptor and PI3K inhibitors but not by CD 73 inhibitors.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that H1299 membranes activate ERK 1/2 in HMC-1 cells by a mechanism that involves autocrine formation of adenosine and is mediated by CD 73 and A3 receptor. In addition, we discovered that there is an important difference between the ERK 1/2 MAP kinase signal transduction in HMC-1 and LAD-2 cells, PKC is an inhibitor of the H1299 activation of ERK 1/2 in LAD-2 cells. In contrast, the H1299 membrane activation of ERK 1/2 kinase in HMC-1 cells is mediated by PKC. Furthermore, we can conclude that H1299 membranes activate AKT in an A3 receptor dependent mechanism that is mediated by PI3K.

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      MA06.06 - An Ex-Vivo Patient-Derived, Immunocompetent (PDI) Culture System to Evaluate Immunotherapeutic Agents’ Anti-Tumor Efficacy (Now Available) (ID 14299)

      14:05 - 14:10  |  Presenting Author(s): Zachary E. Tano  |  Author(s): Stefan Kiesgen, Navin Chintala, Jordan Dozier, John Messinger, Kay See Tan, Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      Anti-tumor efficacy of human immunotherapeutic agents, such as antibodies, chimeric antigen receptor (CAR) and T-cell receptor transduced T cells, are currently being investigated in immunodeficient mice prior to clinical translation. We developed and optimized an ex-vivo culture system utilizing malignant pleural effusions (MPEs) to compliment these investigations in a human, immunocompetent, tumor-like environment. We hypothesized that CAR T cells’ cytotoxicity will vary by the different immune compositions in each MPE, which are conditions unavailable in current efficacy assays.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Mesothelin-targeted CAR T cells from multiple donors were exposed to MPEs derived from non-small cell lung cancer patients (n=15) and RPMI culture medium. Influence of the MPEs on CAR T-cell efficacy was evaluated by viability and phenotype (flow cytometry), cytotoxicity (chromium release assay), and gene expression (NanoString). Group-based trajectory modeling was used to stratify the inhibitory effect of MPEs. MPE composition (ELISA and Luminex assays) was evaluated to interpret its influence on CAR T cells.

      4c3880bb027f159e801041b1021e88e8 Result

      With the incorporation of our optimized protocols, T cells retain their viability, phenotype (CD4/CD8), and percentage of CAR expression when cultured in MPEs. MPE soluble factor levels remained stable over multiple freeze/thaw cycles. CAR T cells co-cultured in MPE exhibited variable antigen-specific cytotoxicity (Fig. A). MPE-induced T-cell inhibition was stratified into groups of strong, mild, or no inhibition. (Fig. B). Compared to MPEs with either mild or no inhibition, MPEs with strong inhibition had significantly higher levels of TGFβ-2 (average TGFβ-2 level in strong vs. mild inhibition: 402 vs. 50 pg/mL, p<0.05) (Fig. C), IL-6, RANTES, and IL-5.

      pdi culture system.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      We present the first human immunocompetent culture system that can be used to evaluate immunotherapeutic agents’ efficacy prior to their clinical translation. Furthermore, analyses of the culture system’s soluble factors sheds light on their relative influence on T-cell efficacy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA06.07 - Genetic and Epigenetic Alterations are Associated with Tumor Mutation Burden in Non-Small Cell Lung Cancer (Now Available) (ID 12822)

      14:10 - 14:15  |  Presenting Author(s): Liang-Liang Cai  |  Author(s): Hua Bai, Zhi-Jie Wang, Shuhang Wang, Jian-Chun Duan, Shu-Geng Gao, Jie He, Jie Wang

      • Abstract
      • Presentation
      • Slides

      Background

      Although several studies have indicated that tumor mutation burden (TMB) is associated with non-small cell lung cancer (NSCLC) development and clinical efficacy of immune checkpoint inhibitors (CPIs), identification of factors associated with TMB is still a major biological issue. It is well-known that DNA transcription can be regulated through methylation and demethylation, gene silencing caused by DNA hypermethylation is associated with cancer development. However, the relationship between DNA methylation and TMB in NSCLCs remains unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The landscape of DNA sequence in Chinese NSCLCs population were surveyed by using whole-exome sequencing (WES) by profiling 178 lung tissues (89 without any systemic anti-cancer therapy tumors and matched normal lung tissues). According to the 104 median-level of TMB in our cohort, high TMB (n=16, 252-465 range mutations per tumor) and low TMB (n=13, 57-79 range mutations per tumor) groups were divded. The NSCLC methylome between high and low TMB was characterized on a genome-wide scale using Illumina Infinium MethylationEPIC arrays combined with the WES data.

