Virtual Library

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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 8
    • Now Available
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      OA04.01 - A Phase III Randomized Study of Nivolumab/Ipilimumab vs Nivolumab for Previously Treated Stage IV Squamous Cell Lung Cancer (Now Available) (ID 872)

      15:15 - 16:45  |  Presenting Author(s): Lyudmila Bazhenova  |  Author(s): Mary Redman, Scott Gettinger, Fred R. Hirsch, Philip Mack, Lawrence H Schwartz, David R Gandara, Jeffrey D Bradley, Thomas Stinchcombe, Natasha B Leighl, Suresh S Ramalingam, Susan Tavernier, Katherine Minichiello, Karen Kelly, Vassiliki A Papadimitrakopoulou, Roy S. Herbst

      • Abstract
      • Presentation
      • Slides

      Background

      Lung-MAP is a master protocol for patients (pts) with stage IV previously treated SqNSCLC. S1400I enrolled pts who were not eligible for a biomarker-matched sub-study. (Lung-MAP Sub-Study S1400I, NCT02785952)

      Method

      S1400I is phase III randomized trial for immunotherapy-naïve patients with ECOG 0-1 not selected by PD-L1 expression. Pts were assigned 1:1 to nivolumab and ipilimumab (N+I) vs nivolumab (N). N was given at 3 mg/kg q 2w, I was given at 1 mg/kg q 6w. The primary endpoint was overall survival (OS). Secondary endpoints: investigator-assessed progression-free survival (IA-PFS), response by RECIST 1.1, and toxicity.

      Result

      From December 18, 2015 to April 23, 2018, 275 pts enrolled and 252 determined eligible (125 N+I and 127 N). Median follow up for patients still alive was 17.4 months. The study was closed for futility at an interim analysis. Baseline characteristics were similar across arms. mOS was 10.0 m (8.0-12.8) and 11.0 m (8.2-13.5) for N+I and N. HR 0.97 (0.71-1.31), p 0.82. mPFS was 3.8 m (2.3-4.2) and 2.9 m (1.8-3.9) for N+I and N. HR 0.84 (0.64-1.09), p 0.19. The response rate was 18% (12-25) in N+I and 17 % (11, 24) in N. Outcomes were similar across TMB subgroups and PD-L1 expression levels. Most AE were low grade. There were 5 grade 5 AE in N+I arm and 1 in N arm. Grade ≥3 treatment-related AEs occurred in 48(39%) of pts on N+I vs 38(31%) on N. irAE reported in 39% of pts on N+I and 34% of patients on N. Drug-related AEs led to discontinuation in 25% of pts on N+I and 16% of pts on N.

      OS and PFS based on TMB and PD-L1

      N+I

      Median in months

      N

      Median in months
      HR p
      OS PD-L1 ≥5 14.1 (5.8-17.5) 12.0 (8.2-19.8) 1.06 (0.58-1.92) 0.86
      OS PD-L1 <5 8.3 (6.0-10.7) 10.3 (6.3-13.5) 1.01 (0.62-1.65) 0.97
      OS TMB ≥10 13.1 (9.3-17.0) 11.4 (8.2-16.1) 0.86 (0.56-1.32) 0.48
      OS TMB <10 7.6 (5.7-10.2) 10.0 (6.3-15.2) 1.08 (0.68-1.71) 0.74
      PFS PD-L1 ≥ 5 3.9 (1.7-7.1) 2.9 (1.8-4.7) 0.65 (0.38-1.08) 0.10
      PFS PD-L1 <5 4.4 (2.1-6.0) 1.6 (1.5-3.0) 0.64 (0.41-1.01) 0.06
      PFS TMB ≥ 10 4.2 (3.4-5.9) 3.4 (1.8-5.3) 0.75 (0.52-1.10) 0.15
      PFS TMB < 10 1.9 (1.5-4.1) 2.7 (1.6-3.3) 0.92 (0.62-1.39) 0.70

      Conclusion

      S1400I failed to show improvement in outcomes with N+I. Study was closed for futility at interim analysis. Toxicities were not different between two arms. Molecular correlates will be presented at the meeting.

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      OA04.02 - CheckMate 817: First-Line Nivolumab + Ipilimumab in Patients with ECOG PS 2 and Other Special Populations with Advanced NSCLC (Now Available) (ID 1876)

      15:15 - 16:45  |  Presenting Author(s): Fabrice Barlesi  |  Author(s): Clarisse Audigier-Valette, Enriqueta Felip, Tudor-Eliade Ciuleanu, Kevin Jao, Erika Rijavec, Laszlo Urban, Jean-Sébastien Aucoin, Cristina Zannori, Karim Vermaelen, Osvaldo Aren Frontera, Neal Ready, Alessandra Curioni Fontecedro, Helena Linardou, Elena Poddubskaya, Jürgen R. Fischer, Ingrid Iordan, Harry JM Groen, Rathi N Pillai, Sunney Li, Joseph Fiore, Han Chang, Angelic Acevedo, Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      Data are limited for immunotherapy in patients with advanced NSCLC and poor performance status or other comorbidities. CheckMate 817 is a multi-cohort, open-label phase 3b/4 study investigating safety and efficacy of flat-dose nivolumab plus weight-based low-dose ipilimumab in advanced NSCLC. Here we evaluate this regimen as first-line treatment in special populations (cohort A1) and a reference population (cohort A; previously reported).

      Method

      Patients had previously untreated advanced NSCLC. Cohort A1 (n=198) had ECOG PS 2 or ECOG PS 0–1 with 1 of: asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV. Cohort A (n=391) had ECOG PS 0–1. Patients with known EGFR mutations or ALK translocations sensitive to available targeted therapy were excluded from both cohorts. Nivolumab 240 mg Q2W plus ipilimumab 1 mg/kg Q6W was administered for two years or until disease progression/unacceptable toxicity. Safety and efficacy endpoints were assessed; cohort A1 analyses were exploratory.

      Result

      Cohort A1 patients were grouped as: ECOG PS 2 (n=139) and all other special populations (AOSP; n=59). Baseline characteristics were generally balanced between cohorts. Rates of grade 3–4 treatment-related adverse events (TRAEs) were similar between cohorts; within cohort A1, grade 3–4 TRAEs were numerically higher in AOSP versus the ECOG PS 2 subgroup; TRAEs leading to discontinuation were similar across populations (Table). ORR was 25% in cohort A1 (patients with ECOG PS 2, 20%; AOSP, 37%) and 35% in cohort A. PFS was numerically shorter in cohort A1 than cohort A; high TMB (≥10 mut/Mb) and higher PD-L1 expression (≥1% or ≥50%) were associated with numerically longer PFS in both cohorts (Table).

      table_v3.jpg

      Conclusion

      First-line flat-dose nivolumab plus weight-based ipilimumab showed a consistent safety profile in special populations with advanced NSCLC, including those with ECOG PS 2. Patients with either high TMB or higher tumor PD-L1 expression appeared to exhibit improved efficacy.

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      • Abstract
      • Presentation
      • Slides

      Background

      Platinum-based chemotherapy remains 1st line therapy for advanced non-small cell lung cancer (NSCLC) without oncogenic drivers in China. Camrelizumab (SHR-1210, a potent anti‒PD-1 monoclonal antibody) has shown promising activity in multiple malignancies. Here, we report interim analysis results on efficacy and safety of camrelizumab plus carboplatin/pemetrexed as 1st line treatment in Chinese advanced/metastatic non-squamous NSCLC patients with negative oncogenic drivers.

