Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial

Abstract

Importance: Therapeutic options are needed for patients with advanced gastric cancer whose disease has progressed after 2 or more lines of therapy.

Objective: To evaluate the safety and efficacy of pembrolizumab in a cohort of patients with previously treated gastric or gastroesophageal junction cancer.

Design, setting, and participants: In the phase 2, global, open-label, single-arm, multicohort KEYNOTE-059 study, 259 patients in 16 countries were enrolled in a cohort between March 2, 2015, and May 26, 2016. Median (range) follow-up was 5.8 (0.5-21.6) months.

Intervention: Patients received pembrolizumab, 200 mg, intravenously every 3 weeks until disease progression, investigator or patient decision to withdraw, or unacceptable toxic effects.

Main outcomes and measures: Primary end points were objective response rate and safety. Objective response rate was assessed by central radiologic review per Response Evaluation Criteria in Solid Tumors, version 1.1, in all patients and those with programmed cell death 1 ligand 1 (PD-L1)-positive tumors. Expression of PD-L1 was assessed by immunohistochemistry. Secondary end points included response duration.

Results: Of 259 patients enrolled, most were male (198 [76.4%]) and white (200 [77.2%]); median (range) age was 62 (24-89) years. Objective response rate was 11.6% (95% CI, 8.0%-16.1%; 30 of 259 patients), with complete response in 2.3% (95% CI, 0.9%-5.0%; 6 of 259 patients). Median (range) response duration was 8.4 (1.6+ to 17.3+) months (+ indicates that patients had no progressive disease at their last assessment). Objective response rate and median (range) response duration were 15.5% (95% CI, 10.1%-22.4%; 23 of 148 patients) and 16.3 (1.6+ to 17.3+) months and 6.4% (95% CI, 2.6%-12.8%; 7 of 109 patients) and 6.9 (2.4 to 7.0+) months in patients with PD-L1-positive and PD-L1-negative tumors, respectively. Forty-six patients (17.8%) experienced 1 or more grade 3 to 5 treatment-related adverse events. Two patients (0.8%) discontinued because of treatment-related adverse events, and 2 deaths were considered related to treatment.

Conclusions and relevance: Pembrolizumab monotherapy demonstrated promising activity and manageable safety in patients with advanced gastric or gastroesophageal junction cancer who had previously received at least 2 lines of treatment. Durable responses were observed in patients with PD-L1-positive and PD-L1-negative tumors. Further study of pembrolizumab for this group of patients is warranted.

