Virtual Library

Start Your Search

Martin Reck

Moderator of

  • +

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

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 8
    • Now Available
    • +

      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.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      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.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

      • 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.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      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

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      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.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      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)

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      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.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      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

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.



Author of

  • +

    MA08 - Pawing the Way to Improve Outcomes in Stage III NSCLC (ID 127)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • +

      MA08.02 - Durvalumab Impact in the Treatment Strategy of Stage III Non-Small Cell Lung Cancer (NSCLC): An EORTC Young Investigator Lung Cancer Group Survey (Now Available) (ID 608)

      15:15 - 16:45  |  Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Background

      Stage III NSCLC represents a very heterogeneous population with extremely different treatment modalities including surgery, chemotherapy (CT) and radiotherapy (RT), mostly in combination. The results of the PACIFIC trial have now been reported in full including an overall survival (OS) benefit with durvalumab in addition to concomitant CT-RT. An electronic European survey was circulated to evaluate the impact of durvalumab in the staging and treatment strategy of stage III disease.

      Method

      A Young Investigator EORTC Lung Cancer Group survey containing 31 questions, was distributed between 31/01/18 and 31/03/19 to EORTC LCG and several European thoracic oncology societies’ members

      Result

      206 responses were analyzed (radiation oncologist: 50% [n=103], pulmonologist: 26.7% [n=55], medical oncologist: 22.3% [n=46]; 81.5% with >5 years experience in treating NSCLC). Italy (27.7%, n=57), Netherlands (22.8%, n=47), France (13.6%, n=28), and Spain (11.6%, n=24) contributed most. 83.5% (n=172) confirmed that they had access to durvalumab at the time of the survey. 97.6% (n=201) report that treatment decision is made by a multidisciplinary board. Regarding staging, 76.7% (n=158) support the need of a mediastinal pathological staging in case of suspect lymph-nodes, with a preference for EBUS/EUS (61.2%, n=126). 81.6% (n=168) treated more than half of patients with a concomitant CT-RT with the 1st cycle of chemotherapy in 39.7% (n=81). 95.1% consider durvalumab as practice changing, especially given the OS results (77.9%, n=152/195). 30% (n=119/395) will give patients concomitant CT-RT if PD-L1 >1%, and in borderline resectable cases 17.7% (n=70/395) will propose concomitant CT-RT instead of surgery. Durvalumab administration will be given regardless of PDL1 status in 13.1% (n=27) and 28.6% (n=59) would consider the possibility of a rebiopsy after CT-RT in case of negative PD-L1. 38.8% (n=80) foresee some problems with PD-L1 testing in this population due to availability of cytologic or small histologic samples. About 53.8% (n=105/195) normally will start durvalumab within 6 weeks after CT-RT and 48.5% (n=100) would also use durvalumab after sequential CT-RT

      Conclusion

      Durvalumab results are changing the treatment approach to stage III unresectable (and maybe resectable) NSCLC and planned strict adherence to the patient population as recruited to the PACIFIC study, was not demonstrated. This survey was released after the EMA approval of durvalumab and PD-L1 status seems to play a role in the treatment strategies, but surprisingly almost half of the clinicians will use durvalumab after sequential CT-RT without safety or efficacy data.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

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

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • +

      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  |  Author(s): Martin Reck

      • 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)

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • +

      OA14.01 - KEYNOTE-024 3-Year Survival Update: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer (ID 1465)

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

      • Abstract
      • Slides

      Background

      In the phase 3 KEYNOTE-024 trial (NCT02142738), first-line pembrolizumab significantly improved PFS (hazard ratio [HR] 0.50, P<0.001) and OS (HR 0.60, P=0.005) vs platinum-based chemotherapy in patients with advanced NSCLC, PD-L1 tumor proportion score (TPS) ≥50%, and no targetable EGFR/ALK alterations (median follow-up, 11.2 months). We present data with 3-years minimum follow-up.

      Method

      Patients were randomized to pembrolizumab 200 mg Q3W for 2 years or platinum doublet (investigator’s choice) for 4‒6 cycles plus optional maintenance (nonsquamous), with stratification by ECOG PS (0/1), tumor histology (squamous/nonsquamous), and region (East Asia/non‒East Asia). Patients in the chemotherapy arm could cross over to pembrolizumab upon disease progression if they met eligibility criteria. The primary endpoint was PFS; OS was a key secondary endpoint. Response per investigator by RECIST version 1.1 is reported.