      Method

      In this open-label, randomized, multicenter phase 3 study (SHR-1210-303), patients with advanced/metastatic, non-squamous NSCLC with negative EGFR or ALK were stratified by sex and smoking history (≥ 400/year versus ˂ 400/year) and were randomly assigned (1:1) to receive 4 to 6 cycles of carboplatin (AUC=5) plus pemetrexed (500 mg/m2) with or without camrelizumab (200 mg), followed by pemetrexed with or without camrelizumab as maintenance therapy up to disease progression or intolerable toxicity. Treatment was given every 3 weeks. Crossover to camrelizumab monotherapy was permitted for patients in the chemotherapy arm who had confirmed disease progression. The primary endpoint was PFS per blinded independent central review according to RECIST v1.1. Secondary endpoints included ORR, DCR, DoR and OS. Data of subgroup analysis will be reported. Clinical Trials.gov number: NCT03134872.

      Result

      Between May 12, 2017 and Jun 6, 2018, 419 patients were randomized, among whom 205 received camrelizumab plus chemotherapy and 207 received chemotherapy treatment. After a median follow-up of 11.9 months, median PFS was 11.3 months (95% CI 9.5‒not reached) in camrelizumab plus chemotherapy arm and 8.3 months (95% CI 6.0‒9.7) in chemotherapy arm (HR 0.61 [95% CI 0.46‒0.80], p=0.0002). ORR, DCR, DoR and OS with camrelizumab plus chemotherapy were superior to chemotherapy (Table 1). Grade 3/4 adverse events occurred in 66.8% of patients in camrelizumab plus chemotherapy arm and 51.2% of patients in chemotherapy arm. There were 5 treatment-related deaths in camrelizumab plus chemotherapy arm and 4 in chemotherapy arm.

      Table 1. Responses per blinded independent central review and overall survival in the total study population

      Camrelizumab plus chemotherapy

      (n=205)

      Chemotherapy alone

      (n=207)
      p-value
      Objective response rate 60.0% (53.0‒66.8) 39.1% (32.4‒46.1) p<0.0001
      Disease control rate 87.3% (82.0‒91.6) 74.4% (67.9‒80.2) p=0.0009
      Duration of response (months) 17.6 (11.6‒NR) 9.9 (8.5‒13.8) p=0.0356
      Overall survival (months) NR (17.1‒NR) 20.9 (14.2‒NR) p=0.0272
      Data are shown in % (95% CI) or median (95% CI). NR: not reached.

      Conclusion

      First-line camrelizumab plus chemotherapy shows substantial clinical benefit in patients with advanced/metastatic non-squamous NSCLC with negative EGFR or ALK in terms of PFS, ORR, and OS and acceptable safety profiles. The combination should become novel standard 1st line therapy for this population.

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      OA04.04 - Discussant - OA04.01, OA04.02, OA4.03 (Now Available) (ID 3742)

      15:15 - 16:45  |  Presenting Author(s): Martin Sebastian

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA04.05 - KEYNOTE-021: TMB and Outcomes for Carboplatin and Pemetrexed With or Without Pembrolizumab for Nonsquamous NSCLC (Now Available) (ID 2630)

      15:15 - 16:45  |  Presenting Author(s): Corey Jay Langer  |  Author(s): Shirish Gadgeel, Hossein Borghaei, Amita Patnaik, Steven F. Powell, Ryan D Gentzler, James Chih-Hsin Yang, Matthew A. Gubens, Lecia Sequist, Mark Awad, Razvan Cristescu, Deepti Aurora-Garg, Andrew Albright, Andrey Loboda, Julie Kobie, Jared K. Lunceford, Mark Ayers, Gregory M Lubiniecki, Bilal Piperdi, M. Catherine Pietanza, Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      KEYNOTE-021 cohort C was the first study to show antitumor activity for pembrolizumab plus platinum-based chemotherapy in previously untreated advanced nonsquamous NSCLC; the combination significantly improved efficacy vs platinum-based chemotherapy alone in cohort G. We explored the relationship between TMB and outcomes in KEYNOTE-021 cohorts C and G.

      Method

      All patients in cohort C received pembrolizumab plus carboplatin and pemetrexed. Patients in cohort G were randomized 1:1 to pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone. TMB was determined by whole-exome sequencing of tumor and matched normal DNA. Association of TMB (continuous, log10 transformed) with outcomes for pembrolizumab plus chemotherapy and chemotherapy alone were assessed using logistic regression for ORR and Cox proportional hazards models for PFS and OS adjusted for ECOG PS; statistical significance was determined at the 0.05 level without multiplicity adjustment. The correlation of TMB (continuous, log10­ transformed) with PD-L1 TPS (square root scale) was assessed in the combined population. The clinical utility of TMB for ORR using a prespecified TMB cutpoint of 175 Mut/exome (~13 Mut/Mb by FoundationOne CDx) was assessed for pembrolizumab + chemotherapy.

      Result

      TMB data were evaluable for 70 patients: 12/24 (50.0%) in cohort C, 32/60 (53.3%) in the cohort G pembrolizumab plus chemotherapy arm, and 26/63 (41.3%) in the cohort G chemotherapy only arm; median age was 65 years (IQR, 57-70) and 61% were female. Baseline characteristics were generally similar in the TMB-evaluable and total populations. TMB as a continuous variable was not significantly associated with ORR, PFS, or OS for pembrolizumab plus chemotherapy (one-sided P = 0.180, 0.187 and 0.081, respectively) or chemotherapy alone (one-sided P = 0.861, 0.795 and 0.763, respectively). There was no significant correlation between TMB and TPS (r=0.12, P=0.34). ORR (95% CI) in patients treated with pembrolizumab plus chemotherapy was 60.8% (38.5-80.3) in the 23 patients with TMB <175 and 71.4% (47.8-88.7) in the 21 patients with TMB ≥175.

      Conclusion

      In this exploratory analysis, TMB was not significantly associated with efficacy of pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone as first-line therapy for metastatic nonsquamous NSCLC. TMB was not significantly correlated with PD-L1 expression. Among pembrolizumab plus chemotherapy-treated patients, ORR was high in both the TMB low and high subgroups. Sample size is a limitation of this study; exploration in larger datasets is required to understand any differential efficacy of pembrolizumab plus chemotherapy vs chemotherapy alone based on TMB status.

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      OA04.06 - Evaluation of TMB in KEYNOTE-189: Pembrolizumab Plus Chemotherapy vs Placebo Plus Chemotherapy for Nonsquamous NSCLC (Now Available) (ID 1936)

      15:15 - 16:45  |  Presenting Author(s): Marina Chiara Garassino  |  Author(s): Delvys Rodriguez-Abreu, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Giovanna Speranza, Martin Reck, Rina Hui, Michael Boyer, Razvan Cristescu, Deepti Aurora-Garg, Andrew Albright, Andrey Loboda, Julie Kobie, Jared K. Lunceford, Mark Ayers, Gregory M Lubiniecki, Bilal Piperdi, M. Catherine Pietanza, Edward Garon

      • Abstract
      • Presentation
      • Slides

      Background

      First-line pembrolizumab plus chemotherapy with pemetrexed and platinum significantly improved OS (HR 0.49, P < .001), PFS (HR 0.52, P < .001) and ORR (47.6% vs 18.9%, P < .001) vs placebo plus chemotherapy with pemetrexed and platinum for metastatic nonsquamous NSCLC in the double-blind phase 3 KEYNOTE-189 study (NCT02578680); benefit was observed in all analyzed subgroups, including PD-L1 TPS <1%, 1-49%, and ≥50%. We explored the association of TMB with efficacy in KEYNOTE-189.

