Additional data from the KEYNOTE-859 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer

The phase 3 KEYNOTE-859 study (NCT03675737) showed that adding pembrolizumab to chemotherapy significantly improved the primary endpoint of OS (median 12.9 months vs 11.5 months; HR 0.78, 95% CI 0.70-0.87; P < 0.0001) and the secondary endpoints of PFS (6.9 months vs 5.6 months; HR 0.76, 95% CI 0.67-0.85; P < 0.0001) and ORR (51.3% vs 42.0%; P = 0.00009) compared with chemotherapy alone in patients with HER2-negative, previously untreated locally advanced or metastatic G/GEJ adenocarcinoma. The safety profile of pembrolizumab plus chemotherapy was as expected. To further characterize the efficacy of pembrolizumab plus chemotherapy in KEYNOTE-859 and explore the potential influence of subsequent therapy on outcomes, we did a post hoc analysis of time from randomization to objective tumor progression on next-line therapy or death from any cause (PFS2). 1579 patients were randomized 1:1 to pembrolizumab 200 mg or placebo given IV Q3W for ≤35 cycles; all patients were to receive investigator’s choice of 5-FU + cisplatin or capecitabine + oxaliplatin. The HR and associated 95% CI for PFS2 in the ITT population were calculated using a Cox regression model with Efron’s tie-handling method stratified by the randomization stratification factors of geographic region, PD-L1 CPS, and choice of chemotherapy. Data are from the interim analysis (03 October 2022 cutoff). After a median study follow-up of 31.0 months (range, 15.3-46.3), 355 (44.9%) of 790 participants in the pembrolizumab group and 369 (46.8%) of 789 participants in the placebo group received ≥1 subsequent systemic anticancer therapy. The use of specific therapies was well balanced between arms; 339 (42.9%) in the pembrolizumab group and 346 (43.9%) in the placebo group received chemotherapy, 137 (17.3%) and 138 (17.5%) received a VEGF/VEGFR inhibitor, 66 (8.4%) and 72 (9.1%) received a PD-1/PD-L1 inhibitor, and 92 (11.6%) and 96 (12.2%) received other systemic anticancer therapy. Median PFS2 was 11.2 months (95% CI 10.5-12.2) in the pembrolizumab group versus 10.0 months (95% CI 9.2-10.5) in the placebo group (HR 0.76, 95% CI 0.68-0.85). Results of this post hoc analysis suggest that the benefit of adding pembrolizumab to first-line chemotherapy is maintained when evaluating PFS2, which has a similar HR as PFS. These data further support pembrolizumab plus chemotherapy as a new first-line treatment option for locally advanced or metastatic HER2-negative G/GEJ adenocarcinoma.