Dr Shiu on the FDA Approval of Pembrolizumab Plus Chemotherapy in Advanced HER2– Gastric/GEJ Adenocarcinoma

Kai-Keen Shiu, MD, medical oncology consultant, Gastrointestinal Oncology Service, University College London Hospitals NHS Foundation Trust, honorary associate professor, the UCL Cancer Institute, discusses the significance of the FDA approval of pembrolizumab (Keytruda) in combination with fluoropyrimidine- and platinum-containing chemotherapy as a first-line treatment in patients with locally advanced, unresectable or metastatic, HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.

On November 16, 2023, the FDA approved pembrolizumab plus chemotherapy for this patient population based on data from the phase 3 KEYNOTE-859 trial (NCT03675737), in which the combination elicited statistically significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) vs chemotherapy alone. The multicenter, randomized, double-blind, placebo-controlled trial showed that at a median follow-up of 31.0 months (range, 15.3-46.3), patients treated with the pembrolizumab combination (n = 790) experienced a median OS of 12.9 months (95% CI, 11.9-14.0), whereas patients given chemotherapy alone (n = 789) had a median OS of 11.5 months (95% CI, 10.6-12.1; HR, 0.78; 95% CI, 0.70-0.87; P < .0001).

Shiu begins by stating that the combination of first-line nivolumab (Opdivo) and chemotherapy was approved for patients with gastric cancer, esophageal cancer, or GEJ adenocarcinoma based on findings from the phase 3 CheckMate-649 trial (NCT02872116). Thus, the approval of pembrolizumab plus chemotherapy in this patient population is noteworthy because the KEYNOTE-859 trial is similar to CheckMate-649 in terms of its size and global reach, as both trials spanned multiple countries, he imparts. Although the ORR, PFS, and OS benefits with pembrolizumab plus chemotherapy align closely with those observed with nivolumab plus chemotherapy, the key distinction between these regimens lies in the biomarker determining treatment response: PD-L1 combined positive score (CPS), Shiu explains.

The approval of pembrolizumab plus chemotherapy significantly expands the treatment options for patients with HER2-negative gastric/GEJ adenocarcinoma, Shiu continues. Unlike the CheckMate-649 trial, which had relatively strict enrollment criteria regarding PD-L1 mutations, the KEYNOTE-859 study appeared to include all comers, regardless of PD-L1 status, he says.

Despite the belief that patients with a PD-L1 score of less than 1 may experience marginal or minimal benefits from immunotherapy vs chemotherapy, the KEYNOTE-859 trial demonstrated benefits with pembrolizumab plus chemotherapy for patients with a CPS of 1 or more, as well as for those with a CPS of 10 or more, he explains. This FDA approval signifies the potential to offer immunotherapy to a broader range of patients with gastric/GEJ adenocarcinoma with lower PD-L1 scores, Shiu concludes.