      4c3880bb027f159e801041b1021e88e8 Result

      The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures in high TMB lung cancer. Combining with clinical data, cigarette smoking associated with high TMB were observed in our cohort. Cancer-specific epigenetic alterations were observed in 294,141 CpG sites, comprising both tumor hyper- (769,38) and hypo- (217,203) methylation in high TMB lung cancer while none in low. These different methylations sites cover 1232 genes including 25 HOX genes.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Global DNA hypomethylation and TP53 mutation, associated with increased chromosomal instability, were associated with TMB in NSCLCs.The high TMB NSCLCs are characterized by numerous copy number alterations and aberrantly methylated sites and display distinct mutational signatures. 25 hypermethylated HOX genes can be potentially useful as DNA methylation markers for prediction of TMB level. The results provide insights into the epigenetic impact of TMB, which may contribute to improve precison management of NSCLCs.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA06.08 - Discussant - MA 06.05, MA 06.06, MA 06.07 (Now Available) (ID 14594)

      14:15 - 14:30  |  Presenting Author(s): Jyoti Patel

      • Abstract
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      Abstract not provided

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      MA06.09 - XRCC6BP1: A DNA Repair Gene in Cisplatin Resistant Lung Cancer Stem Cells That May Predict Survival Outcomes in Patients (Now Available) (ID 14024)

      14:30 - 14:35  |  Presenting Author(s): Martin P Barr  |  Author(s): Robert Farrell, Saravjeet Singh, Emma Foley, Yuexi He, Lauren Brady, Vincent Young, Ronan Ryan, Siobhan Nicholson, Niamh Leonard, Sinead Cuffe, Stephen Finn

      • Abstract
      • Presentation
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      Background

      Alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating resistance to chemotherapeutic agents.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      DNA Repair Pathway RT2 Profiler Arrays were used to elucidate key DNA repair genes implicated in chemoresistant NSCLC cells using cisplatin resistant (CisR) and corresponding parental (PT) H460 cells. DNA repair genes significantly altered in CisR cells were validated at the mRNA and protein level. The translational relevance of differentially expressed genes was examined in a cohort of chemo-naïve matched normal and tumour lung tissues from NSCLC patients. Loss of function studies were carried out using siRNA technology. The effect of XRCC6BP1 gene knockdown on apoptosis was assessed by FACS. Cellular expression and localisation of XRCC6BP1 protein and γH2AX foci in response to cisplatin were examined by immunofluorescence (Cytell™). To investigate a role for XRCC6BP1 in lung cancer stem cells, Side Population (SP) studies were used to characterise stem-like subpopulations within chemoresistant cells. XRCC6BP1 mRNA analysis was also examined in ALDH1+ and ALDH1- subpopulations. Immunohistochemistry analysis was carried out in resected lung tumour tissues and XRCC6BP1 expression was correlated with survival in addition to a number of clinicopathological parameters such as tumour stage & grade, gender, smoking status and chemotherapy.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified a number of critical DNA repair genes that are differentially regulated between PT and CisR NSCLC cells. XRCC6BP1 mRNA and protein expression was significantly increased H460 CisR cells relative to their PT counterparts. Relative to matched normal lung tissues, XRCC6BP1 mRNA was significantly increased in lung adenocarcinoma patients. Gene silencing of XRCC6BP1 induced significant apoptosis of chemoresistant cells and reduced their DNA repair capacity. Immunofluorescence studies showed an increase in XRCC6BP1 protein expression and gH2AX foci in CisR cells. SP analysis revealed a significantly higher stem cell population in resistant cells, while XRCC6BP1 mRNA expression was considerably increased in SKMES-1, H460 and H1299 CisR cells positive for ALDH1 activity (ALDH1+) compared to ALDH1- cells. IHC scoring of XRCC6BP1 demonstrated poor survival outcomes for NSCLC patients with high expression of this DNA repair gene.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data highlight the potential of targeting components of the DNA repair pathway, in particular XRCC6BP1, in chemoresistant lung cancer. Furthermore, XRCC6BP1 may play an important role in subsets of lung cancer stem cells which, at least in part, may be responsible for driving and maintaining the cisplatin resistant phenotype in NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA06.10 - Germline Mutation in ATM Affect Lung Cancer Risk with High Effect (Now Available) (ID 12792)

