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Julie R Brahmer

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

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 8
    • Now Available
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      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  |  Author(s): Delvys Rodríguez-Abreu, Andrew G. Robinson, Rina Hui, Tibor Csőszi, Andrea Fülöp, Maya Gottfried, Nir Peled, Ali Tafreshi, Sinead Cuffe, Mary O'Brien, Suman Rao, Katsuyuki Hotta, Tara Garay, Erin Jensen, Victoria Ebiana, Julie R. Brahmer

      • 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.

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      OA14.02 - IMpower131: Final OS Results of Carboplatin + Nab-Paclitaxel ± Atezolizumab in Advanced Squamous NSCLC (ID 1915)

      11:30 - 13:00  |  Presenting Author(s): Federico Cappuzzo  |  Author(s): Robert Jotte, Ihor Vynnychenko, Daniil Stroyakovskiy, Delvys Rodriguez Abreu, Maen Hussein, Ross Soo, Henry J Conter, Toshiyuki Kozuki, KC Huang, Vilma Graupner, Shawn Sun, Tien Hoang, Helen Jessop, Mark McCleland, Marcus Ballinger, Alan Sandler, Mark A Socinski

      • Abstract
      • Slides

      Background

      IMpower131 (NCT02367794) is a randomised Phase III trial of atezolizumab + chemotherapy vs chemotherapy alone as first-line therapy in Stage IV squamous NSCLC. Here we report the final OS results (Arm B vs Arm C).

      Method

      Enrolled patients were randomised 1:1:1 to Arm A (atezolizumab 1200 mg q3w + carboplatin AUC 6 q3w + paclitaxel 200 mg/m2 q3w), Arm B (atezolizumab + carboplatin + nab-paclitaxel 100 mg/m2 qw) or Arm C (carboplatin + nab-paclitaxel) for 4 or 6 cycles followed by atezolizumab maintenance therapy (Arms A and B) until loss of clinical benefit or progressive disease. Coprimary endpoints were investigator-assessed PFS and OS in the ITT population. Data cutoff: October 3, 2018.

      Result

      1021 patients were enrolled, with 343 in Arm B and 340 in Arm C. Median age was 65 years (range, 23-83 [Arm B] and 38-86 [Arm C]) and ≈80% of patients were male. The proportion of patients with high (14% vs 13%), positive (39% vs 37%) or negative (47% vs 50%) PD-L1 expression was similar between arms. Median OS in the ITT population was 14.2 months in Arm B vs 13.5 months in Arm C (HR, 0.88 [95% CI: 0.73, 1.05]; P = 0.158; Table), not crossing the boundary for statistical significance. In the PD-L1–high subgroup, median OS was 23.4 vs 10.2 months, respectively (HR, 0.48 [95% CI: 0.29, 0.81]; not formally tested). Treatment-related Grade 3-4 AEs and treatment-related SAEs occurred in 68.0% and 21.0% (Arm B) and 57.5% and 10.5% (Arm C) of patients; no new safety signals were identified, consistent with previous analyses.

      Conclusion

      Final OS in Arm B vs C did not cross the boundary for statistical significance. Clinically meaningful OS improvement was observed in the PD-L1–high subgroup, despite not being formally tested. No new or unexpected safety signals were reported.

      Arm B

      Atezolizumab + Carboplatin
      + Nab-Paclitaxel

      (n = 343)

      Arm C

      Carboplatin +
      Nab-Paclitaxel

      (n = 340)

      HR (95% CI)

      Median OS, mo

      ITT

      14.2

      13.5

      0.88 (0.73, 1.05); P = 0.16

      PD-L1 high (TC3 or IC3)

      23.4

      10.2

      0.48 (0.29, 0.81)

      PD-L1 positive (TC1/2/3 or IC1/2/3)

      14.8

      15.0

      0.86 (0.67, 1.11)

      PD-L1 negative (TC0 or IC0)

      14.0

      12.5

      0.87 (0.67, 1.13)

      Median PFS, mo

      6.5

      5.6

      0.75 (0.64, 0.88)

      Confirmed ORR, n/N (%)a

      170/342 (49.7)

      139/339 (41.0)

      a Patients were classified as missing or unevaluable when no post-baseline response assessments were available or all post-baseline response assessments were unevaluable.

