Domvanalimab and zimberelimab in advanced gastric, gastroesophageal junction or esophageal cancer: a phase 2 trial

Dual inhibition of T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed cell death protein 1 (PD-1) may enhance antitumor immunity in advanced gastroesophageal cancers. Here we report the EDGE-Gastric study, an ongoing, multicenter, international, phase 2 study with three cohorts, one in the first-line setting (cohort A) and two in the second-line or greater setting (cohorts B and C). Cohort A comprises four arms: two nonrandomized (A1 and A2) and two randomized (A3 and A4). In arm A1, presented here, dual blockade of TIGIT and PD-1 with domvanalimab (Fc-silent anti-TIGIT) and zimberelimab (anti-PD-1) plus oxaliplatin, leucovorin, fluorouracil (FOLFOX) was evaluated in patients with previously untreated advanced HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Among 41 treated patients, the confirmed objective response rate was 59% (90% confidence interval (CI) 44.5–71.6%), median progression-free survival was 12.9 months (90% CI 9.8–14.6 months) and median overall survival was 26.7 months (90% CI 18.4 months to not estimable (NE)). In patients with tumor area positivity ≥1% (PD-L1 positive) and tumor area positivity ≥5% (PD-L1 high), respectively, the objective response rate was 62% (90% CI 45.1–77.1%) and 69% (90% CI 45.2–86.8%), median progression-free survival was 13.2 months (90% CI 11.3–15.2 months) and 14.5 months (90% CI 11.3 months–NE), and median overall survival was 26.7 months (90% CI 19.5 months–NE) and not reached (90% CI 17.4 months–NE). Immune-related adverse events were reported in 27% of patients; the safety profile was consistent with that reported for anti-PD-1 plus platinum-based chemotherapy. Dual TIGIT and PD-1 blockade with domvanalimab and zimberelimab plus chemotherapy demonstrated encouraging efficacy, and the regimen is being evaluated in the phase 3 STAR-221 trial. ClinicalTrials.gov identifier: NCT05329766 . As presented at the ESMO Congress 2025: in this international, single-arm phase 2 trial, first-line treatment of patients with advanced gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma with domvanalimab (Fc-silent anti-TIGIT) and zimberelimab (anti-PD-1) plus FOLFOX (oxaliplatin, leucovorin and fluorouracil) led to encouraging objective response rates and survival outcomes, which will be validated in a phase 3 trial.