Pembrolizumab as a first-line treatment for advanced gastric cancer

The efficacy of incorporating PD-1 antibodies in first-line therapy for advanced gastric or gastro-esophageal junction adenocarcinoma was established in the CHECKMATE 649 study. 1 Janjigian YY Shitara K Moehler M et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021; 398: 27-40 Summary Full Text Full Text PDF PubMed Scopus (938) Google Scholar , 2 Shitara K Ajani JA Moehler M et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022; 603: 942-948 Crossref PubMed Scopus (102) Google Scholar However, the results of the CHECKMATE 649 study met statistical significance in the PD-L1 combined positive score (CPS) of 5 or higher, PD-L1 CPS of 1 or higher, and intention-to-treat populations, which has led to geographical variations in regulatory approvals and international guidelines on the addition of nivolumab to chemotherapy regimens in advanced gastric or gastro-esophageal junction adenocarcinoma. In The Lancet Oncology, Sun Young Rha and colleagues 3 Rha SY Oh D-Y Yañez P et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023; (published online Oct 21.)https://doi.org/10.1016/S1470-2045(23)00515-6 Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar report the results of the phase 3 KEYNOTE-859 trial, in which the efficacy and safety of pembrolizumab plus chemotherapy was compared with placebo plus chemotherapy as first-line treatment for patients with advanced gastric or gastro-esophageal junction adenocarcinoma. The results of the primary efficacy analysis (overall survival) in KEYNOTE-859 were similar to those reported in CHECKMATE 649 (appendix), indicating that the addition of PD-1 antibodies to chemotherapy confers a survival benefit. However, in KEYNOTE-859, the prespecified patient populations were patients with a PD-L1 CPS of 1 or higher and a CPS of 10 or higher. In contrast, patients with a PD-L1 CPS of 5 or higher was the primary population analysed in the CHECKMATE 649 study, the results of which resulted in the licensed indication of nivolumab in the European Union and in the current European Society for Medical Oncology Guideline recommendation. Therefore despite almost identical results, the licensed indication of pembrolizumab in patients with advanced gastric or gastro-esophageal junction adenocarcinoma could further influence future revisions of international guidelines. In KEYNOTE-859, overall survival benefit in the PD-L1 negative (CPS <1) population was minimal, and the addition of pembrolizumab had no benefit with regard to progression-free survival in patients with PD-L1-negative tumours. In KEYNOTE-859, the incidence of potentially immune-related adverse events was three times higher in the pembrolizumab group than in the placebo group (213 [27%] of 785 patients in the pembrolizumab group vs 73 [9%] of 787 patients in the placebo group) with predominant endocrinopathy, which generally lasts a long time before resolution. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trialParticipants in the pembrolizumab plus chemotherapy group had a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group. Therefore, pembrolizumab with chemotherapy might be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma. Full-Text PDF