      CI, confidence interval; HR, hazard ratio; IC, tumour-infiltrating immune cell; ITT, intention-to-treat; OS, overall survival; ORR, objective response rate; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TC, tumour cell.
      TC3 or IC3: PD-L1 expression on ≥50% of TC or ≥10% of IC; TC1/2/3 or IC1/2/3: PD-L1 expression on ≥1% of TC or IC; TC0 and IC0: PD-L1 expression on <1% of TC and IC.

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      OA14.03 - Clinical Rationale and Preclinical Evidence for Chimeric Antigen Receptor (CAR) T Cell Therapy Clinical Trial in KRAS-Mutant Lung Cancer (ID 3075)

      11:30 - 13:00  |  Presenting Author(s): Janna Claire Minehart  |  Author(s): Takashi Eguchi, Aurore Morello, Prasad S Adusumilli

      • Abstract
      • Slides

      Background

      Chimeric antigen receptor (CAR) T cells are engineered to express a synthetic receptor that redirects specificity to a tumor-associated antigen (TAA). Mesothelin (MSLN) is a TAA expressed by solid tumors, notably in mesothelioma and lung adenocarcinoma (ADC). Our group clinical trial of MSLN-targeted CAR T cells in mesothelioma demonstrated a favorable safety profile and evidence of antitumor activity. In this study, we evaluated the feasibility and utility of MSLN-targeted CAR T cell therapy in advanced, KRAS-mutant lung ADC.

      Method

      Tissue microarray from stage I-III lung ADC tumors (n=1438) were reviewed by two pathologists, then stained for MSLN expression on cell-surface and cytoplasm. Of 327 patients with distant recurrences, adequate tissue was available from 34 autologous metastatic sites for MSLN expression evaluation. Healthy donor T cells were retrovirally transduced with a MSLN-targeted CAR. In vitro function against lung ADC cell lines with heterogenous MSLN expression resembling human tumors was assessed via chromium release assay, ELISA, and flow cytometry. In vivo antitumor efficacy (n=30) was evaluated by median survival and tumor bioluminescence in mice bearing lung ADC tumors.

      Result

      The incidence of cell-surface MSLN expression was higher in metastases than matched primary tumors (65% vs 38%) and higher in KRAS-mutant than wild type tumors (42% vs 32%). CAR T cells secrete cytokines and lyse lung ADC cell lines in proportion to their cell-surface MSLN expression. No activity against MSLN-very low mesothelial or MSLN-negative lung ADC cell lines was observed. In vivo, a single dose of CAR T cells eradicates established primary and metastatic MSLN-high tumors without evidence of on-target off-tumor toxicity.

      Conclusion

      Therapeutically-relevant cell surface MSLN expression is enriched in a population of KRAS-mutant lung ADC patients with poor prognosis and limited treatment options. MSLN-targeted CAR T cells exhibit antigen-specific and antigen density-dependent cytotoxicity against lung ADC cells in vitro and in vivo with no on-target, off-tumor toxicity to normal tissues. These results provide strong rationale for our upcoming MSLN-targeted CAR T cell therapy clinical trial in metastatic, KRAS-mutant lung ADC patients.