      Method

      616 patients were randomized 2:1 to pembrolizumab plus chemotherapy or placebo plus chemotherapy. TMB was determined by whole-exome sequencing of tumor and matched normal DNA. Association of TMB (continuous log10 transformed) with outcomes in each arm was assessed using Cox proportional hazards models (OS, PFS) and logistic regression (ORR); statistical significance was determined at the 0.05 level without multiplicity adjustment. The clinical utility of TMB on outcomes was assessed using prespecified TMB cutpoints of 175 and 150 Mut/exome (~13 and ~10 Mut/Mb by FoundationOne CDx). Data cutoff was 21 Sep 2018.

      Result

      293 (48.3%) treated patients had evaluable TMB data: 207 for pembrolizumab plus chemotherapy, 86 for placebo plus chemotherapy. Baseline characteristics and outcomes were generally similar in the TMB-evaluable and total populations. TMB as a continuous variable was not significantly associated with OS, PFS, or ORR for pembrolizumab plus chemotherapy (one-sided P = .174, .075 and .072, respectively) or placebo plus chemotherapy (two-sided P = .856, .055 and .434, respectively). Pembrolizumab plus chemotherapy improved OS, PFS, and ORR for TMB ≥175 and <175 (Table). Results were similar for TMB ≥150 and <150.

      Conclusion

      TMB was not significantly associated with efficacy of pembrolizumab plus chemotherapy or placebo plus chemotherapy as first-line therapy for metastatic nonsquamous NSCLC. Pembrolizumab plus chemotherapy had a similar OS benefit in the TMB-high and low subgroups.

      TMB ≥175 TMB <175

      Pembrolizumab plus Chemotherapy

      n = 100

      Placebo plus Chemotherapy

      n = 34

      Pembrolizumab plus Chemotherapy

      n = 107

      Placebo plus Chemotherapy

      n = 52
      Median OS (95% CI), mo 23.5
      (20.2-NE)
      13.5
      (7.0-NE)
      20.2
      (15.8-NE)
      9.9
      (7.4-19.1)
      HR (95% CI) 0.64 (0.38-1.07) 0.64 (0.42-0.97)
      Median PFS (95% CI), mo 9.2
      (7.6-14.0)
      4.7
      (4.0-5.5)
      9.0
      (6.7-11.1)
      4.8
      (4.5-6.6)
      HR (95% CI) 0.32 (0.21-0.51) 0.51 (0.35-0.74)
      ORR, % (95% CI) 50.0
      (39.8-60.2)
      11.8
      (3.3-27.5)
      40.2
      (30.8-50.1)
      19.2
      (9.6-32.5)

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      OA04.07 - Mutations Associated with Sensitivity or Resistance to Immunotherapy in mNSCLC: Analysis from the MYSTIC Trial (Now Available) (ID 901)

      15:15 - 16:45  |  Presenting Author(s): Naiyer A Rizvi  |  Author(s): Byoung Chul Cho, Niels Reinmuth, Ki Hyeong Lee, Alexander Luft, Myung-Ju Ahn, Vassiliki A Papadimitrakopoulou, John Victor Heymach, Urban Scheuring, Brandon Higgs, Jiabu Ye, Michael Kuziora, Song Wu, Feng Liu, Han Si, Solange Peters

      • Abstract
      • Presentation
      • Slides

      Background

      In the Phase 3 MYSTIC study (NCT02453282), blood tumour mutational burden, at various thresholds from ≥12 to ≥20 mut/Mb (bTMB≥20), has been associated with improved OS and PFS with first-line durvalumab (D; anti-PD-L1) +/- tremelimumab (T; anti-CTLA-4) versus platinum-based chemotherapy (CT). Specific gene mutations have been associated with resistance (STK11 and KEAP1) or sensitisation (ARID1A) to anti-PD-(L)1 monotherapy. However, the relationship between gene alterations and response to anti-PD-(L)1 ± anti-CTLA-4 are not well characterised. Here we explore associations between mutations and survival outcomes in the MYSTIC patient population.

      Method

      Circulating tumour DNA from baseline blood specimens was profiled using the GuardantOMNI platform. Samples were available from 1003 patients (89.7% of ITT; 943 mutation-evaluable). Survival outcomes were analysed in patients with (m) or without (wt) non-synonymous somatic mutations in STK11, KEAP1, or ARID1A.

      Result

      In the mutation-evaluable population, STK11m, KEAP1m, and ARID1Am frequencies were 16%, 18% and 12%, respectively (19%, 20%, and 11% [nonsquamous]; 7%, 13%, and 15% [squamous]). Across treatment arms, patients with STK11m or KEAP1m had a shorter median OS (mOS) than patients with STK11wt (D, 10.3 vs 13.3 mo; D+T, 4.4 vs 11.3 mo; CT, 6.7 vs 13.1 mo) or KEAP1wt (D, 7.6 vs 14.6 mo; D+T, 9.2 vs 11.3 mo; CT, 6.3 vs 13.3 mo) mNSCLC. In the D+T arm, patients with ARID1Am had a longer mOS than patients with ARID1Awt mNSCLC (D, 8.6 vs 13.7 mo; D+T, 23.2 vs 9.8 mo; CT, 10.6 vs 12.4 mo). Additional mutational analyses will be presented.

      Conclusion

      In these analyses from the MYSTIC study, poorer outcomes were observed across treatment arms in patients with mNSCLC and mutations in STK11 or KEAP1 compared with those without the corresponding mutations. In patients receiving D+T, ARID1Am was associated with survival benefits compared with ARID1wt. These data are exploratory and require further validation.

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      OA04.08 - Discussant - OA04.05, OA04.06, OA4.07 (Now Available) (ID 3743)

      15:15 - 16:45  |  Presenting Author(s): Melissa Johnson

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA07 - Precision Medicine Involves Biology and Patients (ID 132)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 9
    • Now Available
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      OA07.01 - Osimertinib Plus Platinum/Pemetrexed in Newly-Diagnosed Advanced EGFRm-Positive NSCLC; The Phase 3 FLAURA2 Study (Now Available) (ID 2383)

      11:00 - 12:30  |  Presenting Author(s): Pasi A Jänne  |  Author(s): David Planchard, Paul Howarth, Alexander Todd, Kunihiko Kobayashi

      • Abstract
      • Presentation
      • Slides

      Background

      Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both sensitizing EGFR and T790M mutations. Osimertinib is considered the standard of care for patients with newly-diagnosed advanced/metastatic NSCLC harbouring EGFR-activating mutations, based on results of the phase 3 FLAURA trial, which demonstrated a statistically and clinically significant progression-free survival (PFS) benefit for osimertinib over erlotinib or gefitinib. Evidence indicates that adding chemotherapy to gefitinib improves efficacy outcomes versus EGFR TKI monotherapy in newly-diagnosed patients with EGFRm NSCLC (Nakamura et al JCO 2018;36:9005). Adding platinum/pemetrexed to osimertinib could further improve outcomes for newly-diagnosed patients with EGFRm-positive NSCLC.