      Result

      305 patients were randomized (pembrolizumab, n=154; chemotherapy, n=151). At data cutoff (February 15, 2019), median (range) follow-up was 44.4 (39.6‒52.9) months. 210 patients had died (pembrolizumab, n=97; chemotherapy, n=113). 98 (64.9%) patients crossed over from chemotherapy to anti‒PD-(L)1 therapy during/outside of the study. Median (95% CI) OS in the pembrolizumab arm was 26.3 (18.3‒40.4) months vs 14.2 (9.8‒18.3) months in the chemotherapy arm (HR, 0.65; 95% CI, 0.50‒0.86). 36-month OS rate was 43.7% in the pembrolizumab arm vs 24.9% in the chemotherapy arm. Despite longer mean treatment duration in the pembrolizumab arm (11.1 vs 4.4 months), grade 3‒5 treatment-related adverse events (AEs) were less frequent with pembrolizumab vs chemotherapy: 31.2% vs 53.3%. 38 patients in the pembrolizumab arm completed 2 years (35 cycles) of therapy. Among these, 34 were alive, 31 (81.6%) had an objective response (including 3 with complete response), and median duration of response was not reached (range, 4.2‒46.7+ months). OS rate 12 months after completing pembrolizumab treatment (ie, ~36 months after initiating treatment) was 97.4% (95% CI, 82.8‒99.6). Among the 38 patients who completed 2 years, 5 (13.2%) had treatment-related grade 3-4 AEs; no fatal treatment-related AEs occurred. 10 patients who completed 2 years (1 completed 34 cycles) and subsequently progressed received second-course pembrolizumab; 7 had an objective response, 8 remain alive.

      Conclusion

      With >3 years’ follow-up, first-line pembrolizumab monotherapy continued to provide durable long-term OS benefit vs chemotherapy despite a majority of patients assigned to chemotherapy crossing over to pembrolizumab. Pembrolizumab was associated with less toxicity than chemotherapy. Patients who completed 35 cycles of pembrolizumab had durable clinical benefit and most were alive at data cutoff.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 3
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
    • +

      P1.01-108 - PACIFIC-6: A Phase II Study of Durvalumab Following Sequential Chemoradiotherapy in Patients with Stage III, Unresectable NSCLC (ID 2318)

      09:45 - 18:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Background

      Non-small cell lung cancer (NSCLC) represents 85% of all lung cancers, with ~30% of patients (pts) presenting with Stage III disease. Platinum-based chemoradiotherapy (CRT) has historically been the standard of care (SoC) in this setting, but with poor long-term outcomes. Durvalumab is a selective high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. The phase III PACIFIC trial assessed durvalumab vs placebo in pts with locally advanced, unresectable, Stage III NSCLC, who did not progress following ≥2 overlapping cycles of platinum-based concurrent CRT (cCRT) (Antonia et al, NEJM 2017; 2018). Significant improvements in progression-free survival (PFS) and overall survival (OS) were observed with durvalumab (HR for PFS, 0.52; 95% CI 0.42–0.65; P<0.001; HR for OS, 0.68; 99.73% CI 0.47–0.997; P=0.0025). This data, along with comparable safety profiles between durvalumab and placebo in PACIFIC, supports the PACIFIC regimen (durvalumab following cCRT) as the new SoC in this setting. However, a proportion of pts are ineligible for cCRT for various reasons, and receive sequential CRT (sCRT) instead. PACIFIC-6 (NCT03693300) will assess the safety, efficacy, and quality of life of durvalumab in NSCLC pts who have not progressed following platinum-based sCRT.