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      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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      OA14.05 - Discussant - OA14.01, OA14.02, OA14.03, OA14.04 (Now Available) (ID 3799)

      11:30 - 13:00  |  Presenting Author(s): Jay M Lee

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA14.06 - Hyperprogressive Disease in Advanced Non–Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors (Now Available) (ID 1835)

      11:30 - 13:00  |  Presenting Author(s): Giuseppe Lo Russo  |  Author(s): Diego Signorelli, Claudia Proto, Giulia Galli, Arsela Prelaj, Roberto Ferrara, Michele Sommariva, Massimo Moro, Valeria Cancila, Monica Ganzinelli, Silvia Brich, Sabina Sangaletti, Giancarlo Pruneri, Claudio Tripodo, Mario Paolo Colombo, Licia Rivoltini, Andrea Balsari, Gabriella Sozzi, Mattia Boeri, Marina Chiara Garassino

      • Abstract
      • Presentation
      • Slides

      Background

      Hyperprogressive disease (HPD) is a paradoxical boost in tumour growth described in a subset of cancer patients treated with immune checkpoint inhibitors (ICIs).

      Method

      We retrospectively collected data about all consecutive patients with advanced Non-Small Cell Lung Cancer (aNSCLC) treated with ICIs at our Institution between 04/2013 and 12/2018. Patients were classified according to our previously published clinical/radiological criteria for HPD (Lo Russo G, Clin Canc Res 2018). (Table). All ICIs administered for ≥1 cycle were admitted. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analyses were performed with Cox hazard model.

      Table HPD definition on the basis of 3 concomitant out of the five possible criteria

      HPD CLINICAL & RADIOLOGICAL CRITERIA

      Time-to-treatment failure < 2 months

      Increase of ≥ 50% in the sum of target lesions major diameters between baseline and first radiological evaluation

      Appearance of at least two new lesions in an organ already involved between baseline and first radiological evaluation

      Spread of the disease to a new organ between baseline and first radiological evaluation

      Clinical deterioration with decrease in ECOG performance status ≥ 2 during the first 2 months of treatment

      Result

      We reviewed 301 cases and 257 were evaluable for response. We identified four categories: responders (R, 57 cases, 22.2%), patients with stable disease as best response (SD, 69 cases, 26.8%), patients with progressive disease as best response (P, 78 cases, 30.4%) and patients with HPD (53 cases, 20.6%). Clinical/pathological variables were uniformly distributed among groups, except for a higher rate of patients with Eastern Cooperative Oncology Group Performance Status (ECOG-PS) >1 in HPD group (p = 0.0141). After a median follow-up of 23.49 months (IQR 10.72–44.21 months), median Progression-Free Survival (mPFS) and median Overall Survival (mOS) were 14,2 vs 6,5 vs 2,3 vs 1,5 months ( p < 0.0001) and 32,5 vs 17,8 vs 7,8 vs 4,1months (p < 0.0001) in R, SD, P and HPD group, respectively. The multivariate analyses, between P and HPD groups, adjusted for ICIs line, number of metastatic sites and ECOG-PS according to PFS (HR 2.448, 95% CI 2.137-2.899, p<0.0001) and OS (HR 2.481, 95%CI 2.092-2.950, p < 0.0001) confirmed the worse outcome of HPD group.

      Conclusion

      Our updated analysis confirmed patients with HPD as a distinct category that performs significantly worse than other groups, including P patients. The incidence of HPD in our cohort is relevant. The ICIs’ detrimental effect has to be taken into account and further investigated.

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      OA14.07 - Clinical and Genetic Characterization of Hyperprogression Based on Volumetry in Advanced NSCLC Treated with Immunotherapy (Now Available) (ID 1067)

      11:30 - 13:00  |  Presenting Author(s): Youjin Kim  |  Author(s): Chu Hyun Kim, Se-Hoon Lee, Ho Yun Lee, Hong Sook Kim, Kyunga Kim, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park

      • Abstract
      • Presentation
      • Slides

      Background

      Hyperprogressive disease (HPD), characterized by accelerated tumor progression, has been proposed as a new pattern of progression following immune checkpoint inhibitor (ICI) treatment. The aim of this study was to describe the characteristics of HPD and investigate its predictive markers.

      Method

      Clinical and radiological findings of 335 advanced non-small cell lung cancer (NSCLC) patients treated with ICI monotherapy were retrospectively analyzed. Radiological data were quantitatively and longitudinally analyzed for tumor size and volume by comparing baseline and follow-up computerized tomography results. The findings were matched to individual genomic profiles generated by deep sequencing of 380 genes.