      14:35 - 14:40  |  Presenting Author(s): Xuemei Ji  |  Author(s): Dakai Zhu, Claudio Pikielny, Olga Gorlova, Maria Teresa Landi, John Kirkpatrick Field, Paul Brennan, Mattias Johansson, Rayjean J. Hung, James D McKay, Christopher Ian Amos

      • Abstract
      • Presentation
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      Background

      Genome wide association studies have identified several lung cancer susceptibility regions and common variants influencing lung cancer risk. However, few previous studies investigated the association between germline mutations and lung cancer risk.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We analyzed data from a case-control study with 19053 lung cancer cases and 15446 healthy controls of European ancestry in a discovery phase and performed a validation analysis using a case-control study comprising 4261 lung cancer cases and 4152 healthy controls of European ancestry for replication. Logistic regression was used to identify germline mutations with high effect within exome regions associated with lung cancer risk.

      4c3880bb027f159e801041b1021e88e8 Result

      We found rs56009889 in ATM was statistically associated with lung cancer risk in the discovery set (OR = 3.05, P = 3.68 × 10−8) and was nonsignificantly associated with lung cancer risk in the validation set (OR = 1.83, P = 0.16). Stratified analyses by gender with adjustment for age and smoking status showed that females carrying at least one mutated allele of rs56009889 (T/C + T/T) had an increased risk of lung cancer with ORs being 7.77 (95% CI 3.45 - 17.47) in discovery and 6.73 (95% CI 1.46–30.98) in replication, compared to C/C homozygotes among females. Individuals carrying at least one T allele showed a significant 6.9-fold increased risk for lung adenocarcinoma in discovery (adjusted OR = 6.85; 95% CI 4.37 – 10.75) and approximately a 4.9-fold increased risk in replication (adjusted OR = 4.89; 95% CI 2.01 – 11.91). Never smokers with combined genotypes (T/C + T/T) had a greater than 8-fold increased risk of lung cancer in discovery (adjusted OR = 8.03, 95% CI 4.00 – 16.13), while smokers only showed a 2.13-fold increased risk (adjusted OR = 2.13, 95% CI 1.25 – 3.65). In replication, however, the risks from this variant were comparable between smokers and nonsmokers, although the sample size is small for nonsmokers (adjusted OR = 2.16; 95% CI 0.48 – 9.79 for never-smokers and adjusted OR = 2.07; 95% CI 0.66 – 6.52 for smokers). All the T/T homozygotes of rs56009889 developed lung adenocarcinoma in discovery (P = 0.036). The association exhibited a dose-response relationship between the number of T allele of rs56009889 and lung cancer risk in discovery (Ptrend = 1.07 x 10 -9).

      8eea62084ca7e541d918e823422bd82e Conclusion

      rs56009889 highly affected the risk of lung cancer, mainly of lung adenocarcinoma, primarily in women and never smokers. These germline mutations provide important insights for the prevention of lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA06.11 - Distinct Origins of Lymphatic and Brain Metastasis in Lung Cancer (Now Available) (ID 13333)

      14:40 - 14:45  |  Presenting Author(s): Tao Jiang  |  Author(s): Yan Yan, Caicun Zhou

      • Abstract
      • Presentation
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      Background

      Generally, distant metastases are seeded by lymph node metastases in most solid tumors. This concept provides a mechanistic basis for the TNM staging system and is the rationale for surgical resection of tumor-draining lymph nodes. However, a recent study found that lymphatic and distant metastases could arise from independent subclones in the primary colorectal cancer. The current study aimed to investigate the origins of lymphatic and brain metastasis in lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      39 samples from twelve patients with primary lung cancer and brain metastases were identified. Three of them had the matched lymph node metastases. All tissues and matched peripheral blood samples were collected before any systemic treatment. Whole-exome (>150×) sequencing were conducted on these samples.

