Survival Outcomes With Cadonilimab Versus PD-(L)1 Therapy in Front-Line Gastric Cancer: A Network Meta-Analysis.

BACKGROUND: The FDA Oncologic Drugs Advisory Committee (ODAC) highlighted that the risk-benefit profile for patients with low PD-L1 expression remains unclear in front-line treatment of HER2-negative gastric and gastroesophageal junction (GC/GEJ) cancer with PD-(L)1 therapy. The first PD-1/CTLA-4 bispecific antibody (BsAb), cadonilimab, has been approved, but it is unknown if it can extend the PD-(L)1 regimen to lower PD-L1 patients. AIMS: To indirectly compare the survival outcomes of cadonilimab versus PD-(L)1 therapy in first-line HER2-negative gastric and gastroesophageal junction cancer, with particular focus on patients with low PD-L1 expression, using a network meta-analysis. METHODS: Randomized controlled trials with ICIs as first-line treatment were searched in public databases and FDA ODAC up to December 31, 2024. A network meta-analysis was conducted to evaluate the efficacy and safety of approved ICI-based treatments to refine the optimal approach for front-line GC/GEJ. RESULTS: A total of 7127 patients from eight Phase III trials were included. All ICIs-based therapies significantly improved overall survival (OS) compared to chemotherapy. In indirect comparisons, cadonilimab plus XELOX was associated with numerically more favorable OS (HR = 0.78, 95% CI: 0.62-0.98) compared with PD-(L)1 inhibitors. Numerical trends toward longer survival were observed across subgroups, including patients with PD-L1 < 10 (HR = 0.77, 95% CI: 0.58-1.01) and liver metastasis (HR = 0.67, 95% CI: 0.49-0.93), both historically considered immunotherapy-insensitive populations. All ICIs improved PFS compared to chemotherapy. Cadonilimab was associated with numerically better PFS versus PD-(L)1 inhibitors in indirect comparisons (HR = 0.70, 95% CI: 0.57-0.86). The safety analysis showed no significant increase in severe adverse events. CONCLUSIONS: In this indirect comparison, cadonilimab showed more favorable survival outcomes versus PD-(L)1 inhibitors in first-line GC/GEJ. Subgroup benefits were observed in liver metastasis, while the PD-L1 < 10 subgroup showed numerical trends. These results highlight the importance of selecting appropriate ICIs to optimize outcomes.