      Result

      Among 135 patients with progressive disease (PD), as assessed by RECIST, 48 (14·3% of total and 35·6% among PD) and 44 (13·1% of total and 32·6% among PD) were found to have HPD by volumetric (HPDV) and one-dimensional (HPDR) analysis, respectively. HPDV patients were associated with significantly inferior overall survival (OS) compared with non-HPDV PD patients (median OS (months), 4·7 [95% confidence interval (CI), 3·5–11·9)] vs. 7·9 [95% CI, 6·0–13·5], p=0·004); OS did not differ between HPDR and non-HPDR patients. HPDV status was an independent OS factor. Derived neutrophil-to-lymphocyte ratio (dNLR) greater than 4 and lactate dehydrogenase (LDH) greater than the upper normal limit were significantly associated with HPDV. Moreover, we identified coinciding KRAS and STK11 mutations in the HPDV cohort (3/16), while none were found in the non-HPDV cohort (0/28).

      Conclusion

      Defining HPD treated with ICI based on volumetric measurement is more precise than that based on one-dimensional analysis. Pre-ICI dNLR, LDH, and concurrence of STK11 and KRAS mutations could, thus, be used as potential biomarkers for HPD prediction.

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      OA14.08 - Discussant - OA14.06, OA14.07 (Now Available) (ID 3800)

      11:30 - 13:00  |  Presenting Author(s): Kazuhiko Nakagawa

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    YI04 - Basics of Immunology (ID 110)

    • Event: WCLC 2019
    • Type: Young Investigator Session
    • Track: Young Investigators
    • Presentations: 4
    • Now Available
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      YI04.01 - PD-L1: Basics of Biology (Now Available) (ID 3708)

      13:30 - 15:00  |  Presenting Author(s): Ignacio Gil-Bazo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      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.

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      YI04.03 - The Place of Immunotherapy in NSCLC Therapeutic Algorythm (Now Available) (ID 3710)