      4c3880bb027f159e801041b1021e88e8 Result

      Compared to the primary lesions, both brain and lymph node metastases had the significantly different patterns of somatic genome alterations. The mutational landscape of brain metastases was also distinctly different from matched lymph node metastases. Primary lesions, matched brain and lymph node metastases showed the similar mutation pattern in terms of transition and transversion, and all of samples displayed a higher percentage of C>T transition. Brain metastases had numerically higher tumor mutational burden (TMB) than primary lesions but it did not reach the statistical significance. Notably, we observed the totally distinct origins of lymphatic and brain metastasis in all three matched cases.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The current evidence suggested that brain metastases and matched lymph node metastases had different mutational landscape in patients with lung cancer. Brain metastases had higher TMB than their primary lesions. Lymphatic and brain metastasis had distinct origins in lung cancer. These results had profound clinical implications for application of immunotherapy and improvement of prognosis in patients with lung cancer and brain metastases.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA06.12 - Discussant - MA 06.09, MA 06.10, MA 06.11 (Now Available) (ID 14595)

      14:45 - 15:00  |  Presenting Author(s): Rebecca Heist

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      Abstract not provided

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    MA07 - Towards Survivorship: The Landscape, Supports and Barriers (ID 904)

    • Type: Mini Oral Abstract Session
    • Track: Advocacy
    • Presentations: 11
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 205 AC
    • +

      MA07.01 - No Longer Outliers: Understanding the Needs of Long-Term Lung Cancer Survivors (Now Available) (ID 12955)

      13:30 - 13:35  |  Presenting Author(s): Maureen Rigney  |  Author(s): Jennifer C King, Andrew Ciupek

      • Abstract
      • Presentation
      • Slides

      Background

      Lung cancer is the leading cause of cancer death in most developed and developing countries. But people do survive, sometimes for many years. Those diagnosed with lung cancer experience higher levels of distress and have greater unmet physical and emotional needs compared with other types of cancer. But what of long-term survivors?

      Globally, The Cancer Atlas reported an estimated 1,878,000 people were living with lung cancer in 2012. With the introduction of screening and rapid treatment advancements, that number is only expected to increase. Are we prepared to meet the long term and late effects of lung cancer? First, we must better understand the experiences and identified needs of long-term survivors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      820 people responded to a 120 question online survey that was distributed via social media and targeted outreach. 471 identified as lung cancer patients/survivors and 349 as loved ones. 21% of survivor-respondents indicated they had been diagnosed 5+ years prior.

      Queried on treatment and smoking histories, long-term survivors identified their most prevalent and problematic symptoms and side effects experienced during treatment, shortly after treatment ended and at 5+ years post-diagnosis. They also answered questions regarding treatment decision-making and palliative care discussions and provision of post-treatment survivorship plans.

      4c3880bb027f159e801041b1021e88e8 Result

      74% of long-term survivors had surgery, 43% had experienced a recurrence and 5% had participated in a clinical trial. None were current smokers.

      The most common (and problematic) late and long term symptoms and side effects were shortness of breath (39%), fatigue (28%) and anxiety (24%). Memory problems were also rated as common (27%).

      Long-term survivors indicated that during treatment, physical side effects were most problematic but post-treatment and long-term, emotional effects were more difficult. Financial issues were also more problematic 5+ years after treatment compared with other time periods. Both discussions of palliative care and provision of survivorship care plans were rare.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Long-term lung cancer survivors were once considered ouliers but today those diagnosed are increasingly living five years and longer. How do the late and long-term physical effects of lung cancer and its treatments differ from survivors of other types of cancer? How do long-term survivors manage stigma and survivor guilt? What physical and emotional support and services do they need? This survey provides initial insights into the physical. emotional and financial effects of living longer with lung cancer but more research is needed to allow us to more fully understand how we can support our long-term survivors.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.02 - Line of Therapy and Patient Preferences Treating Lung Cancer: A Discrete-Choice Experiment (Now Available) (ID 14107)

      13:35 - 13:40  |  Presenting Author(s): Andrea Ferris  |  Author(s): John F.P. Bridges, Upal Basu Roy, Ellen Janssen

