Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability-High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials

Abstract

Importance: Immunotherapy has been associated with improved outcomes among patients who have received previous treatment for microsatellite instability-high (MSI-H) tumors.

Objective: To evaluate the antitumor activity of pembrolizumab therapy vs chemotherapy among patients with MSI-H advanced gastric or gastroesophageal junction (G/GEJ) cancer regardless of the line of therapy in which it was received.

Design, setting, and participants: This post hoc analysis of the phase 2 KEYNOTE-059 (third-line treatment or higher) single-arm trial and the phase 3 KEYNOTE-061 (second-line treatment) and KEYNOTE-062 (first-line treatment) randomized trials included patients with advanced G/GEJ cancer from 52 sites in 16 countries enrolled in KEYNOTE-059, 148 sites in 30 countries enrolled in KEYNOTE-061, and 200 sites in 29 countries enrolled in KEYNOTE-062. Patients were enrolled from March 2, 2015, to March 26, 2016, in KEYNOTE-059; from June 4, 2015, to July 26, 2016, in KEYNOTE-061; and from September 18, 2015, to May 26, 2017, in KEYNOTE-062, with data cutoff dates of August 8, 2018; October 26, 2017; and March 26, 2019; respectively.

Interventions: Pembrolizumab monotherapy in KEYNOTE-059, pembrolizumab monotherapy or chemotherapy (paclitaxel) in KEYNOTE-061, and pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil or capecitabine), or chemotherapy alone in KEYNOTE-062.

Main outcomes and measures: Response was assessed centrally using Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1; MSI-H status was determined centrally by polymerase chain reaction testing.

Results: At data cutoff, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 patients (5.3%) in KEYNOTE-061, and 50 of 682 patients (7.3%) in KEYNOTE-062 had MSI-H tumors. Among those with MSI-H tumors, the median overall survival was not reached (NR) for pembrolizumab in KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 or for pembrolizumab plus chemotherapy in KEYNOTE-062. The median progression-free survival (PFS) for pembrolizumab was NR (95% CI, 1.1 months to NR) in KEYNOTE-059 and 17.8 months (95% CI, 2.7 months to NR) in KEYNOTE-061 (vs 3.5 months [95% CI, 2.0-9.8 months] for chemotherapy). In KEYNOTE-062, the median PFS was 11.2 months (95% CI, 1.5 months to NR) for pembrolizumab, NR (95% CI, 3.6 months to NR) for pembrolizumab plus chemotherapy, and 6.6 months (95% CI, 4.4-8.3 months) for chemotherapy. The objective response rate (ORR) for pembrolizumab was 57.1% in KEYNOTE-059 and 46.7% (vs 16.7% for chemotherapy) in KEYNOTE-061. In KEYNOTE-062, the ORR was 57.1% for pembrolizumab , 64.7% for pembrolizumab plus chemotherapy, and 36.8% for chemotherapy.

Conclusions and relevance: Findings from this study indicate that MSI-H status may be a biomarker for pembrolizumab therapy among patients with advanced G/GEJ cancer regardless of the line of therapy in which it was received.