      13:30 - 15:00  |  Presenting Author(s): Rolf Stahel

      • Abstract
      • Presentation
      • Slides

      Abstract

      Place of immunotherapy in the NSCLC treatment algorithm

      Therapy with immune checkpoint inhibitors has entered standard of care for patients with metastatic NSCLC. Data from extended phase I studies are available on the long-term effect of single agent immune checkpoint inhibition in later line. These studies demonstrate a 16% 5-year survival for nivolumab and pembrolizumab in pretreated patients (1), the impact of PD-L1 expression on long term outcome (2) and the importance of obtaining an objective response (3). Nivolumab and pembrolizumab, both PD-1 directed antibodies and atezolizumab, a PD-L1 directed antibody all have been approved for second or later line therapy based on comparative studies with docetaxel monotherapy demonstrating superior survival and an improved toxicity profile. However, results of recent studies in first line treatment have led to a rapid adoption of immune checkpoint inhibition upfront. This started with the results of the KEYNOTE-024 study demonstrating survival benefit of single agent pembrolizumab over platin-based combination therapy for patients with advanced NSCLC with a tumor proportion score of 50% or higher (4). With these results, PD-L1 testing has entered clinical routine. A series of clinical trials examined the survival impact of adding immune checkpoint inhibition to standard platin-based chemotherapy. Based on these results pembrolizumab added to platin-based chemotherapy, carboplatin and pemetrexed in non-squamous NSCLC (KEYNOTE,-189), carboplatin-paclitaxel or nab-paclitaxel in squamous NSCLC (KEYNOTE-407) (5,6), or alternatively atezolizumab combined with bevacizumab, carboplatin and paclitaxel (IMpower150) or with carboplatin and nab-paclitaxel (Impower130) for non-squamous NSCLC (7,8) have become standard of care, independent of the expression of PD-L1 in tumor tissues. The results of these t and additional trials in first line metastatic NSCLC have been summarized recently (9). Obviously, important questions remain to be answered. One open question regards the upfront treatment of patients with tumors having a strong PD-L1 expression. Lacking randomized data the debate remains open whether pembrolizumab alone or its combination with platin-based chemotherapy would ultimately be the best option. The KEYNOTE-042 trial compared pembrolizumab with platin-based chemotherapy in patients with tumors with at least 1% PD-L1 expression. The trial was positive for pembrolizumab, however the analysis of patient subgroups according to PD-L1 expression suggests the benefit to be mostly derived from patients with strongly expressing tumors and thus these results might only marginally impact clinical practice. A second open question regards the optimal selection of patients which could be spared from upfront treatment with chemotherapy and could benefit from single agent immune checkpoint or combined PD-+/PD-L1 and CTLA4 inhibition. Two trials examining the role of nivolumab in first line treatment (CHECKMATE-026 and CHECKMATE-227) demonstrated that a high tumor mutation burden is predictive for a better response to immune checkpoint inhibition. The later trial (10) and the analysis subgroups of the MYSTIC trial are in support of the hypothesis of potential superior effects of combining PD-1/PD-L1 inhibition with CTLA4 inhibition for patients with a high tumor mutation burden, measured directly in tumor tissue or indirectly on circulating tumor DNA, however, formal prove from prospective trials is pending. It is important to note that with the exception of IMpower150 and Impower130, all other trials excluded patients with known EGFR and ALK mutations, the main reason being the relative lack of efficacy of second line immune checkpoint inhibition in these patients. The benefit in progression-free survival and overall survival seen in patients with EGFR mutated tumors when treated with the atezolizumab bevacizumab quadruplicate, but not with the atezolizumab triplicate lends support for the use of the quadruplicate regimen for patients with EGFR mutated tumors failing tyrosine kinases.

      Gettinger, et al. Five-Year Follow-Up of Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: Results From the CA209-003 Study. J Clin Oncol 2018 Jun 10;36(17):1675-1684

      Garon E, 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 Study. J Clin Oncol 2019 Jun 2:JCO1900934

      Horn, L, et al. Safety and clinical activity of atezolizumab monotherapy in metastatic non-small-cell lung cancer: final results from a phase I study. Eur J Cancer 2018 Sep;101:201-209.

      Reck M, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. NEJM 2016 Nov 10;375(19):1823-1833

      Ghandi L, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. NEJM 2018 May 31;378(22):2078-2092.

      Pas-Arez L, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. 2018 Nov 22;379(21):2040-2051.

      Sozinski MA, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. NEJM 2018 Jun 14;378(24):2288-2301.

      West H, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2019 May 20. pii: S1470-2045(19)30167-6.

      Peters S, et al. How to Make the Best Use of Immunotherapy as First-Line Treatment for Advanced/Metastatic Non-Small-Cell Lung Cancer. Ann Oncol 2019 Mar 26. pii: mdz109. doi: 10.1093/annonc/mdz109

      Hellman MD, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. NEJM 2018 May 31;378(22):2093-2104.

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      YI04.04 - How to Select Patients for Immunotherapy (Now Available) (ID 3711)

      13:30 - 15:00  |  Presenting Author(s): Naiyer A Rizvi

      • Abstract
      • Presentation
      • Slides

      Abstract

      With the wide application of immune checkpoint blockade in the treatment of cancer, biomarkers may determine the line of therapy immunotherapy may be administered or when to combine with other agents. Patient selection on clinical characteristics and co-morbidities also need to be incorporated into treatment decision making. An overview of patient characteristics and external influencing factors will be provided in this review including more complicated scenarios such as patients with co-existing autoimmune disease or solid tumor transplant populations.