      • Abstract
      • Presentation
      • Slides

      Background

      Patient preferences now play an important role in cancer research, regulatory science, and value assessment. While there is a growing literature exploring the preference of patients with lung cancer, few studies have explored how preferences vary with patients’ treatment experience. We sought to quantify patient preferences for the benefits and risks of therapy and explore how they vary across line of treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Preferences were estimated using a discrete choice experiment (DCE) developed in partnership with a patient and stakeholder advisory boards. A D-optimal experimental design was used to generate 3 blocks of 9 choice tasks spanning five attributes: progression-free survival (PFS), short-term side effects, long-term side effects, risk of developing late-onset side effects, and mode of administration – each defined across 3 relevant levels. A diverse sample was recruited via email sent to the LUNGevity lung cancer patient database and via social media. A choice mode was estimated use a conditional logistic regression where the dependent variable was the respondents preferred treatment in each profile. The relative attribute importance (conditioned on the chosen attribute levels) was then compared across the respondents’ self-reported line of treatment.

      4c3880bb027f159e801041b1021e88e8 Result

      In total we had 350 eligible respondents, of which 279 (80%) completed as least on DCE task of which 3% did not receive a pharmacotherapy, 39% received first line therapy, and 58% had two or more lines of theory. As with previous studies, PFS was the most important attribute for patients and was similarly valued (P=0.406) among first- and later (second lines and more) lines of treatment (33.4% v 33.8%). Patients on first-line treatment placed great emphasis (P<0.001) on long-term side (18.9% v 14.1%) and late onset side effects (15.3% v 10.3%), but less emphasis (P<0.001) on short-term side effects (27.8% v 29.8 %) and mode of administration (4.6% v 12.0%) than those on later lines.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Population estimate of patient preference remain important, but more effort is needed to understand how patient preference vary across patient with different backgrounds and treatment experiences. We show that line of treatment does not effect how patients value time, but their experience may have an impact on treatment characteristics. Latent class analysis may allow for the identification of groups with similar preferences that could allow for multivariate analyses to explain preference heterogeneity.

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      MA07.03 - Attitudes to Lung Cancer in Europe: Findings from a Global Consumer Survey (Now Available) (ID 12579)

      13:40 - 13:45  |  Presenting Author(s): Jesme Fox  |  Author(s): Aoife McNamara, Maureen Rigney, Greg Manuel, Sarah Winstone

      • Abstract
      • Presentation
      • Slides

      Background

      If lung cancer is diagnosed early, patients’ chances of successful treatment are increased. Stigma
      around lung cancer, as a tobacco-related cancer, can discourage patients from talking to their doctor
      about potential symptoms. In 2017, the GLCC commissioned Populus to undertake an international
      consumer survey in each of the 25 countries of the GLCC members.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      1,000 adults, in 16 European countries, participated via an online survey in July 2017. To assess
      attitudes to lung cancer, they were told that lung cancer is mainly caused by smoking and other
      tobacco products. They were then asked the extent to which they agreed or disagreed with the
      statement: “I have less sympathy for people with lung cancer than for people with other cancers.”

      4c3880bb027f159e801041b1021e88e8 Result

      One in five (20%) people in Europe agreed that they have less sympathy for people with lung cancer
      than other forms of cancer (Chart 1). There was variation between countries with 30% of people in
      Portugal agreeing they have less sympathy in comparison to only 17% agreeing in Denmark, the
      Netherlands, Norway, Russia, Slovenia and Spain. Men in Europe are generally less sympathetic
      than women, and those aged over 55 are most sympathetic. In addition, there was a statistically
      significant correlation between those countries with lower cigarette consumption and people agreeing
      that they have less sympathy for people with lung cancer.

      Chart 1: European attitudes to lung cancer

      glcc - european attitudes - chart 1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Everyone - no matter what the cause of their cancer - deserves to have high quality treatment and
      care. The persistent and varied levels of stigma associated with lung cancer across Europe needs to
      be addressed, so that people experiencing symptoms are not discouraged from seeking early
      intervention.