Trial registration: clinicaltrials.gov Identifier: NCT02335411.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Fuchs has been a consultant for Eli Lilly, Entrinsic Health, Pfizer, Merck, Sanofi, Roche, Genentech, Merrimack Pharmaceuticals, Dicerna, Bayer, Agios, Gilead Sciences, Five Prime Therapeutics, and Taiho. Dr Doi has received personal fees and research funding from Novartis, Merck Sharp & Dohme, Eli Lilly, Chugai Pharma, Kyowa Hakko Kirin, and Daiichi Sankyo; research funding from Taiho, Merck Serono, Astellas Pharma, Janssen, Boehringer Ingelheim, Takeda, Pfizer, Sumitomo Group, Bayer, and Celgene; and personal fees from Amgen. Dr Jang has been a site principal investigator in clinical trials sponsored by AstraZeneca, Merck, Novartis, Lilly, Boston Biomedical, and Bristol-Myers Squibb. Dr Muro has received honoraria from Takeda, Eli Lilly, Merck, Serono, Chugai Pharmaceuticals, Yakult Honsha, and Taiho Pharmaceuticals. Dr Satoh has received honoraria from Chugai Pharmaceuticals, Takeda, Eli Lilly, Merck Serono, Yakult Honsha, Taiho Pharmaceuticals, and Bayer; has been a consultant for Chugai Pharmaceuticals, Eli Lilly, and Ono Pharmaceutical; and has received institutional research funding from Yakult Honsha, Chugai Pharmaceutical, and Ono Pharmaceutical. Dr Sun has been a consultant for Bayer and Taiho and has received institutional research funding from Merck and Bayer. Dr Shah has received institutional research funding from Merck, Roche, and Boston Biomedical. Dr Metges has received honoraria from Eli Lilly, Sanofi, Novartis, and Merck. Dr Garrido has been a consultant to Merck Sharp & Dohme and Eli Lilly. Dr Mandala has received honoraria from and been a consultant for Merck, Bristol-Myers Squibb, Roche, and Novartis. Dr Wainberg has been a consultant for Genentech, ArrayBiopharma, Sirtex, Novartis, and Five Prime Therapeutics. Dr Catenacci has been a consultant for Eli Lilly, Roche/Genentech, Amgen, Taiho, and Five Prime Therapeutics; served on a speakers bureau for Eli Lilly; and received institutional research funding from Amgen and Genentech. Dr Ohtsu has received a grant from Bristol-Myers Squibb. Dr Shitara has received grants from Daiichi Sankyo, Sumitomo Dainippon Pharmaceuticals, Bayer, Yakult Honsha, Chugai Pharmaceuticals, Sanofi, Eli Lilly, Merck Sharp & Dohme, Bristol-Myers Squibb, Taiho Pharmaceuticals, and Onoyakuhin and has received personal fees from Bayer, Chugai Pharmaceuticals, Sanofi, Eli Lilly, Novartis, and Takeda. Dr Geva has been a consultant and advisor for Bayer, Novartis, and Merck Sharp & Dohme; has received honoraria from Bristol-Myers Squibb, Eli Lilly, Roche, Novartis, Medison, and Janssen; and has received travel and expense support from Bristol-Myers Squibb and Roche. Dr Bleeker has received travel support from Merck and has served as a consultant for Bristol-Myers Squibb. Dr Ko has received institutional research support from Merck, Bristol-Myers Squibb, Aduro Biotech, Merrimack, Celgene, and Roche and was a consultant for Seattle Genetics and New Beta Innovations. Dr Ku has received grants from Merck, Bristol-Myers Squibb, Arog Pharmaceuticals, and AstraZeneca and has received personal fees from Merck, Eli Lilly, and AstraZeneca. Dr Philip has received grants from Merck, Celgene, Incyte, Halozyme, Advix, Bayer, Boston Biomedical, Momenta, Novartis, and MacroGenics and has received personal fees from Celgene, Roche, Halozyme, Bayer, Merrimack, Caris, Ipsen, Lexicon, and Cornerstone. Dr Enzinger was a consultant for Merck, Five Prime Therapeutics, Sirtex, and Pfizer. Dr Bang has received institutional grant funding from Merck and has served as a consultant to Merck. Dr Yoon has received honoraria (paid to institution) for serving on advisory boards for Eli Lilly, Genentech, Astellas, LSK, and Five Prime Therapeutics and has received research funding (paid to institution) from Eli Lilly and Genentech. Drs Levitan, Wang, Rosales, and Dalal are employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. No other disclosures were reported.

Figures

Figure 1.. Enrollment of Patients for Cohort 1 of the KEYNOTE-059 Study

Eligible patients were 18 years or older; had histologically or cytologically confirmed recurrent or metastatic gastric or gastroesophageal cancer; and had disease progression after 2 or more prior chemotherapy regimens that included a fluoropyrimidine and a platinum doublet.

Figure 2.. Tumor Response in 223 Patients

Of 259 patients enrolled, 223 had 1 or more postbaseline radiologic imaging assessments. Response was assessed in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by central imaging at baseline and after at least 1 postbaseline tumor assessment. A, Best change from baseline in sum of longest target lesion diameters per patient (n = 223). PD-L1 indicates programmed cell death 1 ligand 1. B, Duration of exposure and first confirmed response (partial or complete response) in responders (n = 30). Bar length indicates time to last imaging assessment. C, Longitudinal change in sum of longest target lesion diameters from baseline in patients with partial or complete response (n = 30).