lba4long term follow up in the keynote 010 study of pembrolizumab pembro for advanced nsclc including in patients pts who completed 2 years of pembro and pts who received a second course of pembro

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Long-term survival in patients (pts) with advanced NSCLC in the KEYNOTE-010 study overall and in pts who completed two years of pembrolizumab (pembro)

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Five Year Survival Update From KEYNOTE-010 : Pembrolizumab Versus Docetaxel for Previously Treated, Programmed Death-Ligand 1-Positive Advanced NSCLC

Altres ajuts: Merck Sharp & Dohme Corp.Introduction: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% and ≥1%. We report 5-year efficacy and safety follow-up for the KEYNOTE-010 study. Methods: Patients were randomized to pembrolizumab 2 mg/kg or 10 mg/kg once every 3 weeks or docetaxel 75 mg/m once every 3 weeks for up to 35 cycles (2 y). Patients who completed pembrolizumab treatment and subsequently had recurrence could receive second-course pembrolizumab for up to 17 cycles (1 y). Pembrolizumab doses were pooled in this analysis. Results: A total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0‒77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44‒0.69) for patients with PD-L1 TPS ≥50% and 0.70 (0.61‒0.80) with PD-L1 TPS ≥1%. The 5-year OS rates for pembrolizumab versus docetaxel were 25.0% versus 8.2% in patients with PD-L1 TPS ≥50% and 15.6% versus 6.5% with PD-L1 TPS ≥1%. Among 79 patients who completed 35 cycles/2 years of pembrolizumab, the OS rate 3 years after completion (∼5 y from randomization) was 83.0%. A total of 21 patients received second-course pembrolizumab; 11 (52.4%) had an objective response after starting the second course and 15 (71.4%) were alive at data cutoff. Exploratory biomarker analysis revealed that higher tissue tumor mutational burden (≥175 mutations per exome) was associated with improved outcomes with pembrolizumab. Conclusions: Pembrolizumab continued to provide long-term benefit than docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1%. Our findings confirm pembrolizumab as a standard-of-care treatment in the second-line or later setting

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

Long-term follow-up in the KEYNOTE-010 study of pembrolizumab (pembro) for advanced NSCLC, including in patients (pts) who completed 2 years of pembro and pts who received a second course of pembro

In the global, open-label, phase 2/3 study KEYNOTE-010, pembro 10 mg/kg or 2 mg/kg Q3W improved OS vs docetaxel in pts with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1% (coprimary analyses) at median follow-up of 13.1 mo. We present long-term results overall, in pts who completed 35 cycles (∼2 y) of pembro, and in pts who received a second course of pembro