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Original Investigation
September 3, 2020

Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial

Author Affiliations
  • 1National Cancer Center Hospital East, Kashiwa, Japan
  • 2University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium
  • 3Seoul National University College of Medicine, Seoul, Korea
  • 4Yale Cancer Center, Smilow Cancer Hospital, New Haven, Connecticut
  • 5Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  • 6Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
  • 7Latvian Oncology Center Rakus Gailezers, Riga, Latvia
  • 8Pontifica Universidad Católica de Chile, Santiago, Chile
  • 9Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
  • 10Samsung Medical Center, Seoul, Republic of Korea
  • 11Grupo Medico Angeles, Guatemala City, Guatemala
  • 12Christie Hospital NHS Trust, Manchester, United Kingdom
  • 13Institute of Cancer of São Paolo, University of São Paolo, São Paolo, Brazil
  • 14SPb SBHI Clinical Oncology, Dispensary, Russia
  • 15Clinica Alemana Santiago, Universidad del Desarrollo, Santiago, Chile
  • 16Currently at Cancer Research Department Fundación Arturo Lopez Perez, Santiago, Chile
  • 17Hospital Clinico de la Universidad de Chile, Santiago, Chile
  • 18Hematology Oncology Practice Eppendorf, and University Cancer Center Hamburg, Hamburg, Germany
  • 19Kobe City Medical Center General Hospital, Japan
  • 20Dana-Farber Cancer Institute, Boston, Massachusetts
  • 21Vall d’Hebron Institute of Oncology, Barcelona, Spain
  • 22Northwestern Medicine, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
  • 23City of Hope Comprehensive Cancer Center, Duarte, California
  • 24University of California, San Francisco
  • 25School of Medicine, University of California, Los Angeles
  • 26Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey
  • 27Vall d’Hebron University Hospital (HUVH) and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain
JAMA Oncol. Published online September 3, 2020. doi:10.1001/jamaoncol.2020.3370
Key Points

Question  What is the antitumor activity of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy in patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer and programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater in the first-line setting?

Findings  Among 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer enrolled in the phase 3 KEYNOTE-062 randomized clinical trial, pembrolizumab was noninferior to chemotherapy for overall survival in patients with advanced G/GEJ cancer with PD-L1 CPS of 1 or greater, with patients receiving pembrolizumab experiencing fewer treatment-related adverse events.

Meaning  Pembrolizumab had a favorable benefit-to-risk profile in patients with advanced G/GEJ cancer with PD-L1 CPS of 1 or greater, including in the first-line setting.

Abstract

Importance  Safe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need.

Objective  To evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater.

Design, Setting, and Participants  The phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017.

Interventions  Patients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2 twice daily), or chemotherapy plus placebo, every 3 weeks.

Main Outcomes and Measures  Primary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater.

Results  A total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03; P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17; P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02; P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively.

Conclusions and Relevance  This phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested.

Trial Registration  ClinicalTrials.gov Identifier: NCT02494583

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