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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 2
    • Now Available
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      MA11.10 - Peripheral T Cell Repertoire Evolution in Resectable NSCLC Treated with Neoadjuvant PD-1 Blockade (Now Available) (ID 1999)

      14:00 - 15:30  |  Author(s): Julie R Brahmer

      • Abstract
      • Presentation
      • Slides

      Background

      Neoadjuvant PD-1 blockade has emerged as a promising treatment for resectable NSCLC. The neoadjuvant setting provides a unique opportunity to examine temporal-spatial dynamics of the T cell repertoire in the peripheral and tumoral compartments in response to PD-1 blockade.

      Method

      T-cell receptor (TCR) repertoire dynamics and composition were assessed in matched tumor, normal lung, and longitudinal peripheral blood from 20 NSCLC patients treated with neoadjuvant nivolumab (NCT02259621) and were correlated with major pathologic response (MPR , ≤10% viable tumor in resected specimen) at the time of resection. Treatment-induced dynamics of activated T cell clonotypes were additionally evaluated using TCR sequencing (TCRseq) of flow-sorted PD-1+ T cell populations. To focus on the phenotype of on-treatment intratumoral T cell clones that were recruited from the periphery, combined single-cell RNAseq/TCRseq was performed on post-treatment tumors of 6 patients (3 MPR and 3 non-MPR).

      Result

      MPR was associated with a more clonal intratumoral TCR repertoire and greater clonotypic sharing between pre-treatment blood and post-treatment tumor bed relative to non-MPR. Peripheral repertoire remodeling in response to anti-PD-1 treatment correlated with increased tumor infiltration. Specifically, in patients with MPR, the post-treatment tumor bed was enriched with T cell clones that were peripherally expanded between 2-4 weeks after PD-1 blockade. Clonotypic tracking of the peripherally expanded clones revealed persistence of those clones in the periphery 1+ years following surgical resection and cessation of PD-1 blockade. Single-cell RNAseq/TCRseq analyses revealed distinct phenotypes of peripherally expanded TIL for patients with MPR, with upregulated gene programs associated with cytotoxicity and cytoprotective effects against oxidative stress. Long-term peripherally-persistent TILs had significant upregulation of genes including GZMK, DUSP2, NKG7, 4-1BB and down-regulation of CTLA-4, CXCL13 and PDCD1 as compared to short-lived clones.

      Conclusion

      Our findings support the notion that neoadjuvant checkpoint blockade expands anti-tumor T cell clones in the periphery that can accumulate in tumor bed, facilitate tumor regression, and promote clonotypic persistence in the periphery. Importantly, our data demonstrate the systemic effect of neoadjuvant PD-1 blockade and indicate that the periphery may be an underappreciated originating compartment of effective anti-tumor immunity.

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      MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)

      14:00 - 15:30  |  Author(s): Julie R Brahmer

      • Abstract
      • Presentation
      • Slides

      Background

      Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.

      Method

      620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.

      Result

      Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.

      Conclusion

      In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

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

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Author(s): Julie R Brahmer

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-24 - Transcriptional Profiling of Neoantigen Specific T Cells in Resectable NSCLC Treated with Neoadjuvant Anti-PD-1 (Now Available) (ID 2357)

      10:15 - 18:15  |  Author(s): Julie R Brahmer

      • Abstract
      • Slides

      Background

      Neoadjuvant nivolumab has a manageable safety profile and can be effective in patients with resectable non-small cell lung cancer (NSCLC). To characterize the immune response in these patients, we sought to evaluate the existence and dynamics of neoantigen specific tumor-infiltrating T cells and identify their molecular phenotype including co-inhibitory checkpoint expression.

      Method

      We evaluated peripheral blood and tumor infiltrating lymphocytes from seven patients treated with nivolumab. To identify neoantigen-specific T cell responses, we used MANAFEST (Mutation Associated Neoantigen Functional Expansion of Specific T cells), an assay we developed that links antigen specificity with unique CD8+ TCR Vβ CDR3 identities. We then carried out single cell TCRseq/RNAseq of tumor infiltrating T lymphocytes (TIL) to enumerate the genome wide digital gene expression and T cell clonotypic identity of each single cell (VDJ+DGE analysis), and particularly those with Vβ CDR3 regions identical to those identified as neoantigen-specific by MANAFEST.