      Method

      The phase 3, open-label, FLAURA2 study aims to assess the efficacy and safety of osimertinib plus cisplatin/carboplatin plus pemetrexed in adults with locally-advanced/metastatic EGFRm-positive (Ex19del and/or L858R) NSCLC who have not received prior therapy for advanced disease. Patients are required to have a WHO performance status (PS) 0-1, life expectancy >12 weeks and not be amenable to curative surgery or radiotherapy. An initial non-randomised run-in phase (n=30) will assess the safety and tolerability of osimertinib 80 mg once daily (QD) with either cisplatin or carboplatin, and pemetrexed, both administered every 3 weeks (Q3W) for 4 cycles, followed by osimertinib 80 mg QD plus pemetrexed maintenance Q3W until progression or discontinuation. Based on evaluation of safety data from the run-in after ≥12 patients from each group have received ≥3 cycles of study treatment or discontinued therapy, the second phase will randomise approximately 556 patients 1:1 to receive osimertinib 80 mg QD with pemetrexed and cisplatin/carboplatin for 4 cycles followed by osimertinib plus pemetrexed maintenance Q3W or osimertinib alone (80 mg QD), to be continued until progression or discontinuation. Randomisation will be stratified by race (Chinese/Asian vs. non-Chinese/Asian vs. non-Asian), WHO PS (0 vs. 1), and tissue EGFR mutation test at enrolment (cobas® EGFR Mutation Test vs local assessment). A futility analysis of the randomized phase is planned for when approximately 83 PFS events have occurred. The primary endpoint is PFS based on investigator assessment of response using RECIST 1.1 criteria (blinded central assessment is included as a sensitivity analysis). Secondary endpoints include overall survival, objective response rate, duration of response, PFS2, health-related quality of life and safety. Effects on CNS metastases in patients with lesions at baseline will be included as an exploratory endpoint. Enrolment is planned for Q3 2019 for the safety run-in and Q1 2020 for the randomized phase.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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      OA07.02 - LKB1 Mutations in Metastatic Non-Small Cell Lung Cancer (mNSCLC): Prognostic Value in the Real World (Now Available) (ID 902)

      11:00 - 12:30  |  Presenting Author(s): Norah Shire  |  Author(s): Asieh Golozar, Jenna Collins, Kathy Fraeman, Beth Nordstrom, Robert McEwen, Brandon Higgs

      • Abstract
      • Presentation
      • Slides

      Background

      Despite recent advances in treating mNSCLC, many patients fail to respond. Identifying genetic markers may help maximize clinical benefit and avoid unnecessary toxicity. LKB1/STK11 alterations (LKB1m) and co-occurring KRAS mutations/LKB1 loss (KRAS/LKB1) have been associated with poor outcomes in patients treated with immunotherapy (IO). Among chemotherapy-treated patients, however, the prognostic value is less understood. This retrospective study examined LKB1m, KRAS/LKB1 and outcomes in patients with mNSCLC receiving IO (as monotherapy or in combination) or chemotherapy in the real-world setting.

      Method

      Adult patients with mNSCLC who initiated first line (1L) treatment between Jan 2013 and Jun 2017 and had been profiled with the FoundationOne assay in routine care were enrolled from the Flatiron Health Oncology electronic medical record database. Associations between LKB1m, LKB1/KRAS and overall survival (OS) or progression-free survival (PFS) were evaluated by line of therapy (1L and second line [2L]) according to histology (non-squamous/squamous and non-squamous only) using multivariate Cox proportional hazards models. All analyses were stratified by IO or chemotherapy.

      Result

      2407 patients (1847 non-squamous) were included; average age was 66.1 years at 1L initiation. 328 (13.6%) patients harbored LKB1m and 157 (6.5%) harbored KRAS/LKB1. Among IO-treated patients in the 2L setting, LKB1m was associated with shorter OS and PFS versus wild type. A similar association was observed in the 1L setting and in the non-squamous only subgroup. In patients receiving chemotherapy, LKB1m was associated with worse outcomes only in the 1L setting. All associations were generally more pronounced among KRAS/LKB1 compared with LKB1m patients.

      Table. Association between LKB1m and OS or PFS in mNSCLC stratified by IO or chemotherapy and lines of therapy
      Mutation group
      LKB1m
      All mNSCLC Non-Squamous
      Outcome IO Chemotherapy IO Chemotherapy
      1L (n = 270) 2L (n = 670) 1L (n =2,137) 2L (n = 863) 1L (n = 187) 2L (n = 498) 1L (n = 1,687) 2L (n = 683)
      LKB1m, N (%) 40 (14.8) 111 (16.6) 288 (13.5) 83 (9.6) 38 (20.3) 97 (19.5) 257 (15.2) 75 (11.0)
      OS
      Median 341 192 340 350 431 201 356 400
      (IQR) (221 – NA) (72 – 523) (284 – 405) (307 – 451) (221 – NA) (73 – 613) (287 – 415) (307 – 453)
      HR 1.43 1.59 1.40 1.07 1.40 1.67 1.43 1.05
      (95% CI) (0.90 – 2.27) (1.25 – 2.03) (1.21 – 1.63) (0.81 – 1.41) (0.84 – 2.32) (1.27 – 2.19) (1.22 – 1.68) (0.78 – 1.42)
      PFS
      Median 122 67 136 122 125 68 136 128
      (IQR) (83 – 295) (46 – 118) (119 – 146) (97 – 147) (81 – 299) (46 – 114) (122 – 149) (98 – 153)
      HR 1.43 1.59 1.40 1.07 1.36 1.55 1.38 1.07
      (95% CI) (0.90 – 2.27) (1.25 – 2.03) (1.21 – 1.63) (0.81 – 1.41) (0.92 – 2.03) (1.22 1.97) (1.20 – 1.59) (0.82 – 1.39)
      KRAS/LKB1
      All mNSCLC Non-squamous
      IO Chemotherapy IO Chemotherapy
      1L (n = 270) 2L (n = 670) 1L (n =2,137) 2L (n = 863) 1L (n = 187) 2L (n = 498) 1L (n = 1,687) 2L (n = 683)
      KRAS/LKB1, N (%) 17 (6.3) 56 (8.4) 140 (6.6) 42 (4.9) 16 (8.6) 52 (10.4) 133 (7.9) 40 (5.9)
      OS
      Median 303 209 356 343 341 230 363 350
      (IQR) (222 – NA) (72 – 666) (272 – 450) (254 – 554) (130 – NA) (72 – 666) (284 – 462) (254 – 554)
      HR 1.46 1.63 1.55 1.27 1.44 1.78 1.61 1.28
      (95% CI) (0.74 – 2.86) (1.16 2.29) (1.26 – 1.90) (0.87 – 1.84) (0.68 – 3.05) (1.22 – 2.59) (1.29 – 2.00) (0.86 – 1.90)
      PFS
      Median 126 67 136 133 174 68 136 133
      (IQR) (77 – 291) (46 – 91) (112 – 160) (91 – 190) (72 – 295) (47 – 91) (112 – 160) (91 – 190)
      HR 1.34 1.81 1.40 1.08 1.34 1.86 1.44 1.05
      (95% CI) (0.80 – 2.24) (1.35 2.44) (1.16 – 1.68) (0.77 – 1.51) (0.76 – 2.36) (1.35 2.57) (1.19 1.75) (0.74 – 1.50)
      Note: Bold text indicates significant results; reference group for LKB1m is LKB1wt; reference group for KRAS/LKB1 is KRASwt/LKB1wt
      Median OS and PFS and IQRs are expressed in days
      Abbreviations: KRAS mutation/LKB1 loss (KRAS/LKB1), Hazard ratio (HR), Interquartile range (IQR), Confidence interval (CI), Immunotherapy (IO), Overall Survival (OS), Progression-free survival (PFS), Wild type (wt)
      Conclusion

      LKB1m and LKB1/KRAS were associated with numerically worse OS and PFS in the 1L setting, irrespective of treatment, and in IO-treated patients in the 2L setting. Results of this real-world study support previous clinical findings and suggest unique relevance of these mutations in 1L chemotherapy and for 1L and 2L IO.

