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KEYNOTE-859: phase 3 evidence for pembrolizumab plus chemotherapy in HER2-negative gastric or gastro-esophageal junction adenocarcinoma.

In previously untreated, locally advanced or metastatic disease, pembrolizumab plus chemotherapy significantly improved overall survival, progression-free survival, and objective response rate versus placebo plus chemotherapy; the authors described toxicity as manageable.

  • Sun Young Rha, MD; Do-Youn Oh, MD; Patricio Yañez, MD; Yuxian Bai, MD; Min-Hee Ryu, MD; Jeeyun Lee, MD; et al.

  • October 21, 2023

  • The Lancet Oncology
  • The Lancet Oncology, Volume 24, Issue 11, Pages 1181–1195
  • 10.1016/S1470-2045(23)00515-6

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Evidence before this study

We searched PubMed and Google Scholar from database inception to June 2, 2023, for randomised, controlled trials published in English, using the terms “PD-1 inhibitor” OR “PD-L1 inhibitor” OR “immune checkpoint inhibitor” AND “previously untreated” OR “treatment naïve” OR “first-line therapy” AND “unresectable” OR “metastatic” AND “gastric cancer” OR “gastroesophageal junction cancer.”

Five randomised controlled trials relevant to the present study were identified. Results of the phase 3 KEYNOTE-062 trial found that among participants with untreated advanced HER2-negative gastric or gastro-esophageal junction cancer and PD-L1 combined positive score (CPS) of 1 or higher, pembrolizumab monotherapy was non-inferior to chemotherapy for overall survival, and both pembrolizumab and pembrolizumab plus chemotherapy were not superior to chemotherapy for the overall survival or progression free survival endpoints tested. In the phase 3 ATTRACTION-4 trial, nivolumab plus chemotherapy significantly improved progression-free survival, but not overall survival in Asian participants with untreated, HER2-negative, unresectable advanced or recurrent gastric or gastro-esophageal junction cancer. The phase 3 CheckMate 649 trial showed that nivolumab plus chemotherapy significantly improved overall survival and progression free survival compared with chemotherapy alone for participants with previously untreated advanced HER2-negative gastric, gastro-esophageal junction, or oesophageal adenocarcinoma and PD-L1 CPS of 5 or higher. The phase 3 ORIENT-16 trial showed that sintilimab plus chemotherapy significantly improved overall survival compared with placebo plus chemotherapy in participants with non-HER2-positive gastric or gastro-esophageal junction adenocarcinoma. Additionally, the phase 3 RATIONALE 305 trial showed that the PD-1 inhibitor tislelizumab plus chemotherapy provided significant and clinically meaningful improvement in overall survival versus chemotherapy alone, with acceptable safety in 546 participants with PD-L1–positive gastric or gastro-esophageal junction adenocarcinoma.

Added value of this study

The KEYNOTE-859 trial demonstrated the efficacy and manageable toxicity of pembrolizumab plus chemotherapy (capecitabine plus oxaliplatin or fluorouracil plus cisplatin) as first-line treatment for participants with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma. Participants in the pembrolizumab plus chemotherapy group had significantly improved overall survival, progression-free survival, and objective response rate compared with the placebo plus chemotherapy group.

Implications of all the available evidence

Data from the KEYNOTE-859 trial provide a novel treatment option to address a high unmet medical need for highly efficacious and safe therapies in the treatment of patients with previously untreated locally advanced unresectable or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma.

Source: The Lancet Oncology

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