First-line cadonilimab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a randomized, double-blind, phase 3 trial

Programmed cell death protein-1 (PD-1) inhibitors plus chemotherapy have been the standard of care in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma; however, the survival benefits are modest in patients with low programmed death ligand 1 (PD-L1) expression. Here we investigated the efficacy and safety of cadonilimab (PD-1/cytotoxic T lymphocyte antigen-4 (CTLA-4) bispecific antibody) plus chemotherapy as first-line treatment in G/GEJ adenocarcinoma. The prespecified interim analysis is reported here. This was a randomized, double-blind, placebo-controlled phase 3 study. Eligible patients were adults with untreated, unresectable, locally advanced or metastatic G/GEJ adenocarcinoma. Patients were randomized 1:1 to receive cadonilimab (10 mg kg⁻¹ every 3 weeks) or placebo plus chemotherapy (every 3 weeks). The primary endpoint was overall survival (OS) in the intention-to-treat population (one-sided significance level, P = 0.025). Secondary endpoints included OS in patients with a PD-L1 combined positive score ≥5, progression-free survival, objective response rate, duration of response and safety. As of 18 August 2023, 610 patients from 75 study centers were randomized to cadonilimab (n = 305) or placebo (n = 305). With a median follow-up of 18.7 months, the cadonilimab group had a significantly longer median OS (14.1 versus 11.1 months; hazard ratio (HR) 0.66; 95% confidence interval (CI) 0.54–0.81; P < 0.001) than the placebo group. The primary endpoint was met. The median progression-free survival was 7.0 months versus 5.3 months (HR 0.53, 95% CI 0.44–0.65). The median OS in patients with a PD-L1 combined positive score ≥5 was 15.3 months versus 10.9 months (HR 0.58, 95% CI 0.41–0.82). The objective response rate was 65.2% versus 48.9% with a median duration of response of 8.8 months versus 4.4 months. Grade ≥3 treatment-related adverse events occurred in 65.9% of the cadonilimab group and 53.6% of the placebo group, and the most common were decreased platelet count, decreased neutrophil count and anemia. Most of the immune-related adverse events were grade 1 or 2. No new safety signals were observed. Cadonilimab plus chemotherapy significantly improved OS with a manageable safety profile in patients with advanced G/GEJ adenocarcinoma. ClinicalTrials.gov registration: NCT05008783.