Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma, with or without peritoneal metastases: a post-hoc analysis on RATIONALE-305 study

Abstract

Background While immunotherapy plus chemotherapy is the current first-line standard for gastric or gastroesophageal junction adenocarcinoma (GC/GEJC), subgroup analyses in patients with peritoneal metastasis are limited and show inconsistent benefits across trials (e.g., ATTRACTION-4, CheckMate 649). This post-hoc analysis evaluated the efficacy of immunotherapy plus chemotherapy in patients with or without peritoneal metastases. Methods This is an exploratory post-hoc analysis of the randomised, double-blind, phase 3 RATIONALE-305 trial. Treatment-na & iuml;ve patients aged >= 18 years with advanced GC/GEJC were enrolled across 13 countries from December 13, 2018, to February 9, 2021. Patients were randomised (1:1) to tislelizumab (200 mg intravenous every 3 weeks) plus chemotherapy or placebo plus chemotherapy until disease progression or unacceptable toxicity. Patients with or without peritoneal metastasis at baseline were identified and reanalysed. Outcomes included overall survival (OS) and progression-free survival (PFS) in the intention-to-treat population, and safety in all patients who received at least one dose of study drug. RATIONALE-305 is registered with ClinicalTrials. gov, NCT03777657. Findings Among the 997 randomised patients, 434 (43.5%) had peritoneal metastases at baseline. Tislelizumab plus chemotherapy significantly improved OS versus placebo plus chemotherapy irrespective of peritoneal metastasis status, with consistent benefits observed in patients with peritoneal metastases (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.64-0.96) and those without peritoneal metastases (HR, 0.79; 95% CI, 0.65-0.95). The OS benefits were greater in patients with a programmed death ligand-1 tumour area positivity score of >= 5%, regardless of peritoneal metastasis status. Significant PFS benefit was also observed with tislelizumab plus chemotherapy in both patients with peritoneal metastasis (HR, 0.80; 95% CI, 0.64-0.98) and without peritoneal metastasis (HR, 0.77; 95% CI, 0.64-0.94). The safety profile was similar between treatment arms and consistent across subgroups. Interpretation Tislelizumab plus chemotherapy significantly improved OS versus placebo plus chemotherapy in patients with GC/GEJC, irrespective of the presence of peritoneal metastases, with a comparable safety profile between treatment arms. Further dedicated prospective studies are warranted to validate these findings in this population.