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      MA07.04 - Discussant - MA 07.01, MA 07.02, MA 07.03 (Now Available) (ID 14596)

      13:45 - 14:00  |  Presenting Author(s): Kim Norris

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA07.05 - Psychosocial Needs and Programs of Cancer Patients/Survivors and Their Relatives: Unmet Needs from an International Study (Now Available) (ID 12062)

      14:00 - 14:05  |  Presenting Author(s): Csaba László Dégi  |  Author(s): Samantha Serpentini, Savita Goswami

      • Abstract
      • Presentation
      • Slides

      Background

      In consideration of the dynamic nature of cancer patients’ needs, systematic understanding of their unmet needs from a socio-ecological perspective may be essential as the patients’ needs and available services are likely to vary by different healthcare systems in different countries. To investigate the role of geographical influence in cancer patients’ unmet needs, this study seeks to compare the unmet needs of and available programs for cancer patients/survivors and their family members by different types of healthcare systems across different countries.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The IPOS Survivorship Online Survey is distributed to international and regional Psycho-Oncology organization members, which covers countries in six continents. Survey participants’ countries where they practice/research will be categorized into four groups by the types of healthcare system: Beveridge Model, Bismarck Model, National Health Insurance Model, and Out-of-Pocket Model.

      4c3880bb027f159e801041b1021e88e8 Result

      With estimated survey to be completed by August 30th, 2018, repeated measures ANOVA will be employed to test differences in patients’ unmet needs by the four healthcare system groups, separately for patients’ unmet needs and their family caregivers’. Differences by individual countries will also be explored.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Findings will provide a global overview and a specific knowledge of the geografical differences in the psychosocial unmet needs and psycho-oncological programs for cancer patients/survivors and their family members/caregivers. Findings will also guide how to prioritize areas of cancer care that require improvement in psycho-oncology interventions and practices; and to highlight critical aspects for delivering quality care that vary by healthcare systems.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.06 - Telephonic Communication In Palliative Care For Better Management Of Terminal Cancer Patients In Rural India -  An NGO Based Approach.  (Now Available) (ID 11905)

      14:05 - 14:10  |  Presenting Author(s): Nabanita Mandal

      • Abstract
      • Presentation
      • Slides

      Background

      Due to financial incapability and absence of manpower poor families often fail to carry their advanced cancer patients to the nodal centres. This pilot study will explore whether communication by mobile phone can lessen this burden.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Initially a plan was generated regarding management of an advanced cancer patient in a nodal centre at District Head Quarter. Subsequently every two week a trained social worker attached to nodal centre will follow up and give necessary advice and emotional support to the patients and their families through their registered mobile phone number. Patient’s family were also encouraged to communicate with the team by phone in case of fresh complain and urgency in between.

      4c3880bb027f159e801041b1021e88e8 Result

      Since initiation in January 2017, 210 cancer patients were contacted by mobile phone every two weeks to enquire about their difficulties. In 76% of the situation trained social workers could give necessary advice by phone regarding management of their physical symptoms. Moreover patient’s family were really overwhelmed by the emotional support offered by the team over phone. Only 24% of cancer patients has to attend the nodal centre for expert advice from Palliative Care specialists.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This novel approach helped
      * In providing regular physical and emotional support to the patients and their families.

      * In significantly reducing the financial and manpower problems of carrying patients to the nodal units.
      * In improve the quality of life of patients by continuous guidance.


      More and more team members can take help of this new strategy for better communication and uninterrupted care.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.07 - Identifying the Severity of Psychosocial Symptoms Among Patients Diagnosed with Lung Cancer. Do We Really Need Emotional Support Groups? (ID 13701)

      14:10 - 14:15  |  Presenting Author(s): Arooj Fatima  |  Author(s): Syed Sammar Abbas Zaidi

      • Abstract

      Background

      Lung cancer is the second most common cancer among men and women. Most of the lung cancers are diagnosed at later stages among those patients who are underprivileged. The diagnosis and treatment of lung cancer is a continuous emotional distress for both patient and their family. We aim to identify the severity of depression, emotional distress, stress and mental fatigue among those patients who are diagnosed with lung cancer .

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A cross sectional study was conducted in Shaukat Khanum Hospital, Lahore from March 2014 to April 2015. Exclusion and Inclusion criteria were made. 150 were enrolled in the study. Socio demographic characteristics were evaluated using Beck Depression Inventory and socio demographic form. Severity of depression was estimated by using Hamilton D (HAM-D). Various variables were analysed including parent’s age, level of education, socioeconomic status, gender and number of children.