      Method

      PACIFIC-6 is a phase II, open-label, multi-centre study to be conducted in 6 countries across Europe and North America. Pts ≥18 years old, with histologically or cytologically documented Stage III, unresectable NSCLC who have not progressed following platinum-based sCRT, and are ECOG PS ≤2 are eligible for inclusion; enrolment is not restricted to a biomarker-defined population. Approximately 150 pts will receive durvalumab (1500 mg intravenously) every 4 weeks for 24 months or until disease progression. Pts will be divided into 2 cohorts according to PS status. Pts will be assessed every 12 weeks, until death, withdrawal of consent, or the end of the study. The primary objective is to assess the safety and tolerability of durvalumab, as defined by grade 3 and 4 treatment-related adverse events (TRAEs) occurring within 6 months from initiation of durvalumab. Secondary objectives include investigator-assessed efficacy measurements such as PFS, overall response rate, duration of response (according to RECIST v1.1), as well as OS, lung-cancer mortality, and further safety assessments of all AEs and serious AEs. Exploratory objectives include assessment of pt-reported symptoms and quality of life, as well as evaluation of the association of tumour-based biomarkers (including PD-L1 expression and tumour mutational burden) with efficacy. Recruitment is ongoing.

      Result

      Section not applicable

      Conclusion

      Section not applicable

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      P1.01-110 - Novel Regimens Versus Standard-of-Care in NSCLC: A Phase II, Randomized, Open-Label, Platform Trial Using a Master Protocol (Now Available) (ID 2288)

      09:45 - 18:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Background

      Although non-small cell lung carcinoma (NSCLC) is intrinsically resistant to immunotherapy agents, a subset of tumors are susceptible to T cell-mediated antitumor effects. Treatment regimens combining agents that target different processes within the cancer immunity cycle have the potential to enhance response in relapsed or refractory NSCLC. GSK3359609 is a humanized IgG4 antibody with potent agonist activity against Inducible T cell Costimulator (ICOS) and no or low depleting effect on antibody-dependent cell-mediated cytotoxicity.

      Method

      This is a randomized, phase II, open-label, platform trial utilizing a master protocol in patients with advanced NSCLC who have progressed on initial PD1/PDL1-based immunotherapy and platinum-based chemotherapy. The trial will consist of several sub-studies, with each sub-study comparing novel combinations vs. current standard-of-care (SOC). No treatment crossover is allowed. Additional sub-studies may be added over time following protocol amendments. In the first sub-study, patients are centrally randomized by internet to SOC (docetaxel) or novel ICOS drug combination (NIDC) (GSK3359609 + docetaxel) in a 1:2 ratio, stratified by squamous versus non-squamous NSCLC and line of PD1/PDL1; randomization to SOC is minimized thereafter. Primary endpoint is overall survival (OS). Secondary endpoints are survival rate at 12 and 18 months; tumor response according to RECIST 1.1 and iRECIST criteria; pharmacokinetic parameters of the novel immunotherapy; and safety. Exploratory endpoints include tumor and blood-based biomarker evaluations such as tumor mutational burden and gene expression. Interim analysis of OS will be done after approximately 45 deaths in both study groups, with ≥18 deaths in the combination immunotherapy group; final analysis will be done after 85 deaths (35 in combination immunotherapy group). The study will employ a Bayesian decision-making framework based on predictive probability of observing a significant improvement in OS in a future phase III trial. A sample size of ≤70 participants in each combination immunotherapy group and ≥35 participants in the SOC group will provide ≥81% power with a type 1 error of ≤2.3% for each pairwise comparison.

      Sub-study 1 will compare the efficacy of GSK3359609 plus docetaxel versus docetaxel alone. At least 105 patients are expected to enroll. GSK3359609/docetaxel will be administered for ≤2 years or 35 visits, or until disease progression, death or unacceptable toxicity. Both drugs are given as an IV infusion (docetaxel 75mg/m2; GSK3359609 80 mg).

      Result

      Study enrollment has begun and the primary endpoint results of sub-study 1 are expected mid-2020.

      Conclusion

      The study will provide information on the efficacy of novel immunotherapies used in combination.

      GlaxoSmithKline (NCT03739710).

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      P1.01-58 - Comprehensive Serial Biomaterial Acquisition in Advanced NSCLC: Feasibility, Challenges and Perspectives (ID 473)

      09:45 - 18:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Background

      Availability of tumour material at baseline and disease progression is increasingly important for patient management in non-small-cell lung cancer (NSCLC), especially in tyrosine kinase and immune checkpoint inhibitor treatment. Here, we report the experience with prospective biobanking for advanced NSCLC from a pilot project in the academic setting.

