Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study

• Published in: The lancet oncology 2024-02, Vol.25 (2), p.212-224
• Main Authors: Shitara, Kohei, Rha, Sun Young, Wyrwicz, Lucjan S, Oshima, Takashi, Karaseva, Nina, Osipov, Mikhail, Yasui, Hisateru, Yabusaki, Hiroshi, Afanasyev, Sergey, Park, Young-Kyu, Al-Batran, Salah-Eddin, Yoshikawa, Takaki, Yanez, Patricio, Di Bartolomeo, Maria, Lonardi, Sara, Tabernero, Josep, Van Cutsem, Eric, Janjigian, Yelena Y, Oh, Do-Youn, Xu, Jianming, Fang, Xiao, Shih, Chie-Schin, Bhagia, Pooja, Bang, Yung-Jue
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Adenocarcinoma; Adverse events; Antitumor activity; Appetite loss; Cancer therapies; Chemotherapy; Cisplatin; Colitis; Committees; Esophageal cancer; Esophagus; Immune checkpoint inhibitors; Immunotherapy; Ischemia; Metastasis; Monoclonal antibodies; Neutropenia; Oxaliplatin; Patients; Pembrolizumab; Placebos; Sepsis; Surgery; Survival; Targeted cancer therapy; Toxicity
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(23)00541-7

The benefit of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma is unknown. We assess the antitumor activity of neoadjuvant and adjuvant pembrolizumab plus chemotherapy in patients with locally advanced resectable gastric or gastro-oesophageal adenocarcinoma. The KEYNOTE-585 study is a multicentre, randomised, placebo-controlled, double-blind, phase 3 study done at 143 medical centres in 24 countries. Eligible patients were aged 18 years or older with untreated, locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma, and an Eastern Cooperative Oncology Group performance status 0–1. Patients were randomly assigned (1:1) by an interactive voice response system and integrated web response system to neoadjuvant pembrolizumab 200 mg intravenously or placebo (saline) plus cisplatin-based doublet chemotherapy (main cohort) every 3 weeks for 3 cycles, followed by surgery, adjuvant pembrolizumab or placebo plus chemotherapy for 3 cycles, then adjuvant pembrolizumab or placebo for 11 cycles. A small cohort was also randomly assigned (1:1) to pembrolizumab or placebo plus fluorouracil, docetaxel, and oxaliplatin (FLOT)-based chemotherapy (FLOT cohort) every 2 weeks for four cycles, followed by surgery, adjuvant pembrolizumab, or placebo plus FLOT for four cycles, then adjuvant pembrolizumab or placebo for 11 cycles. Patients were stratified by geographic region, tumour stage, and chemotherapy backbone. Primary endpoints were pathological complete response (reviewed centrally), event-free survival (reviewed by the investigator), and overall survival in the intention-to-treat population, and safety assessed in all patients who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT03221426, and is closed to accrual. Between Oct 9, 2017, and Jan 25, 2021, of 1254 patients screened, 804 were randomly assigned to the main cohort, of whom 402 were assigned to the pembrolizumab plus cisplatin-based chemotherapy group and 402 to the placebo plus cisplatin-based chemotherapy group, and 203 to the FLOT cohort, of whom 100 were assigned to the pembrolizumab plus FLOT group and 103 to placebo plus FLOT group. In the main cohort of 804 participants, 575 (72%) were male and 229 (28%) were female. In the main cohort, after median follow-up of 47·7 months (IQR 38·0–54·8), pembrolizumab was superior t