Seeking New Approaches to Patients With Small Cell Lung Cancer.

The fundamental approach to the treatment of small cell lung cancer (SCLC) has not changed in the last several decades, with most advances being restricted to improved radiation approaches. The standard first-line chemotherapy regimen in the United States and Europe remains cisplatin or carboplatin plus etoposide in the treatment of limited stage (LS-SCLC) and extensive stage (ES-SCLC) disease. Radiation therapy is administered to those patients with LS-SCLC, whose cancer is confined to the chest in a single tolerable radiation field. This article will summarize a number of exciting observations regarding the biology of SCLC and how a deeper understanding of newly integrated targets and target pathways may lead to new and better therapeutic approaches in the near future

Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study.

Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC. Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided P = .0048 for PFS and .0128 for OS. Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91; P = .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98; P = .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%. Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC

Patient-Reported Health-Related Quality of Life in KEYNOTE-604: Pembrolizumab or Placebo Added to Etoposide and Platinum as First-Line Therapy for Extensive-Stage SCLC.

In the phase 3 KEYNOTE-604 study (NCT03066778), pembrolizumab plus etoposide and platinum chemotherapy (EP) significantly (p = 0.0023) improved progression-free survival versus placebo plus EP in previously untreated extensive-stage SCLC (ES-SCLC). We present health-related quality of life (HRQoL) results from KEYNOTE-604. Patients with stage IV SCLC were randomized 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles plus four cycles of EP. Secondary end points included mean change from baseline to week 18 in the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) global health status/quality of life (GHS/QoL) scale and time to deterioration in the composite outcome of cough, chest pain, or dyspnea from QLQ-C30 and QLQ-Lung Cancer Module 13. Two-sided, nominal p values are reported. A total of 439 patients completed at least one QLQ-C30 and QLQ-Lung Cancer Module 13 assessment (pembrolizumab + EP, n = 221; placebo + EP, n = 218). GHS/QoL scores improved from baseline to week 18: least squares mean (95% confidence interval [CI]) changes were 8.7 (5.3-12.1) for pembrolizumab plus EP and 4.2 (0.9-7.5) for placebo plus EP. Between-group differences in least squares mean scores were improved for pembrolizumab plus EP (4.4 [95% CI: 0.2-8.7], p = 0.040]). Median time to deterioration for the composite end point was not reached and 8.7 (95% CI: 5.9-not reached) months, respectively (hazard ratio = 0.80 [95% CI: 0.56-1.14], p = 0.208). First-line pembrolizumab plus EP therapy maintained HRQoL in patients with ES-SCLC and may be associated with greater improvement than placebo plus EP. Together with the efficacy and safety findings in KEYNOTE-604, HRQoL data support the benefit of pembrolizumab in ES-SCLC