      Method

      Main objective was the longitudinal collection of snap-frozen in addition to formalin-fixed paraffin-embedded (FFPE) biopsies required for routine diagnostics, along with blood samples and detailed clinical annotation using standardized questionnaires.

      Result

      Over five years, 205 patients were enrolled yielding 387 cryoconserved biopsies and 1098 serum, plasma and buffy-coat samples. The feasibility of obtaining cryoconserved in addition to FFPE biopsies was 89 % for newly diagnosed cases, but dropped down to 56 % and 47 % at first and second disease progression, respectively. Main obstacle was increased procedural risk due to patient deterioration, but no complications occurred. Biopsies had a tumour cellularity of 34 % and yielded 13.6 µg DNA and 12 µg RNA in median.

      Conclusion

      Despite the poor condition and limited prognosis of most NSCLC patients, systematic, serial biomaterial acquisition including routine collection of cryoconserved biopsies is feasible in order to facilitate individualized management and support research that will advance therapeutic options.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
    • +

      P1.18-01 - RELAY EU/US Subset: Ramucirumab Plus Erlotinib Improves Progression-Free Survival in First-Line EGFR Mutation-Positive NSCLC (Now Available) (ID 356)

      09:45 - 18:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Background

      Dual blockade of EGFR and VEGFR pathways in EGFR mutation-positive NSCLC augments anti-tumor efficacy versus EGFR inhibition alone. The RELAY (NCT02411448) phase 3 study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for erlotinib plus ramucirumab versus erlotinib plus placebo in patients with previously untreated EGFR mutation-positive metastatic NSCLC (median PFS 19.4 vs 12.4mo, HR 0.591 (95% CI 0.461–0.760), p<0.0001). Here we report efficacy and safety data of the EU/US subset.

      Method

      Eligible patients (untreated, metastatic NSCLC with an EGFR exon 19 deletion or exon 21 (L858R) substitution mutation and no CNS metastasis) were randomized (1:1) to receive 150 mg daily oral erlotinib plus 10 mg/kg intravenous ramucirumab (RAM+ERL) or placebo (PL+ERL) Q2W until progressive disease or unacceptable toxicity. Patients were stratified by geographic region (East Asia vs ‘other’, i.e. EU/US). Primary endpoint was investigator-assessed PFS. Other key objectives included safety, ORR, DoR, PFS2, and OS.

      Result

      In the EU/US, 113 (25.2%) of 449 total patients (58 RAM+ERL, 55 PL+ERL) were randomized between Feb 2016-Feb 2018. Baseline characteristics were balanced between treatment arms: ~60% female, ~52% never-smokers and ~66% Ex19del. RAM+ERL improved PFS and had a longer DoR (Table). PFS2 and OS data were immature. Grade≥3 TEAEs occurring in >5% of patients included (RAM+ERL vs PL+ERL): hypertension (29.8% vs 7.3%), diarrhea (12.3% vs 1.8%), AST increased (7.0% vs 3.6%), ALT increased (7.0% vs 1.8%), dermatitis acneiform (5.3% vs 9.1%), fatigue (5.3% vs 0%), and rash (0% vs 5.5%).

      Abbreviations: CI=confidence interval; DoR=duration of response; ERL=erlotinib; HR=hazard ratio; N=total population; n=total responders; NR=no response; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PL=placebo; RAM=ramucirumab
      RAM + ERL (N=58) PL + ERL (N=55) Unstratified HR (95% CI) p-value
      PFS
      Median, months (95% CI) 20.6 (14.7-26.0)
      10.9 (8.3-19.4)
      0.605 (0.362-1.010) 0.0523

      Censoring rate

      52% 38%

      ORR, % (95% CI)

      74.1 (62.9-85.4) 76.4 (65.1-87.6) NA 0.8319
      DoR, for responders only n=43 n=42
      Median, months (95% CI) 18.0 (12.7-22.0) 10.0 (7.1-17.7) 0.527 (0.296-0.939) 0.0274

      Censoring rate

      54% 33%
      PFS2
      Median, months (95% CI) NR NR 0.632 (0.304-1.313) 0.2143
      Censoring rate 79% 67%
      OS
      Median, months (95% CI) NR NR 1.096 (0.465-2.582) 0.8344
      Censoring rate 81% 82%

