Esophagus to Small Intestine
JAMA. 2025;333(15):1305-1314
First-line sugemalimab plus chemotherapy for advanced gastric cancer: The GEMSTONE-303 randomized clinical trial
Importance: Gastric cancer, including gastroesophageal junction cancer, is one of the most commonly diagnosed cancers worldwide, with high mortality. Sugemalimab is a fully human anti-programmed death-ligand 1 (PD-L1) antibody. The combination of sugemalimab and chemotherapy showed promising anti-tumor activity and safety in a phase 1b study among patients with treatment-naive, unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. This combination was further evaluated in the GEMSTONE-303 phase 3 trial.
Objective: To evaluate the efficacy of sugemalimab in combination with capecitabine and oxaliplatin (CAPOX) compared with placebo plus CAPOX as first-line treatment for patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 combined positive score (CPS) of 5 or greater.
Design, setting, and participants: GEMSTONE 303 is a phase 3, randomized, double-blind, placebo-controlled study conducted at 54 sites in China that enrolled patients from April 9, 2019, through December 29, 2021, with follow-up to July 9, 2023. A total of 479 eligible patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS of 5 or greater who did not receive any prior systemic therapy were randomized.
Intervention: Patients received sugemalimab (1200 mg intravenously) (n = 241) or placebo (n = 238) every 3 weeks for up to 24 months, plus CAPOX every 3 weeks for up to 6 cycles.
Main outcomes and measures: Primary outcomes were overall survival and investigator-assessed progression-free survival.
Results: Baseline characteristics were well balanced between the 2 groups. Most patients were male (71.4% in sugemalimab group, 74.8% in placebo group). Median follow-up was 25.1 months in the sugemalimab group and 26.3 months in the placebo group. The sugemalimab group demonstrated significant improvements in overall survival (median 15.6 months [95% confidence interval {CI}: 13.3–17.8] vs. 12.6 months [95% CI: 10.6–14.1]; hazard ratio [HR] = 0.75 [95% CI: 0.61–0.92]; p = 0.006) and progression-free survival (median 7.6 months [95% CI: 6.4–7.9] vs. 6.1 months [95% CI: 5.1–6.4]; HR = 0.66 [95% CI: 0.54–0.81]; p < 0.001). Grade 3 or higher treatment-related adverse events occurred in 53.9% of patients in the sugemalimab group and 50.6% in the placebo group.
Conclusions and relevance: Sugemalimab plus chemotherapy significantly prolonged overall survival and progression-free survival with a manageable safety profile in previously untreated patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.