LBA79 - Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials

In randomized open-label trials, pembro monotherapy demonstrated an OS benefit vs chemo in pts with previously treated (KEYNOTE-010, NCT01905657) or treatment naïve (KEYNOTE-042, NCT02220894), PD-L1+(TPS ≥1%), advanced NSCLC. Associations between tTMB and efficacy were retrospectively explored in a subset of pts with evaluable tTMB in these trials.tTMB was determined by whole exome sequencing of tumor and matched normal DNA. tTMB was evaluable for 253 (24%) pts in KEYNOTE-010 and 793 (62%) pts in KEYNOTE-042. For each study, association of tTMB (continuous log10 scale) with outcomes in each arm was evaluated using Cox proportional hazards models (OS, PFS) and logistic regression (ORR). Statistical significance was determined at the 0.05 level, unadjusted for multiplicity. Clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mut/exome*.Baseline characteristics of the tTMB evaluable subset and total study population were similar. tTMB was not correlated with TPS (continuous score) in both pembro and chemotherapy (chemo) arms (r<0.18). tTMB was associated with OS, PFS and ORR for pembro (pembro arms pooled) in KEYNOTE-010 (1-sided p=0.006, 0.001, 0.009, respectively) and in KEYNOTE-042 (all 1-sided p<0.001); whereas tTMB was in general not associated with outcomes for chemo. In both trials, improvements in OS, PFS and ORR were generally observed for pembro treated pts with high tTMB ≥175 (Table).In this exploratory analysis, associations between higher tTMB levels and improved clinical outcome with pembro monotherapy were observed in pts with PD-L1+ NSCLC. While the results suggest that tTMB may provide additional information regarding the clinical benefit of pembro monotherapy among pts with PD-L1+ NSCLC tumors, the analyses and effect estimates were limited to observational subsets of the randomized cohorts.TableLBA79TableTMB ≥175 Mut/exome*TMB <175 Mut/exome*KEYNOTE-010Pembroa N=81Chemob N=51Pembroa N=83Chemob N=38Median OS (95% CI)14.1 (10.0-19.2)7.6 (5.0-10.7)9.3 (8.3-12.5)7.2 (4.5-14.3)OS HR (95% CI)0.56 (0.38-0.83)0.85 (0.56-1.30)Median PFS (95% CI)4.2 (2.2-10.0)2.4 (2.1-6.0)3.7 (2.1-4.5)3.4 (2.1-7.5)PFS HR (95% CI)0.59 (0.40-0.87)1.09 (0.72-1.63)ORR % (95% CI)23.5 (14.8-34.2)9.8 (3.3-21.4)16.9 (9.5-26.7)21.1 (9.6-37.3)KEYNOTE-042Pembroc N=189Chemod N=165Pembroc N=234Chemod N=214Median OS (95% CI)21.9 (17.0-26.7)11.6 (9.9-14.2)12.0 (9.2-14.8)12.3 (11.3-16.2)OS HR (95% CI)0.62 (0.48-0.80)1.09 (0.88-1.36)Median PFS (95% CI)6.3 (5.5-8.5)6.5 (6.2-8.1)4.1 (3.1-4.3)6.3 (6.1-8.1)PFS HR (95% CI)0.75 (0.59-0.95)1.27 (1.04-1.55)ORR % (95% CI)34.4 (27.5-41.9)30.9 (24.0-38.6)18.8 (14.0-24.4)22.4 (17.0-28.6)*Cutpoint derived by meta-analysis of TMB and gene expression data from pembro clinical trials across multiple tumor types;apembro 10mg/kg (Q3W)+pembro 2mg/kg Q3W;bdocetaxel 75mg/m2 Q3W;cpembro 200mg Q3W;dplatinum-based chemo.KEYNOTE-10 (NCT01905657), originally posted July 23, 2013; KEYNOTE-042 (NCT02220894), originally posted August 20, 2014.Joanne Tomassini of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA.Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA.Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USAR.S. Herbst: Advisory / Consultancy: AbbVie Pharmaceuticals; Advisory / Consultancy: ARMO Biosciences; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Advisory / Consultancy: EMD Serrano; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Genmab; Advisory / Consultancy: Heat Biologics; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme Corp.; Advisory / Consultancy: Nektar; Advisory / Consultancy: NextCure; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Shire PLC; Officer / Board of Directors: Junshi Pharmaceuticals; Advisory / Consultancy: Spectrum Pharmaceuticals; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Tocagen; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Infinity Pharmaceuticals. G. Lopes: Research grant / Funding (institution): MSD; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GI Therapeutics; Honoraria (self), Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: ER Squibb Sons, LLC; Travel / Accommodation / Expenses: Janssen; Honoraria (self), Research grant / Funding (self): Merck. D.M. Kowalski: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD; Advisory / Consultancy: Bristol-Myers Squibb. M. Nishio: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Daiichi Sankyo Healthcare; Advisory / Consultancy: Merck Serono; Research grant / Funding (institution): Astellas. Y. Wu: Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Sanofi; Advisory / Consultancy: Merck & Co., Inc.. G. de Castro Junior: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy: TEVA; Advisory / Consultancy: Yuhan; Advisory / Consultancy: Merck Serono. P. Baas: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (institution), Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Aldeyra Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Theradex. D. Kim: Research grant / Funding (institution): Alpha Biopharma; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Hanmi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): ONO Pharmaceuticals; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): TP Therapeutics; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Yuhan. M.A. Gubens: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Beyond Spring; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Heron; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck & Co., Inc.; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Roche. R. Cristescu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. D. Aurora-Garg: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. A. Al