      Conclusion

      The EU/US subset analysis was consistent with the full ITT population where RAM+ERL demonstrated a statistically significant improvement in PFS over PL+ERL. Efficacy and tolerability were similar to that of the overall RELAY study population. Ramucirumab is an effective and safe addition to standard-of-care EGFR-TKI for treating EGFR mutation-positive metastatic NSCLC.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      P1.18-02 - The AEGEAN Phase 3 Trial of Neoadjuvant/Adjuvant Durvalumab in Patients with Resectable Stage II/III NSCLC (ID 1375)

      09:45 - 18:00  |  Author(s): Martin Reck

      • Abstract

      Background

      For patients (pts) with early stage non-small cell lung cancer (NSCLC) (Stages I–IIIA) surgery is the primary treatment. Adjuvant and neo-adjuvant chemotherapy (CTx) are both accepted approaches for resectable NSCLC, and result in modest but clinically meaningful improvements in overall survival (OS) compared with surgery alone; nevertheless, recurrence rates remain high and improved therapies are needed. Checkpoint inhibitors that block programmed death 1 (PD-1)/PD ligand 1 (PD-L1) have shown benefit as monotherapy and in combination with CTx in NSCLC. Durvalumab (durva), a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, significantly improved progression-free survival and OS in pts with unresectable Stage III NSCLC who did not progress following chemoradiotherapy (Antonia et al, NEJM 2017; 2018). The AEGEAN study (NCT03800134) will assess the activity and long-term clinical outcomes of durva plus CTx prior to surgery, as well as further administration of durva post-surgery, in pts with resectable Stages II and III NSCLC.

      Method

      The AEGEAN trial is a Phase 3, double-blind, placebo-controlled, multi-center study. Approximately 300 pts with resectable Stage II and III NSCLC will be randomized 1:1 to receive either durva (1500 mg intravenously) or placebo every 3 weeks (wks) alongside platinum-based CTx (4 cycles) prior to surgery, followed by either durva or placebo alone every 4 wks for an additional 12 cycles post-surgery. Pts will be stratified by disease stage and PD-L1 expression levels (<1% vs ≥1%); the number of pts with EGFR/ALK mutations will be capped at 20%. Tumor size (according to RECIST v1.1 criteria) will be evaluated at completion of neo-adjuvant CTx prior to surgery, every 12 wks for the first year; every 24 wks for 2–4 years; then yearly thereafter. The primary endpoint is major pathological response (≤10% residual viable tumor in the resected primary lung tumor after neoadjuvant treatment) in the full analysis set (FAS). Secondary endpoints include safety assessments, a range of efficacy measures including complete pathological response (FAS and PD-L1-TC ≥1%) and OS, pt-reported outcomes, durva pharmacokinetics and immunogenicity. This trial is currently recruiting.

      Result

      Section not applicable

      Conclusion

      Section not applicable

  • +

    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
    • +

      P2.01-24 - CANOPY-2: Phase 3 Study of Canakinumab Plus Docetaxel as Second/Third Line Therapy in Locally Advanced/Metastatic NSCLC (ID 2539)

      10:15 - 18:15  |  Author(s): Martin Reck

      • Abstract

      Background

      Pembrolizumab, a PD-1 inhibitor combined with platinum-based chemotherapy is standard first-line therapy for eligible patients without a targetable mutation, stage IIIB/IV NSCLC. Currently, there is no data to guide treatment following progression on sequential/concomitant use of platinum-based chemotherapy and PD-1 inhibitors. Activation of inflammation and elevated baseline C-reactive protein (CRP) levels are associated with lower response/resistance to immunotherapies. Canakinumab is a high-affinity anti-IL-1β monoclonal antibody that demonstrated a significant reduction in incidence of fatal and nonfatal lung cancer in patients with increased CRP levels (CANTOS study).