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      OA07.03 - Clinical Outcome of Non-Small Cell Lung Cancer with EGFR/HER2 Exon 20 Insertions Identified in the LC-SCRUM-Japan (Now Available) (ID 629)

      11:00 - 12:30  |  Presenting Author(s): Hibiki Udagawa  |  Author(s): Shingo Matsumoto, Yuichiro Ohe, Miyako Satouchi, Naoki Furuya, Young Hak Kim, Takashi Seto, Kenzo Soejima, Daisuke Hayakawa, Terufumi Kato, Shingo Miyamoto, Kadoaki Ohashi, Sho Saeki, Hiromitsu Ohta, Daichi Fujimoto, Akimasa Sekine, Kiyotaka Yoh, Koichi Goto

      • Abstract
      • Presentation
      • Slides

      Background

      In-frame insertions in exon 20 (Ex20ins) of EGFR/HER2 occur in 2-5 % of non-small cell lung cancer (NSCLC). There is no approved targeted therapy for patients with these mutations. Historical control data would be valuable for the development of novel targeted therapies for these rare cancers.

      Method

      A nationwide genome screening project in Japan (LC-SCRUM-Japan) has been established for the development of molecular-targeted therapies for lung cancers. In this project, 161 cancer-related genes have been analyzed by a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. The therapeutic efficacy and survival of the patients with non-squamous (non-sq) NSCLC harboring EGFR/HER2 Ex20ins were evaluated using a large-scale clinico-genomic database in the LC-SCRUM-Japan.

      Result

      A total of 3441 advanced non-sq NSCLC patients were successfully analyzed from 2015 to 2018. EGFR Ex20ins were detected in 73 patients (2%; M766_A767insASV/A767_S768insSVD/H773_V774insH/D770_N771insNPH/N771_P772insPH/others=22/17/5/4/4/21) and HER2 Ex20ins were detected in 128 patients (4%; A775_G776insYVMA/G776delinsVC/P780_Y781insGSP/others=95/16/10/7). The median age of the patients was 62 (range, 33-90) years. Eighty-one patients (40%) were male and 114 (57%) were never smoker. Two-hundred patients (99%) were diagnosed as adenocarcinoma and 1 as adenosquamous-cell carcinoma. Based on our database, the median overall survivals in patients with EGFR Ex20ins were 22.4 (95%CI, 15.3-36.8) months, and those with HER2 Ex20ins were 18.8 (13.6-30.3) months. In the patients with EGFR/HER2 Ex20ins, the objective response rate (ORR) and median progression-free survivals (mPFS) of 1st-line platinum-containing chemotherapies were 32% and 6.0 (5.7-7.0) months, respectively. The ORR and mPFS of docetaxel with or without ramucirumab were 26% and 5.1 (3.8-5.9) months, respectively. The ORR and mPFS of PD-1 inhibitor were 0% and 2.0 (1.6-2.6) months, respectively. No significant difference in the therapeutic efficacy of these drugs was observed between the patients with EGFR Ex20ins and HER2 Ex20ins. In 19 patients with EGFR Ex20ins treated with 1st/2nd generation EGFR-TKIs, the ORR was 5% (a M766_A767insASV-positive tumor responded to afatinib) and the mPFS was 2.1 (1.3-4.2) months.

      Conclusion

      The patients with EGFR/HER2 Ex20ins-positive NSCLC showed poor responses to PD-1 inhibitors and 1st/2nd generation EGFR-TKIs. These historical data are highly informative in evaluating the efficacy of novel targeted therapies for EGFR/HER2 Ex20ins-positive NSCLC.

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      OA07.04 - Discussant - OA07.01, OA07.02, OA07.03 (Now Available) (ID 3758)

      11:00 - 12:30  |  Presenting Author(s): Vladmir Cláudio Cordeiro De Lima

      • Abstract
      • Presentation
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      Abstract not provided

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      OA07.05 - High-Grade Chemotherapy-Induced Peripheral Neuropathy (CIPN):  An Analysis of ECOG-ACRIN Lung Cancer Clinical Trials (Now Available) (ID 1431)

      11:00 - 12:30  |  Presenting Author(s): Sawsan Rashdan  |  Author(s): Suzanne E Dahlberg, David E. Gerber, Alan Sandler, Joan H Schiller, David Johnson, Suresh S Ramalingam

      • Abstract
      • Presentation
      • Slides

      Background

      High-grade (CTCAE grade ≥3) CIPN implies severe symptoms and limitation of self-care activities of daily living (ADL). To date, studies characterizing the incidence of and factors associated with CIPN have been conducted almost exclusively in breast cancer populations. As such, they generally evaluate only women and lack assessment of platinum-based chemotherapy. We therefore examined the incidence and factors associated with high-grade CIPN among patients treated on ECOG-ACRIN advanced non-small cell lung cancer (NSCLC) clinical trials.

      Method

      We included two completed trials in the analysis: E1594 (comparison of 4 chemotherapy regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, carboplatin-paclitaxel) and E4599 (carboplatin-paclitaxel ± bevacizumab). We identified patients who developed treatment-related grade ≥3 CIPN. Multivariable logistic regression modeling was performed to estimate adjusted odds ratios. For the treatment variable, the reference group ended up combining the cisplatin+paclitaxel and cisplatin+docetaxel arms since their results were not significantly different from one another. Body-mass index (BMI) was categorized by median value (25.2 kg/m2).

      Result

      Among 1,989 total patients, 167 (8.4%) developed grade ≥3 CIPN. Incidence was highest for the carboplatin-paclitaxel regimen (9.9%) and lowest for cisplatin-paclitaxel (4.5%) (P=0.006). Grade ≥3 CIPN was associated with BMI (9.9% for ≥25.2 kg/m2 vs 6.9% for <25.2 kg/m2; P=0.02) and sex (6.9% for men vs 10.4% for women; P=0.006). There was a non-significant trend toward association with age (10.4% for ≥70 years versus 7.8% for <70 years; P=0.08). In multivariate analysis, chemotherapy regimen, sex, and BMI remained independently associated with grade ≥3 CIPN.

      Conclusion

      Carboplatin-paclitaxel chemotherapy, female sex, and high BMI are associated with the development of high-grade CIPN. Given the clinical severity of this condition and the potential for long-term persistence, consideration of risk-based monitoring and treatment selection may be warranted.

