Abstract 1442P
Background
In the phase III KEYNOTE-062 study (NCT02494583) in advanced GC or gastroesophageal junction adenocarcinoma (N = 763), first-line pembro was noninferior to chemo for OS in patients with PD-L1 CPS ≥1 but showed clinically meaningful improvement in patients with CPS ≥10; pembro + chemo did not show superior survival in patients with CPS ≥1 or in patients with CPS ≥10. We explored the association of TMB status and clinical outcomes in KEYNOTE-062.
Methods
In patients with available TMB data, the association of TMB (square root scale), assessed via F1CDx, with clinical outcomes was evaluated. Within each treatment group, confirmed ORR and PFS by blinded central radiology review per RECIST v1.1 and OS were evaluated using logistic regression (ORR) and Cox proportional hazards regression (PFS; OS) to calculate 1-sided (pembro; pembro + chemo) and 2-sided (chemo) P values. The clinical utility of TMB was assessed using the prespecified cutoff of 10 mut/Mb. Clinical data cutoff: March 26, 2019.
Results
306/763 patients (40%) had evaluable TMB data (pembro, 107; pembro + chemo, 100; chemo, 99). The overall prevalence of TMB ≥10 mut/Mb was 16%. The sample size of patients with high or low TMB was balanced across the 3 groups. TMB was significantly associated with ORR, PFS, and OS with pembro and pembro + chemo (P < 0.05) but not with chemo (P > 0.05). Patient outcomes by TMB cutoff are reported in the Table Table: 1442P
| TMB≥10 | TMB≥10 | TMB<10 | TMB<10 | |
| P (n=18) vs C (n=17) | P+C (n=15) vs C (n=17) | P (n=89) vs C (n=82) | P+C (n=85) vs C (n=82) | |
| ORR, % (95% CI) | 56 (31-79) vs 41 (18-67) | 73 (45-92) vs 41 (18-67) | 7 (3-14) vs 48 (36-59) | 46 (35-57) vs 48 (36-59) |
| PFS, HR (95% CI) | 0.52 (0.24-1.13) | 0.62 (0.39-0.97) | 1.73 (1.26-2.38) | 0.97 (0.82-1.14) |
| OS, HR (95% CI) | 0.34 (0.14-0.82) | 0.54 (0.33-0.89) | 1.41 (1.02-1.95) | 1.01 (0.86-1.20) |
HRs are adjusted for ECOG PS.
.Conclusions
This prespecified exploratory analysis from the randomized KEYNOTE-062 trial provides evidence of an association between TMB and clinical response with first-line pembro monotherapy and pembro + chemo but not with chemo in patients with GC. Data further suggest a survival benefit in pembro-treated patients with TMB ≥10 mut/Mb, which include a majority of patients with tumors with high microsatellite instability.
Clinical trial identification
NCT02494583.
Editorial acknowledgement
Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA) and funded by Merck Sharp & Dohme Corp.
Legal entity responsible for the study
Merck Sharp & Dohme Corp.
Funding
Merck Sharp & Dohme Corp.
Disclosure
K-W. Lee: Honoraria (self): Bristol-Myers Squibb, Eli Lilly, and Genexine; Research grant/Funding (institution): Ono Pharmaceutical, Merck Sharp & Dohme Corp., AstraZeneca/MedImmune, Merck KGaA, Pfizer, MacroGenics, Green Cross Corporation, Five Prime Therapeutics, Pharmacyclics, LSK BioPharma, ALX Oncology, Zymeworks, BeiGene, Genexine, Daiichi Sankyo, and Taiho Ph. E. Van Cutsem: Advisory/Consultancy: Array, Astrazeneca, Bayer, Biocartis, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre-Fabre, Roche, Servier, Sirtex, Taiho; Research grant/Funding (institution): Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. Y-J. Bang: Advisory/Consultancy: AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serano, Bayer, BMS, Eli Lilly, Taiho, Daiich-Sankyo, Astellas, BeiGene, GreenCross, Samyang Biopharm, Hanmi, Genexine; Research grant/Funding (institution): MSD,AstraZeneca, Novartis, Genentech/Roche, Merck Serano, Bayer, BMS, GSK, Pfizer, Eli Lilly, Boeringer-Ingelheim, MacroGenics, Boston Biomedical, FivePrime, Curis, Taiho, Takeda, Ono, Daiichi Sankyo, Astellas, BeiGene, Green Cross, CKD Pharma, Genexine. C.S. Fuchs: Leadership role: CytomX Therapeutics, Evolveimmune Therapeutics; Shareholder/Stockholder/Stock options, Exercised stock options: CytomX and Entrinsic Health; Advisory/Consultancy: Agios, Bain Capital, CytomX, Daiichi Sankyo, Eli Lilly, Entrinsic Health, Genetech, Merck, Taiho, Unum. M. Garrido: Honoraria (self): BMS, MSD, Novartis, Roche, Pfizer, Bayer; Advisory/Consultancy: MSD, Bayer; Speaker Bureau/Expert testimony: MSD, BMS; Travel/Accommodation/Expenses: BMS, Novartis. H.C. Chung: Honoraria (self): Merck-Serono, Lilly, Foundation Medicine; Advisory/Consultancy: Taiho, Celltrion, MSD, Lilly, Quintiles, BMS, Merck-Serono, Gloria, Beigene, Amgen, Zymework; Research grant/Funding (institution): Lilly, GSK, MSD, Merck-Serono, BMS/Ono, Taiho, Amgen, Beigene. J. Lee: Advisory/Consultancy: Oncologie, Seattle Genetics; Research grant/Funding (self): Astra Zeneca, Merck Sharp and Dohme, Eli Lilly and Company. H.R. Castro: Speaker Bureau/Expert testimony: Pfizer; Travel/Accommodation/Expenses: Novartis, Roche. J. Chao: Advisory/Consultancy: Amgen, Macrogenics, Ono Pharmaceuticals, Foundation Medicine; Speaker Bureau/Expert testimony: Merck; Travel/Accommodation/Expenses: Amgen, Foundation Medicine, Macrogenics; Research grant/Funding (institution): Merck, Brooklyn Immunotherapeutics. Z.A. Wainberg: Advisory/Consultancy: Merck, Ibsen, Lilly, Five prime, QED, Molecular Templates, Daiichi, Astra Zeneca; Travel/Accommodation/Expenses: Lilly, Merck, Novartis, Daiichi. Z.A. Cao, D. Aurora-Garg, J. Kobie, R. Cristescu, P. Bhagia: Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA ; Shareholder/Stockholder/Stock options: Merck & Co., Inc., Kenilworth, NJ, USA. S. Shah: Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. J. Tabernero: Advisory/Consultancy: Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partn. K. Shitara: Honoraria (self): Novartis, AbbVie, and Yakult; Advisory/Consultancy: Astellas, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono, MSD, Taiho, Novartis, AbbVie, and GlaxoSmithKline; Research grant/Funding (institution): Astellas, Lilly, Ono, Sumoitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, MSD and Medi Science. All other authors have declared no conflicts of interest.