      Method

      CANOPY-2 (NCT03626545) is a multicenter, phase 3 study evaluating safety and efficacy of docetaxel ± canakinumab in patients with squamous/non-squamous, stage IIIB-IV NSCLC. This study includes a safety run-in part (part 1 – open label) to confirm recommended phase 3 regimen (RP3R) to be used in randomized phase 3 part (part 2 – double blind, placebo-controlled). Key inclusion criteria: adult patients pretreated with one prior platinum-based chemotherapy and one prior PD-(L)1 inhibitor therapy for locally advanced/metastatic disease, either together/sequentially and then progressed; ECOG PS 0-1. In part 1, ~9 patients will be enrolled to have at least 6 evaluable patients and ~226 patients will be randomized (1:1, stratified by number of prior lines of therapy and histology) in part 2 to docetaxel ± canakinumab. Primary objectives: to confirm RP3R of canakinumab + docetaxel, as determined by incidence of DLTs in first 42 days of administration (part 1) and overall survival (part 2). Secondary objectives are to assess efficacy (overall response rate, disease control rate, duration of response, time to response, progression-free survival by investigator per RECIST v1.1), safety, pharmacokinetics, immunogenicity of canakinumab, and patient reported outcomes. Enrollment is ongoing.

      Result

      Section not applicable

      Conclusion

      Section not applicable

  • +

    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: 1
    • Now Available
    • +

      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.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    PR04 - Press Conference (ID 95)

    • Event: WCLC 2019
    • Type: Press Conference
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/10/2019, 10:45 - 11:30, CC7.1 A&B
    • +

      PR04.02 - KEYNOTE-024 3-Year Survival Update: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer (Now Available) (ID 3622)

      10:45 - 11:30  |  Presenting Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    YI04 - Basics of Immunology (ID 110)

    • Event: WCLC 2019
    • Type: Young Investigator Session
    • Track: Young Investigators
    • Presentations: 1
    • Now Available
    • +

      YI04.02 - Immuno-Oncology Trials: Other Endpoints Needed? (Now Available) (ID 3709)

      13:30 - 15:00  |  Presenting Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Abstract

      The implementation of immunotherapies has completely changed and improved management of patients with non-small-cell lung cancer (NSCLC). In contrast to cytotoxic agents and targeted therapies immunotherapies do not directly affect the tumor but lead to an indirect reactivation of T-cell mediated immune reaction. Therefore different endpoints may be required for an appropriate assessment of efficacy of these novel compounds.

      In various trials it could be demonstrated that in contrast to conventional anti tumor therapies, which show an impact on early overall survival (OS), immunotherapies seem to impact the long term survival rates, leading to a phenomenon, which is characterized as „plateau of long term survival“.

      In contrast other conventional markers of efficacy like response rate (RR) or progression free survival (PFS) do not appear as the best endpoints to reflect the complete efficacy of immunotherapies at least not in biomarker unselected populations. In a number of randomized phase 3 trials in untreated as well as pretreated patients no significant differences in PFS were shown despite the fact that these trials demonstrated a clear survival benefit in favour of the immunotherapies or immunotherapy combinations. In addition exploratory analyses revealed a survival benefit even in patients, who received immunotherapies beyond progression suggesting that indeed response and PFS may be suboptimal endpoints.

      Reflecting these experiences clearly new statistical approaches are needed to focus on OS as probably the most relevant endpoint and to provide the opportunity to capture the late impact of immunotherapies on OS with the prolongation of long-term survival in an adequate way. Currently the first modifications of conventional statistical models are in development evaluating for example the model of disproportional hazard ratios and others in upcoming trials.

      Another significant problem is the appearance of „crossing“ Kaplan Meier curves, which has frequently been observed in trials with immunotherapy combinations. These curves suggest, that there are different subpopulations with different sensitivities toward the novel treatments represented. Reflecting the lack of valid predictive biomarkers, which are able to separate the different subgroups, innovative statistical models are needed to define and to describe the benefitting populations.

      Lastly the „explosion“ of numerous clinical trials investigating novel immunotherapy combinations will require a modification of our traditional endpoints. Given the number of novel agents and the speed of development it won´t be feasible to conduct individual signal generating phase II trials for each of these agents. New models of platform trials with a new model of statistical assessment are required to provide the opportunity to investigate multiple combinations in one trial and to provide the flexibility to add novel combinations, which just may have been developed to ongoing protocols.

      In summary immunotherapies have substantially contributed to therapeutic improvements in NSCLC, but they are requesting a change of our conventional consideration of efficacy. Besides all endpoints of objective efficacy it will be of paramount importance that future endpoints also cover patient relevant endpoints like tolerability, improvement of quality of life or duration of symptom control.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.