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      OA07.06 - Patient Knowledge and Expectations Related to Return of Genomic Results in the Lung-MAP (SWOG 1400) Biomarker-Driven Clinical Trial (Now Available) (ID 730)

      11:00 - 12:30  |  Presenting Author(s): Joshua A Roth  |  Author(s): Meghna S Trivedi, Stacy Gray, Donald Patrick, Wylie Burke, Debbie Delaney, Kate Watabayashi, Paul Litwin, Parth Shah, Katherine D. Crew, Monica Yee, Mary Redman, Vassiliki A Papadimitrakopoulou, Karen Kelly, David R Gandara, Dawn L Hershman, Scott D Ramsey

      • Abstract
      • Presentation
      • Slides

      Background

      Biomarker-driven clinical trials (BDCTs)--where participants qualify for targeted therapy sub-studies based on tumor genomic testing results--represent a new paradigm in oncology clinical trials. However, BDCTs’ complex designs are difficult to communicate to patients considering participation, and deficits in knowledge and expectations have implications for shared decision-making and informed consent. The objective of this pilot study was to evaluate patient knowledge and expectations related to return of genomic results in the Lung-MAP (SWOG 1400) BDCT.

      Method

      From 8/2017 to 4/2019, we recruited a subset of participants with advanced non-small cell lung cancer (NSCLC) from among patients enrolled in the Lung-MAP genomic screening study (SWOG 1400). Participants completed a 38-item telephone survey conducted by trained staff within 30 days of consent. Survey questions assessed patient knowledge about the benefits and risks of study participation and expectations about return of genomic results in the study. The survey was structured as 5-level scale responses (‘strongly disagree’ [1] to ‘strongly agree’ [5]) and true/false/don’t know. Survey questions were adapted from prior studies that evaluated knowledge and expectations about return of genomic results. Descriptive statistics (means, medians, proportions) were assessed in this preliminary analysis.

      Result

      Among 123 participants, median age was 67, 61.0% were male, 95.1% were white, 22.0% had a 4-year college education or more, and 28.5% had a household income of <$25,000/year. In the overall sample, 82.9% ‘strongly/somewhat agreed’ with the statement ‘I received enough information about the testing in Lung-MAP to understand the benefits of enrolling’ and 73.2% ‘strongly/somewhat agreed’ with the statement ‘I received enough information…to understand the risks of enrolling’. Among the sub-group that ‘strongly/somewhat agreed’ with understanding trial benefits: 89.2% correctly believed that it was ‘true’ that test results would help to select their cancer treatment (8.8% responded ‘don’t know’), 8.8% correctly believed it was ‘false’ that the somatic testing in the study would provide information to find out if family members had increased risk of cancer (40.2% responded ‘don’t know’), and 11.8% correctly believed it was ‘false’ that results would tell them about their risk of developing diseases besides cancer (38.2% responded ‘don’t know’).

      Conclusion

      Among participants in a large BDCT, a majority of participants had serious deficits about the reporting of genomic results despite reporting to have enough information to understand benefits and risks. Our findings suggest that further research is needed to identify effective approaches to communicating information about BDCTs to improve patient knowledge about return of genomic results.

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      OA07.07 - Quality of Life (QoL) Analysis in Lung Cancer: A Systematic Review of Phase III Trials Published Between 2012 and 2018 (Now Available) (ID 1958)

      11:00 - 12:30  |  Presenting Author(s): Maria Lucia Reale  |  Author(s): Emmanuele De Luca, Pasquale Lombardi, Laura Marandino, Clizia Zichi, Daniele Pignataro, Eleonora Ghisoni, Rosario Francesco Di Stefano, Annapaola Mariniello, Elena Trevisi, Gianmarco Leone, Leonardo Muratori, Anna La Salvia, Cristina Sonetto, Paolo Bironzo, Massimo Aglietta, Silvia Novello, Giorgio Vittorio Scagliotti, Francesco Perrone, Massimo Di Maio

      • Abstract
      • Presentation
      • Slides

      Background

      We previously reported that QoL is not included among endpoints and QoL results are underreported in a high proportion of phase III trials in oncology. Here we describe QoL prevalence and heterogeneity in QoL reporting in lung cancer phase III trials.

      Method

      We selected all primary publications of lung cancer phase III trials evaluating anticancer drugs published between 2012 and 2018 by 11 major journals. We analyzed QoL inclusion among endpoints, presence of QoL results and methodology of QoL analysis.

      Result

      122 publications were identified. In 39 (32.0%) publications, QoL was not listed among endpoints: 10/17 (58.8%) early stage/locally advanced NSCLC, 15/54 (27.8%) first-line of advanced NSCLC; 10/41 (24.4%) second and further lines of advanced NSCLC, 4/10 (40.0%) SCLC. Proportion of trials not including QoL was similar over time: 32.9% publications in 2012-2015 vs. 30.6% in 2016-2018. QoL was not listed among endpoints in primary publication in 16/80 (20.0%) for-profit trials vs. 23/42 (54.8%) no-profit trials. Out of 83 trials including QoL among endpoints, QoL results were not reported in 36 primary publications (43.4%). Proportion of trials not reporting QoL results in primary publication significantly increased over time (30.6% 2012-2015 vs. 61.8% 2016-2018, p=0.005). Overall, QoL data were not available in 65/122 (61.5%) primary publications, due to the absence as endpoint or unpublished results. QoL data were not available in primary publication in 48/80 (60.0%) for-profit trials vs. 27/42 (64.3%) no-profit trials. QoL data were lacking in 48/78 (70.6%) publications of trials with overall survival as primary endpoint, 27/54 (50.0%) with other primary endpoints and 28/54 (51.9%) publications with a positive result. For trials including QoL among endpoints but lacking QoL results in primary publication, probability of secondary publication was 6.3%, 30.1% and 49.8% after 1, 2 and 3 years respectively, without evidence of improvement in time to publication comparing 2012-2015 vs. 2016-2018. Out of 83 trials including QoL, most common tools were EORTC QLQ-C30 (42, 50.6%); EORTC LC13 (39, 47.0%); EQ-5D (37, 44.6%); LCSS (19, 22.9%); FACT-L (15, 18.1%). Out of 58 trials with available results, common methods of analysis were mean scores or changes (45, 77.6%), time to deterioration (31, 53.4%) and proportion of responders (19, 32.8%). Availability of a secondary QoL publication allowed a higher number of methods of QoL analysis (p<0.001).

      Conclusion

      QoL is not assessed in a high proportion of phase III trials evaluating lung cancer patients, a setting where attention to QoL should be particularly high, due to symptoms and limited life expectancy. Furthermore, the timely inclusion of QoL results in primary publications is worsening in recent years. Secondary publications allow a more complete description of QoL results, but imply a delay in their availability.

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      OA07.08 - Discussant - OA07.05, OA07.06, OA07.07 (Now Available) (ID 3759)

      11:00 - 12:30  |  Presenting Author(s): Mary O'Brien

      • Abstract
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      Abstract not provided

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      OA07.09 - Daniel C. Idhe Lectureship Award for Medical Oncology (Now Available) (ID 3904)

      11:00 - 12:30  |  Presenting Author(s): Shao Weng Daniel Tan

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      Abstract not provided

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    PC04 - Is Chemotherapy Necessary for Advanced NSCLC Patients With PD-L1 50% or More? (ID 86)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Advanced NSCLC
    • Presentations: 2
    • Now Available
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      PC04.01 - Pro: Chemotherapy Is Necessary (Now Available) (ID 3571)

      11:30 - 13:00  |  Presenting Author(s): Marina Chiara Garassino

      • Abstract
      • Presentation
      • Slides

      Abstract

      As first-line therapy single agent pembrolizumab showed better outcomes than chemotherapy (CT) in patients with NSCLC and PD-L1 expression ≥50% [1]. Recently has been published another phase 3 trial in which patients with aNSCLC with an expression of PD-L1 ≥1%, treated with pembrolizumab as single agent, results in better overall survival (OS) than CT in first-line, mainly in subgroup with PD-L1 ≥50% [2].

