Esophagus to Small Intestine
Lancet Oncol. 2023;24(11):1181–95
Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): A multicenter, randomized, double-blind, phase 3 trial
Background: Programmed cell death 1 (PD-1) inhibitors combined with chemotherapy have shown efficacy in gastric or gastroesophageal junction cancer. The authors compared the efficacy and safety of pembrolizumab plus chemotherapy with placebo plus chemotherapy in participants with locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma.
Methods: KEYNOTE-859 is a multicenter, double-blind, placebo-controlled, randomized, phase 3 trial, done at 207 medical centers across 33 countries. Eligible participants were aged 18 years and older with previously untreated histologically or cytologically confirmed locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to receive pembrolizumab or placebo 200 mg, administered intravenously (i.v.) every 3 weeks for up to 35 cycles. All participants received investigator’s choice of fluorouracil (i.v., 800 mg/m2 per day) administered continuously on days 1–5 of each 3-week cycle plus cisplatin (i.v., 80 mg/m2) administered on day 1 of each 3-week cycle or capecitabine (oral, 1000 mg/m2) administered twice daily on days 1–14 of each 3-week cycle plus oxaliplatin (i.v., 130 mg/m2) administered on day 1 of each 3-week cycle. Randomization was done using a central interactive voice-response system and stratified by geographical region, PD ligand 1 (PD-L1) status, and chemotherapy in permuted block sizes of 4. The primary end point was overall survival, assessed in the intention-to-treat (ITT) population, and the populations with a PD-L1 combined positive score (CPS) of ≥ 1, and PD-L1 CPS of ≥ 10. Safety was assessed in the as-treated population, which included all randomly assigned participants who received at least 1 dose of study intervention. Here, the results of the interim analysis are reported.
Findings: Between November 8, 2018, and June 11, 2021, 1579 of 2409 screened participants (66%) were randomly assigned to receive pembrolizumab plus chemotherapy (pembrolizumab group; n = 790) or placebo plus chemotherapy (placebo group; n = 789). Most participants were male (527 of 790 participants [67%] in the pembrolizumab plus chemotherapy group; 544 of 789 participants [69%] in the placebo plus chemotherapy group) and White (426 [54%]; 435 [55%]). Median follow-up at the data cut-off was 31.0 months (interquartile range [IQR], 23.0–38.3). Median overall survival was longer in the pembrolizumab group than in the placebo group in the ITT population (12.9 months [95% confidence interval {CI}: 11.9–14.0] vs. 11.5 months [95% CI: 10.6–12.1]; hazard ratio [HR] = 0.78 [95% CI: 0.70–0.87]; p < 0.0001), in participants with a PD-L1 CPS of ≥ 1 (13.0 months [95% CI: 11.6–14.2] vs. 11.4 months [95% CI: 10.5–12.0]; HR = 0.74 [95% CI: 0.65–0.84]; p < 0.0001), and in participants with a PD-L1 CPS of ≥ 10 (15.7 months [95% CI: 13.8–19.3] vs. 11.8 months [95% CI: 10.3–12.7]; HR = 0.65 [95% CI: 0.53–0.79]; p < 0.0001). The most common grade 3–5 adverse events of any cause were anemia (95 of 785 participants [12%] in the pembrolizumab group vs. 76 of 787 participants [10%] in the placebo group) and decreased neutrophil count (77 [10%] vs. 64 [8%]). Serious treatment-related adverse events occurred in 184 participants (23%) in the pembrolizumab group and 146 participants (19%) in the placebo group. Treatment-related deaths occurred in 8 participants (1%) in the pembrolizumab group and 16 participants (2%) in the placebo group. No new safety signals were identified.
Interpretation: Participants 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 gastroesophageal junction adenocarcinoma.