Trial registration: ClinicalTrials.gov Identifiers: NCT02335411, NCT02370498, and NCT02494583.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Chao reported receiving manuscript-writing assistance from Merck Sharp & Dohme during the conduct of the study and receiving grants from Brooklyn ImmunoTherapeutics and Merck and personal fees from Amgen, AstraZeneca, Boston Biomedical, Daiichi Sankyo, Foundation Medicine, MacroGenics, Merck, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Dr Fuchs reported receiving personal fees from Agios Pharmaceuticals, Amylin Pharmaceuticals, Bain Capital, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Entrinsic Health, EvolveImmune Therapeutics, Genentech, Merck, Taiho Pharmaceutical, and Unum Therapeutics; owning stock in CytomX Therapeutics and Entrinsic Health; cofounding EvolveImmune Therapeutics; serving as the director of CytomX Therapeutics and EvolveImmune Therapeutics; and providing expert testimony for Amylin Pharmaceuticals and Eli Lilly outside the submitted work. Dr Shitara reported receiving grants from Astellas Pharma, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck, Medi Science, Ono Pharmaceutical, Sumitomo Dainippon Pharma, and Taiho Pharmaceutical and personal fees from AbbVie, Astellas Pharma, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Takeda Pharmaceutical, and Yakult Honsha outside the submitted work. Dr Tabernero reported receiving personal fees from Array BioPharma, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Genentech, Genmab, HalioDx, Halozyme Therapeutics, Imugene, Inflection Biosciences, Ipsen Biopharmaceuticals, Kura Oncology, Menarini, Merck Serono, Merck Sharp & Dohme, Merrimack Pharmaceuticals, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign, Rafael Pharmaceuticals, Roche Diagnostics, Sanofi, SeaGen (formerly Seattle Genetics), Servier Laboratories, Symphogen, Taiho Pharmaceutical, and VCN Biosciences outside the submitted work. Dr Muro reported receiving grants from Merck Sharp & Dohme during the conduct of the study and receiving grants from Amgen, Astellas Pharma, Daiichi Sankyo, Merck Sharp & Dohme, Merck Serono, Ono Pharmaceutical, Parexel, Pfizer, Sanofi, Solasia Pharma, and Taiho Pharmaceutical and personal fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Sanofi, Takeda Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Dr Van Cutsem reported receiving grants from Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Ipsen Biopharmaceuticals, Merck KGaA, Merck Sharp & Dohme, Novartis, Roche, and Servier Laboratories and serving on the advisory boards of Array BioPharma, AstraZeneca, Bayer, Biocartis, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Halozyme Therapeutics, Incyte, Ipsen Biopharmaceuticals, Merck KGaA, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Servier Laboratories, Sirtex Medical, and Taiho Pharmaceutical outside the submitted work. Dr Bang reported receiving grants from Astellas Pharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Boston Biomedical, Bristol Myers Squibb, CKD Pharmaceuticals, Curis, Daiichi Sankyo, Eli Lilly, Five Prime Therapeutics, Genentech, Genexine, GlaxoSmithKline, GC Pharma, MacroGenics, Merck Serono, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical and serving as a consultant or advisor for Astellas Pharma, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Genentech, Genexine, GC Pharma, Hanmi Pharmaceutical, Merck Serono, Merck Sharp & Dohme, Novartis, Samyang Biopharm, and Taiho Pharmaceutical outside the submitted work. Dr De Vita reported serving as a consultant or advisor for Celgene and Eli Lilly outside the submitted work. Dr Chau reported receiving grants from Merck Sharp & Dohme during the conduct of the study and receiving grants from Eli Lilly, Janssen-Cilag, and Sanofi Oncology and personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Five Prime Therapeutics, Merck Serono, Merck Sharp & Dohme, Oncologie, Pierre Fabre, and Roche outside the submitted work. Dr Elme reported receiving grants from Merck Sharp & Dohme during the conduct of the study and receiving grants from Roche and personal fees from Amgen, Astra Zeneca, Ipsen Biopharmaceuticals, Merck Sharp & Dohme, and Roche outside the submitted work. Dr Özgüroğlu reported receiving grants from Merck Sharp & Dohme during the conduct of the study and receiving personal fees from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Janssen Pharmaceuticals, Novartis, Roche, and Sanofi outside the submitted work. Dr Catenacci reported receiving grants from Merck Sharp & Dohme and personal fees from Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Five Prime Therapeutics, Foundation Medicine, Genentech, Gritstone Oncology, Guardant Health, Merck, Pieris Pharmaceuticals, Taiho Pharmaceutical, and Tempus Labs during the conduct of the study. Dr Yoon reported receiving grants from Merck and personal fees from BeiGene, Bristol Myers Squibb, and MacroGenics outside the submitted work. Dr Wainberg reported receiving grants from Bristol Myers Squibb, Five Prime Therapeutics, Merck Serono, Novartis, and Ipsen Biopharmaceuticals and personal fees from AstraZeneca, Bayer, Daiichi Sankyo, Eli Lilly, MacroGenics, and Merck outside the submitted work. No other disclosures were reported.

Figures

Figure.. Kaplan-Meier Estimates of Overall Survival Among Patients With Advanced Gastric or Gastroesophageal Junction Cancer by Line of Therapy

Combination indicates pembrolizumab plus chemotherapy; MSI-H, microsatellite instability–high. A, All patients in KEYNOTE-061 clinical trial. B, Patients with MSI-H tumors in KEYNOTE-061 clinical trial. C, All patients in KEYNOTE-062 clinical trial. D, Patients with MSI-H tumors in KEYNOTE-062 clinical trial. The tick marks on each survival curve indicate censored patients.