      After the approval and subsequent use of pembrolizumab as single agent in first-line in NSCLC with PD-L1 ≥50%, in 2018 several phase III trials explored the combination of immunotherapy agents (pembrolizumab and atezolizumab), with no regards of PD-L1 status, in association with standard CT, gaining better outcomes than CT alone in first-line NSCLC [3-8].

      A matter of debate is what we have to do in patients with PD-L1 ≥50% due to the absent comparison between combination therapy and ICI as single agent and similar results in 1-year OS among these treatments [1,3-4].

      So, why should we suggest the use of combination over ICIs as single agent in patients with PD-L1 ≥50% in first-line?

      First of all, we can see that trials of combination therapy report benefit with CT plus ICI across all PD-L1 subgroups, with a greater magnitude of benefit in patients with PD-L1 ≥50% with no regards of kind of drugs used (either CT and ICI) and histology (squamous or non-squamous) [3-8]. This magnitude of benefit is supported from an higher objective-response rate (ORR) in patients treated with combination therapy over ICI as single agent in subgroups of patients with PD-L1 ≥50% [1-4], suggesting combination therapy as best choice even in patients with highly symptomatic disease with the purpose of obtaining a fast shrinkage of tumor.

      Analyzing Kaplan-Meyer curves of single agent trials [1,2], you can observe that there is a violation of proportional hazard assumptions. We can see a crossing of the curves within first 3-6 months suggesting us that there’s a subgroup of patients who have a worse prognosis when treated with single agent immunotherapy over CT. This worse prognosis could be possibly partially due to a phenomenon called hyperprogressive disease [9], a quicken tumor growth during treatment with ICIs in NSCLC irrespectively of the line of therapy. If we look at Kaplan-Meyer curves of all combination studies, we can see that the combination of CT plus ICI abrogates the crossing curves [3,4,6,8], probably overcoming hyperprogessive disease with the addiction of CT by modulating tumor microenvironment.

      In subgroups of patients with liver and/or brain metastases, generally considered at worse prognosis, combination therapy demonstrates a benefit. In a retrospective analysis of KEYNOTE189 [10] were evaluated outcomes of patients with brain and/or liver metastases. In this analysis the addiction of pembrolizumab to CT grants a benefit over CT alone either in progression-free survival, OS and ORR in patients with liver and/or brain metastases. Another evidence of benefit in patients with liver metastases in combination therapy was seen in IMpower150, in which the addiction of atezolizumab to bevacizumab plus CT seemed to add something even though there’s a bias due to the use of bevacizumab [5].

      In advanced NSCLC treated with ICI as single agent [1,2] we see a lower benefit in non-smoker than in current or former smoker patients, whilst in combination studies this difference isn’t seen regardless kind of drug and histology [3,6-8].

      Even gender may be a possible reason to choose combination instead of ICI as single agent. As we previously do for smoking habit, we indirectly compare trials with single agent and with combination. We can see that in KEYNOTE024 there’s a stronger benefit using pembrolizumab in males over females. This reported benefit for male patients is lost in combination treatment, with slight better outcomes in women instead, with no regards of drugs used and histology [3,4,6-8].

      Finally, basing on preclinical evidences, we know that the combination between CT and ICIs may enhance the immune system activity due to immunological effect of cytotoxic agents through the expression of PD-L1 on the surface of tumor cells, the depletion of myeloid-derived suppressor cells and T-regulatory cells and the augmentation of the presentation of antigens by cancer cells [10].

      At the state of the art the aim of our discussion remains an unanswered question but based on what we previously said, at least in patients with high tumor burden, in never smokers, we suggest CT plus ICI as first-line in aNSCLC with PD-L1 ≥50%.This could allow us not to lose patients in the first six months of treatment.

      [1] Reck M et al.Pembrolizumab versus chemotherapy for PD-L1 positive non-small cell lung cancer. NEJM 2016; 375: 1822-1833

      [2] Mok TSK et al. Pembrolizumab versus chemotherapy for previously untreated , PD-L1 expressing, locally advanced or metastatic non-small cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019; 393: 1819-1830

      [3] Gandhi L et al. Pembrolizumab plus chemotherapy in metastatic non-small cell lung cancer. NEJM 2018; 378: 2078-2092

      [4] Paz-Ares L et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. NEJM 2018; 379: 2040-2051

      [5] Socinski MA et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. NEJM 2018; 378(24): 2288-2301

      [6] Cappuzzo F et al. IMpower130: efficacy and safety from a randomise phase 3 study of carboplatin and nab-paclitaxel with or without atezolizumab in 1L advanced non-squamous NSCLC. Presented at ESMO 2018

      [7] Jotte R et al. IMpower131: primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. Presented at ASCO 2018

      [8] Papadimitrakopoulou VA et al. IMpower132: PFS and safety results with 1L atezolizumab + carboplatin/cisplatin + pemetrexed in stage IV non-squamous NSCLC. Presented at WCLC 2019

      [9] Proto C et al. Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out. Cancer Treat Rev 2019; 75:39-51

      [10] Garassino MC et al. Outcomes among patients with metastatic nonsquamous NSCLC with liver metastases or brain metastases treated with pembrolizumab plus pemetrexed-platinum: results from the KEYNOTE-189 study. Presented at AACR 2019

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      PC04.02 - CON: ICI Is Enough (Now Available) (ID 3572)

      11:30 - 13:00  |  Presenting Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Abstract

      The implementation of anti PD-1 / anti PD-L1 checkpoint inhibitors has completely changed management of patients with advanced non-small-cell lung cancer (NSCLC). On the way to an individualized use of these agents a correlation between the PD-L1 expression on tumor cells and immune cells and efficacy of immunotherapies could be demonstrated across different agents and treatment lines.

      In particular a clear correlation between survival and PD-L1 expression on tumor cells (TPS-score) has prospectively been evaluated and validated for the anti-PD1 antibody pembrolizumab defining a TPS score of =/> 50% as a predictor for enhanced outcome by pembrolizumab and showing impressive 4 and 5 year overall survival rates for untreated patients with a TPS-Score of =/> 50% of 48% and 29.6% respectively (1,2).

      Two prospectively randomized phase III trials confirmed the superior efficacy of pembrolizumab monotherapy with a significant prolongation of overall survival compared to platinum based chemotherapy in untreated patients with a TPS-score of =/> 50% (3,4).

      Recently the concept of combining immunotherapies with chemotherapies has demonstrated superior efficacy compared to chemotherapy patients with advanced NSCLC independent from the PD-L1 expression and the question appears, whether such a combination would also be the preferred treatment for the selected group of patients with a TPS-score of =/>50%.

      Analysing this question a couple of points need to be addressed:

      First of all this important question has never been addressed appropriately in a prospective trial and in none of the combination trials a immunotherapy monotherapy arm was part of investigated schedule. Therefore all assumptions remain subjective and exploratory.

