Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study

Abstract

Background: The multicohort, phase II, nonrandomized KEYNOTE-059 study evaluated pembrolizumab ± chemotherapy in advanced gastric/gastroesophageal junction cancer. Results from cohorts 2 and 3, evaluating first-line therapy, are presented.

Methods: Patients ≥ 18 years old had previously untreated recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma. Cohort 3 (monotherapy) had programmed death receptor 1 combined positive score ≥ 1. Cohort 2 (combination therapy) received pembrolizumab 200 mg on day 1, cisplatin 80 mg/m2 on day 1 (up to 6 cycles), and 5-fluorouracil 800 mg/m2 on days 1-5 of each 3-week cycle (or capecitabine 1000 mg/m2 twice daily in Japan). Primary end points were safety (combination therapy) and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by central review, and safety (monotherapy).

Results: In the combination therapy and monotherapy cohorts, 25 and 31 patients were enrolled; median follow-up was 13.8 months (range 1.8-24.1) and 17.5 months (range 1.7-20.7), respectively. In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. In the monotherapy cohort, grade 3-5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis). The objective response rate was 60.0% [95% confidence interval (CI), 38.7-78.9] (combination therapy) and 25.8% (95% CI 11.9-44.6) (monotherapy).

Conclusions: Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy and in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma.

Clinical trial: ClinicalTrials.gov NCT02335411.

Keywords: 5-Fluorouracil; Capecitabine; Cisplatin; Gastric cancer; Pembrolizumab.

Conflict of interest statement

Y-JB: consultant or advisory role: AstraZeneca, Novartis, Roche, Genentech, Merck Sharp & Dohme, Pfizer, Bayer, Bristol-Myers Squibb, Eli Lilly, Merck Serono, Five Prime, Merrimack, Taiho, Ono, ADC Therapeutics, Green Cross, Samyang Biopharma; research funding (institution): AstraZeneca, Novartis, Roche/Genentech, Merck Sharp & Dohme, Merck Serono, Pfizer, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Boehringer Ingelheim, MacroGenics, Boston Biomedical, Five Prime, Chong Kun Dang Bio, Ono pharmaceutical, Otsuka, Taiho, Takeda, BeiGene, Hanmi, Green Cross, Curis. Y-KK: consultant or advisory role: Bristol-Myers Squibb, Ono Pharmaceutical, Daehwa, Novartis; research funding: LSK Biopharma. DVC: consultant or advisory role: Merck, Bristol-Myers Squibb, Eli Lilly, Genentech/Roche, Amgen, Taiho, Five Prime. KM: honoraria: Chugai Pharmaceutical, Takeda Pharmaceutical, Eli Lilly Japan K.K., Merck Serono, Taiho, Yakult Honsha; research funding to institution: Shionogi & Co., Ltd., Merck Sharp & Dohme, K.K., Daiichi Sankyo, Kyowa Hakko Kirin Co. Ltd., Gilead Sciences. CSF: consultant or advisory role: Agios, Bain Capital, Bayer, Celgene, Dicerna, Five Prime Therapeutics, Gilead Sciences, Eli Lilly, Entrinsic Health, Genentech, KEW, Merck, Merrimack Pharmaceuticals, Pfizer, Sanofi, Taiho, and Unum Therapeutics. He also serves as a Director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health. RG: honoraria: Bristol-Myers Squibb, Eli Lilly, Medison, Roche, Novartis, Janssen; consulting or advisory role: Bayer, Merck Sharp & Dohme, Novartis; travel, accommodation, expenses: Roche, Bristol-Myers Squibb. HH: consultant or advisory role: Ono Pharmaceutical, Chugai Pharmaceutical; research funding (institution): AstraZeneca, Chugai Pharmaceutical, Merck Serono, Merck Sharp & Dohme, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Boehringer Ingelheim, Sumitomo Dainippon Pharma, Daiichi Sankyo, Eli Lilly; TG: research funding (institution): AstraZeneca. Merck Sharp & Dohme consultant or advisory role: AstraZeneca and AbbVie. SIJ: research funding (institution): AstraZeneca. MG: consultant or advisory role: Merck Sharp & Dohme, Eli Lilly. CB: honoraria: Bristol-Myers Squibb, Eli Lilly, Amgen, Merck Sharp & Dohme; consultant or advisory role: Roche, Servier; research funding (institution): Roche. TD: consultant or advisory role: Eli Lilly, Chugai Pharmaceutical, Kyowa Hakko Kirin Co., Novartis, Merck Sharp & Dohme, Daiichi Sankyo, Amgen; research funding (institution): Taiho, Novartis, Merck Serono, Astellas, Merck Sharp & Dohme, Janssen, Boehringer Ingelheim, Takeda, Pfizer, Eli Lilly, Sumitomo Group, Chugai Pharmaceutical, Bayer, Kyowa Hakko Kirin Co., Daiichi Sankyo, Celgene. HY: research funding (institution): Eli Lilly, Genentech; honoraria (institution): Eli Lilly, Genentech, Astellas, Five Prime Therapeutics, LSK Biopharma. MJS, SS, and JW: employee: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. RPD: former employee: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. ZAW: consultant or advisory role: Genentech, Array Biopharma, Sirtex, Novartis, Five Prime Therapeutics. HCC: consultant or advisory role: Taiho, Celltrion, Merck Sharp & Dohme, Eli Lilly, Quintiles, Bristol-Myers Squibb; speaker’s bureau: Merck Serono, Eli Lilly, Foundation Medicine; research funding (institution): Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Merck Serono, Bristol-Myers Squibb/Ono Pharmaceutical, Taiho.

Figures

Fig. 1

Antitumor activity. a Best change from baseline in the sum of longest target lesion diameters per patient by PD-L1 expression in cohort 2 (n = 24)a. b Duration of exposure and best response in confirmed responders in cohort 2 (n = 15)b. c Maximum percentage change from baseline in the sum of longest diameter of target lesions per patient (n = 28)a. d Duration of exposure and best response in confirmed responders (n = 8)b. aPatients with measurable disease per RECIST v1.1 by central review at baseline who had ≥ 1 evaluable postbaseline assessment. bPatients with measurable disease per RECIST v1.1 by central review at baseline who had ≥ 1 postbaseline assessment and had confirmed response. Bar length indicates time to last dose of study drug. Time to first confirmed response is shown. PD-L1, programmed death ligand 1; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1

Fig. 2

Kaplan–Meier estimates of a progression-free survival and b overall survival in cohort 2, and c progression-free survival and d overall survival in cohort 3