      Result

      Neoantigen-specific TCRs were detected in peripheral blood in all 3 patients with major pathologic response (MPR) and in 3 of 4 patients without MPR. Several of these clonotypes were found in the resected tumor and underwent peripheral expansions upon PD-1 blockade. In one notable patient, MD043-011, MANAFEST detected a T cell clonotype specific for a CARM1 R208W mutation, despite this patient having no evidence of pathologic response. This neoantigen-specific clonotype represented 3.4% of TIL. Two years later, this patient recurred with a solitary brain metastasis. Single cell analyses of TIL in the primary lung lesion and brain metastasis revealed the same neoantigen-specific T cell clonotype was detected in the metastatic lesion. Strikingly, this clonotype exhibited a differential expression profile in the primary and recurrent lesion, with the clonotype in the primary tumor having an enrichment and upregulation of heat shock proteins indicating molecular stress and the clone in the metastatic lesion having an upregulation of checkpoint molecules, including CTLA4, TIM3, and LAG3. T cell cloning and validation experiments, as well as identification of transcriptional programs associated with MPR, are ongoing.

      Conclusion

      The coupling of MANAFEST with single cell VDJ+ DGE analysis enabled us to characterize antigen specific clonotypes after differential expansion using the TCR as a molecular barcode. The presence of alternate co-inhibitory immune checkpoints on neoantigen-specific TIL from non-responding tumors suggests a potential driver of resistance to anti-PD-1 in early stage NSCLC. Ultimately, this integrative approach may provide key insights in predicting and understanding clinical response to neoadjuvant PD-1 blockade in NSCLC.

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    PC02 - Combining with Chemo: Old School Is New Again (ID 84)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      PC02.03 - IO Should Be Given as a Single Agent (Now Available) (ID 3563)

      14:00 - 15:30  |  Presenting Author(s): Julie R Brahmer

      • Abstract
      • Presentation
      • Slides

      Abstract

      Programmed cell death 1 (PD-1) checkpoint pathway inhibitors have greatly changed the treatment paradigm for advanced stage non-small cell lung cancer (NSCLC). Durvalumab is approved for use as a single agent after chemotherapy combined with radiation for stage 3 NSCLC.(1) Pembrolizumab is approved for use in the first line treatment setting for advanced NSCLC not amenable to radiation for patients whose tumor has a tumor proportion score (TPS) of 1% or greater in the United States.(2) For patients whose tumor has a TPS of > 50%, it is approved for use in the first-line treatment setting in multiple countries throughout the world.(3) However, PD-1 checkpoint blockade combinations, either anti-PD1 or anti-PD-L1 antibodies, with chemotherapy regardless of PD-L1 status have shown benefit as well. (4,5,6)

      Single agent immunotherapy (IO) has several advantages. Cost of combination therapy is an issue. While these PD-1 pathway blocking antibodies are expensive as single agents, combining them with chemotherapy adds to the cost, time in infusion, and adds chemotherapy related side effects. So, if patients can, single agent immunotherapy is still preferred, particularly in a population i.e. TPS > 50% who is more likely to benefit compared to chemotherapy. Some would say the same is true for patients with TPS > 1, but here the data for single agent IO compared to combinations with chemotherapy is mixed. While trials comparing this scenario, i.e. comparing single agent PD-1 antibody compared to chemotherapy plus IO, head to head have not yet been done, it is hard not to do cross trial comparisons as seen in table 1. Clearly though, chemotherapy and IO combinations have increased objective response rates regardless of PD-L1 TPS status where response rates range from 57.9%-62.1%.(4,5,6,7,10)