      4c3880bb027f159e801041b1021e88e8 Result

      68% of the participants exhibited severe range of depression. 27% showed moderate depression where as 5% participants were showing the mild range of depression. An inverse co relation was found between educational status, occupational status (paid or unpaid), their marital status, socioeconomic family status and depression. Women 71% were found be more depressed than males.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We concluded that majority of patients from psychosocial symptoms particularly depression and it is mainly associated with some factors. There is need to incorporate patients into the diagnosis and treatment process so that we can over come the effects of depression on the health outcomes of patients diagnosed with lung cancer. This can only be possible through appropriate education and emotional support programmes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.08 - Discussant - MA 07.05, MA 07.06, MA 07.07 (Now Available) (ID 14597)

      14:15 - 14:30  |  Presenting Author(s): Jennifer C King

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA07.09 - Willingness to Perform Multiple Biopsies to Improve Quality of Lung Cancer Care: Understanding the Oncologists’ Perspective (Now Available) (ID 14096)

      14:30 - 14:35  |  Presenting Author(s): Upal Basu Roy  |  Author(s): Margery Jacobson, Andrea Ferris

      • Abstract
      • Presentation
      • Slides

      Background

      Biomarker testing of advanced-stage non-small cell lung cancer (NSCLC) at the time of diagnosis is required to determine if a patient will benefit from a targeted therapy or immunotherapy. A patient may, however, need additional biopsies (rebiopsy) if the cancer recurs to determine the next line of therapy or to determine eligibility for a new drug or participation in a clinical trial. A LUNGevity study, conducted with 340 patients, revealed that patients were willing to undergo rebiopsies if that meant access to additional treatment options at the time of recurrence. However, only 36% of patients reported that their doctors recommended repeat biopsies at progression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To understand this patient-physician communications gap, we conducted an IRB-approved semi-structured survey-based study of 130 oncologists from academic research centers, community cancer centers, and private practice.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 130 oncologists surveyed,

      - Ninety percent of oncologists reported recommending a rebiopsy to their patients. However, when stratified by advanced-stage patient volume, oncologists with higher advanced-stage patient volumes reported higher rebiopsy and testing rates than those with low volumes (95% vs. 78%, p<0.05). Only 29% of the oncologists prescribed a rebiopsy in the past one year.

      - Major barriers to rebiopsy reported by oncologists included cost/reimbursement of a rebiopsy and treatment delay for 2nd- or subsequent lines of therapy

      - Among the types of biomarker testing performed at the time of progression, oncologists were more likely to prescribe testing for biomarkers with approved treatments (driver mutations – 94%, PD-L1 – 85%) unlike biomarkers for treatments in clinical development (43%) (p<0.05).

      - A forward linear regression analysis revealed that positive predictors of rebiopsy included treatment at a NCI Designated Cancer Center, while treatment at a community cancer center or private practice, presence of driver mutations at the time of diagnosis, and performance status of patient were negative predictors of rebiopsy

      - When presented with specific treatment scenarios for biomarkers (EGFR and ALK) that have 2nd-line treatment options, oncologists differed in their approach, suggesting a need for oncologist education about rebiopsying and subsequent biomarker testing

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study demonstrates that rebiopsy practices vary by practice settings and volume of advanced-stage lung cancer patients. Even when rebiopsies are prescribed, a comprehensive biomarker profile of the tumor may not be obtained, due to variations in tests requested. A major implication is the need for appropriate oncologists’ education to ensure practice change for delivery of optimal care to lung cancer patients.

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      MA07.10 - Utilizing a Personalized Navigation Program to Identify Barriers and Increase Clinical Trial Participation Among Lung Cancer Patients (Now Available) (ID 13482)

      14:35 - 14:40  |  Presenting Author(s): Andrew Ciupek  |  Author(s): Tara Perloff, Achintya Jaitly, Jennifer C King

      • Abstract
      • Presentation
      • Slides

      Background

      Only about 5% of cancer patients participate in clinical trials. We previously conducted a survey of U.S. lung cancer patients and found that only 22% reported discussing clinical trials with their oncologist at the time of making treatment decisions. We hypothesized that a personalized navigation program could both increase rates of trial discussion and identify barriers to participation among lung cancer patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We asked callers to Lung Cancer Alliance's 1-800 support line if they had considered clinical trial participation and referred willing callers to a navigator for further discussion. Navigators provided basic clinical trial education and a personalized list of trial matches. Patients were encouraged to discuss these trials with their treating oncologist. Navigators then regularly followed up with participants, via email or phone, at two to four-week intervals, to offer further support and collect outcomes information.