      Second: We have seen a dramatic improvement of survival expectation together with a relevant prolongation of treatment duration by the adaption of immunotherapies in management of advanced NSCLC. Therefore tolerability, symptom control and quality of life become essential parameters for feasibility of treatment. Across all chemo-immunotherapy combination trials the frequency of CTC grade 3-5 treatment related adverse events (TRAEs) was substantially higher compared to the pembrolizumab monotherapy arms. In particular in an updated report of the Keynote 189 trial the frequency of TRAEs grade 3-5 was 71.9% for the combination of pembrolizumab and chemotherapy compared to 17.8% in the Keynote 42 trial and 31.2% in the Keynote 24 trial leading to a treatment discontinuation rate of 33.6% compared to 9% and 13.6% in the Keynote 42 and 24 trial (4,5,6).

      Considering the symptomatic efficacy ICI monotherapy has shown a clinical relevant improvement of symptoms during treatment compared to chemotherapy assessed by the QLA-C30 GHS/QOL score together with a substantial prolongation of time to symptom deterioration in the Keynote-24 (7). This unique pattern of symptomatic efficacy, which clearly reflects the patient related impact of anti tumor therapy has so far not been to that extent for the combination trials.

      Third: Besides the impressive activity demonstrated by the use of first line chemo-immunotherapy combinations we are confronted with the rapidly emerging clinical problem, that we suffering effective and tolerable post progression treatment opportunities. So far no specific treatment approaches are available and mostly we are ending up with the use of limited effective docetaxel +/- an antiangiogenic agent. In contrast a first line ICI monotherapy offers the opportunity of a post progression full dosed platinum based combination treatment with clearly higher efficacy compared to docetaxel alone.

      Fourth: Currently the most appropriate endpoint to assess efficacy of immunotherapies remains to be determined and we have seen in various trials that response and PFS might not be the optimal endpoints. In contrast it is general accepted the survival represents the most eminent and meaningful endpoint. Looking on the survival results of the different trials the differences in follow up periods need to be taken into account leading potential differences in the assessment of survival times. However respecting the lack of prospective randomised trials it appears that no benefit in survival in particular long term survival could be generated by the addition of chemotherapy to immunotherapy in the group of patients with a TPS-score =/> 50%. In an exploratory analysis of the Keynote 189 trial the 2 year OS rate for patients with a TPS-score =/> 50% was 51.9% for the combination of chemotherapy and pembrolizumab compared to 51.5% and 44.7% for pembrolizumab monotherapy in the Keynote-24 and -42 trial. Furthermore also the Hazard ratios were comparable across the trials (HR 0.59 for Keynote-189 compared to HR 0.63 and 0.69 in Keynote-24 and -42).

      In summary ICI monotherapy represents the preferred new highly effective and well tolerable first-line treatment opportunity in untreated patients with a TPS-score of =/> 50%. Addition of chemotherapy is associated with poorer tolerability and in particular long-term tolerability.

      Ongoing research might define the few patients, where tumor control cannot be achieved by ICI monotherapy.

      1. Garon EB, Rizvi NA, Rui R, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372 (2015): 2018-2018

      2. Garon EB, Hellmann MD, Rizvi NA et al: Five-Year Overall Survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase I Keynote-001 studay. J Clin Oncol (2019): e-published June 2, 2019-06-01

      3. Reck M, Rodriguez-Abreu D, Robinson AG et al: Pembrolizumab versus chemotherapy for PD-L1 positive non-small-cell lung cancer. N Engl J Med (2016): 1823-1833.

      4. Mok TSK, Wu Y-L, Kudaba I et al: Pembrolizumab versus chemotherapy for previously untreated PD-L1-expressing locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet (2019): 1819-1830.

      5. Gadgeel S, Garrassino MC, Esteban E, et al: Keynote-189: Updated overall survival and progression after the next line of therapy with pembrolizumab plus chemotherapy with pemetrexed and platinum vs placebo plus chemotherapy for metastatic nonsquamous NSCLC: ASCO 2019, abstract 9013

      6. Reck M, Rodriguez-Abreu D, Robinson AC et al: Updated analysis of Keynote-024: Pembrolizumab vers platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 Tumor Poportion Score of 50% or greater: J Clin Oncol 37 (2019): 537-546

      7- Brahmer J, Radriguez-Abreu D, Robinson AG et al: Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (Keynote-024): a multicentre, intenational, randomised, open-label phase 3 trial. Lancet Oncology 18 (2017): 1600-1609.

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    WS06 - Women in Thoracic Oncology Networking Event (ID 355)

    • Event: WCLC 2019
    • Type: Workshop
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 13
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      WS06.01 - Welcome (ID 3828)

      07:00 - 08:00  |  Presenting Author(s): Enriqueta Felip, Narjust Duma, Angel Qin, Heather A Wakelee

      • Abstract

      Abstract not provided

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      WS06.02 - Lessons Learned – Women Leaders in Thoracic Oncology (ID 3829)

      07:00 - 08:00  |  Presenting Author(s): Enriqueta Felip, Heather A Wakelee

      • Abstract
      • Slides

      Abstract not provided

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      WS06.03 - Networking Table 1: Mentor-Mentee Relationship (ID 3830)

      07:00 - 08:00  |  Presenting Author(s): Heather A Wakelee

      • Abstract

      Abstract not provided

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      WS06.04 - Networking Table 2: How to Negotiate Successfully (ID 4066)

      07:00 - 08:00  |  Presenting Author(s): Enriqueta Felip

      • Abstract

      Abstract not provided

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      WS06.05 - Networking Table 3: Early Career Investigators (ID 4067)

      07:00 - 08:00  |  Presenting Author(s): Ticiana A. Leal

      • Abstract

      Abstract not provided

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      WS06.06 - Networking Table 4: Mid-Career Investigators (ID 4068)

      07:00 - 08:00  |  Presenting Author(s): Nagla Karim

      • Abstract

      Abstract not provided

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      WS06.07 - Networking Table 5: Social Media and Networking (ID 4069)

      07:00 - 08:00  |  Presenting Author(s): Narjust Duma, Angel Qin

      • Abstract

      Abstract not provided

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      WS06.08 - Networking Table 6: Work-Life Balance (ID 4070)

      07:00 - 08:00  |  Presenting Author(s): Silvia Novello

      • Abstract

      Abstract not provided

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      WS06.09 - Networking Table 7: Life and Career Transitions (ID 4077)

      07:00 - 08:00  |  Presenting Author(s): Miyako Satouchi

      • Abstract

      Abstract not provided

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      WS06.10 - Networking Table 8: Nursing in Thoracic Oncology (ID 4078)

      07:00 - 08:00  |  Presenting Author(s): Anne Fraser

      • Abstract

      Abstract not provided

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      WS06.11 - Networking Table 9: I Am Done with My PhD, Now What? (ID 4079)

      07:00 - 08:00  |  Presenting Author(s): Anne-Marie Baird

      • Abstract

      Abstract not provided

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      WS06.12 - Networking Table 10: Social Activism in Medicine (ID 4080)

      07:00 - 08:00  |  Presenting Author(s): Deborah Doroshow, Lecia Sequist

      • Abstract

      Abstract not provided

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      WS06.13 - Networking Table 11: Time Management (ID 4081)

      07:00 - 08:00  |  Presenting Author(s): Pilar Garrido

      • Abstract

      Abstract not provided