      While combinations with chemotherapy show increased response rate regardless of PD-L1 TPS, chemotherapy can have deleterious effects on the immune system. (8) Chemotherapy can alter immune function by causing lymphopenia. Steroids, added to chemotherapy regimens to prevent allergic reactions and control nausea, can suppress pro-inflammatory cytokines and impair Natural Killer (NK) cell function and dendritic cell differentiation or activation. Taxanes specifically can cause inhibition of T-cell and NK-cell activation. Thus, these combinations may prevent immune activation and suppress immune memory. Duration of response in single agent IO in the first line treatment setting is 16.8-20.2+ month.(9,2,3) The duration of response in the IO plus chemotherapy patient population is 7.7-11.2 months.(4,5,6) The data from the chemotherapy IO combinations is too immature to know what the potential five-year survival is compared to the impressive 23.2% 5 year survival rate of the initial trial of pembrolizumab in the treatment-naïve setting(Keynote 001).(9)

      Immunotherapy, particularly PD-1 pathway checkpoint antibodies, have drastically changed the treatment landscape for advanced stage lung cancer patients. Single agent pembrolizumab particularly in patients with TPS > 50% lung cancer results in an impressive long term survival that is not seen with chemotherapy alone. Combining immunotherapy agents with chemotherapy increases disease response but long term survival outcome data and duration of response is immature.

      Table 1 – Overview of Results in NSCLC PD-L1 TPS > 50% patient population

      KeyNote 0243

      KeyNote 0422

      KeyNote 1894,10

      KeyNote 4076

      ORR

      44.8%

      39.5%

      62.1%

      60.3%

      DOR (mo)

      NR (1.9-14.5+)

      20.2

      15.1

      Not reported

      mPFS (mo)

      10.3

      HR 0.5 (0.37-0.68), p<0.001

      7.1

      HR 0.81 (0.67-0.99), p=0.017

      11.1

      HR 0.36 (0.26-0.51)

      8

      HR 0.37 (0.24-0.58)

      mOS (mo)

      30

      HR 0.63 (0.47-0.86), p=0.002

      20

      HR 0.69 (0.56-0.85), p=0.0003

      NR

      HR 0.59 (0.39-0.88)

      NR

      HR 0.64 (0.37-1.10)

      2 year OS

      51.5%

      44.7%

      51.9%

      Not reported

      NR=not reached, ORR=overall response rate, DOR=duration of response, mPFS=median progression free survival, mo=months, mOS=median overall survival, OS=overall survival

      1-Antonia SJ, Villegas A, Daniel D et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350.

      2-Mok TSK, Wu YL, Kubaba I et al. Pembrolizumab versus Chemotherapy for Previously Untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomized, open-label, controlled, phase 3 trial. Lancet 2019 May 4:383(10183):1819-1830.

      3-Reck M, Rodriquez-Abreu D, Robinson AG et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833.

      4-Gandhi L, Rodriquez-Abreu D, Gadgeel S et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018 May 31;378(22):2078-2092.

      5-Socinski MA, Jotte RM, Cappuzzo F et al. Atezolizumab for First-Line treatment of Metastatic Nonsqumaous NSCLC. N Engl J Med 2018 Jun 14;378(24):2288-2301.

      6-Paz-Ares L, Alexander L, Vicente D et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2040-2051.

      7-Reck M, Rodriquez-Abreu D, Robinson AG et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer with PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol 2019 Mar 1;37(7):537-546.

      8-Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological Aspects of Cancer Chemotherapy, Nature Reviews Immunology 2008 (8), 59-73.

      9-Garon, E, Hellmqann M, Carcereny Costa E et al. Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: Results from KEYNOTE-001. J Clin Oncol 37, 2019(suppl; abstr LBA9015).

      10-Gadgeel S, Garassino M, Esteban E et al. KEYNOTE-189: Updated Overall Survival and Progression After the Next Line of therapy with Pembrolizumab plus Chemotherapy with Pemetrexe3d and Platinum vs Placebo Plus Chemotherapy for Metastatic Nonsquamous NSCLC. J Clin Oncol 37, 2019 (Suppl; abstr LBA9013).

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