      4c3880bb027f159e801041b1021e88e8 Result

      We referred sixty callers to a navigator. Only 43% of callers reported a prior clinical trials conversation with their provider. Patients who had not started treatment or were on first-line treatment reported lower discussion rates (30%) than those on later treatment lines (60%). Among patients with follow up, 13 of 20 patients who had not discussed trials with their provider reported doing so after navigation. Ten of eleven patients that had a previous trial conversation initiated an additional one. Primary reasons given for not talking discussing after navigation were having stable disease on a current treatment or waiting for a clinical result. Ten patients reported contacting a trial. Primary reasons for not contacting a trial after discussion were disease progression, choosing a standard of care alternative, or waiting for a clinical result. Four patients have enrolled on a trial. Two patients were determined ineligible for a trial they approached for not meeting listed eligibility criteria and two for reasons not appearing in public trial information.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We identified barriers throughout the clinical trials consideration and enrollment process. One set of barriers was related to care coordination, as exemplified by low rates of trial discussion during early stages of treatment and patient reports of delayed trial consideration when currently receiving treatment or waiting on a clinical result. Communication of trial information was another area presenting barriers, as exemplified by exclusion of patients from trials for reasons not readily apparent from public trial information. Improving integration of trial discussion during care and ensuring availability of accurate, updated trial information may be essential to increase trial participation.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.11 - Drug Price Comparison in Advanced Lung Cancer – High Cost Prices is Accompanied by Patient Benefits? (Now Available) (ID 14015)

      14:40 - 14:45  |  Presenting Author(s): Luciene Bonan

      • Abstract
      • Presentation
      • Slides

      Background

      In our recent decade we are seen new drugs coming up with high speed development to attend personalized conditions in lung cancer treatment. After the first TKI for EGFR mutation, many other target drugs such as TKI for ALK/ROS1 alteration, third-generation EGFR TKI, anti-PD-1/PD-L1 immunotherapies bring together an improvement in survival with better quality of life than chemotherapies. But this new specialty drugs are also testing the affordability of the market with new launched ceiling prices. Frequently, their prices have been settled down in a context of an unmet condition appeal rather than the truly health benefits. In pricing it is a common practice to use the external reference price between countries to align the prices based on international market. But if the first price is launched (frequently in USA) in countries that don’t use metrics based on evidence or clinical benefits, the price plateau could be replicated even without necessarily deserving this price. The objective of this presentation is to show the price comparison of drugs included in TKI class and immunotherapy class between high and middle-income countries. Then to compare the cost-treatment of therapies commonly used in advanced lung cancer and their magnitude of clinical benefit.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All local currencies were converted to US dollars using PPP factor. The magnitude of effect was evaluated based on the ESMO Magnitude of Clinical Benefit Score.

      4c3880bb027f159e801041b1021e88e8 Result

      USA has the highest drug price followed by Brazil, especially in recent launched drugs. Costs of advanced lung cancer treatment significantly increase 5 times more when compared first-generated TKI and new generation TKI. Immunotherapy for second line costs 6 times more than first line with EGFR TKI and could cost more than 7 to 130 times the chemotherapy with docetaxel. Clinical benefits do not reach the same scale.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The market of anticancer drug increasing 10% annually, but clinical benefits don’t advance in the same compass. Specialized drugs come into the market with pricing warrant of unmeet conditions, but if we think in precision medicine all new drug-target biomarker could be priced higher because it will cover a rare or unmet condition. In the context of precision medicine, is it fear a patient pays more because he has a different biomarker for the same clinical condition? If countries do not start to evaluate and pricing drugs based on value, market strategists will continue to test the ceiling price that health systems can(not) afford.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.12 - Discussant - MA 07.09, MA 07.10, MA 07.11 (Now Available) (ID 14598)

      14:45 - 15:00  |  Presenting Author(s): Govind Babu Kanakasetty

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS05 - Diagnostic Dilemma in Lung Cancer (ID 784)

    • Type: Mini Symposium
    • Track: Pathology
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 201 BD