Alpha-fetoprotein-producing gastric or gastro-esophageal junction (AFP-G/GEJ) cancer, a rare gastric cancer subtype, exhibits increased angiogenesis and more immunosuppression than non-AFP-G/GEJ cancer. The potential benefits of anti-angiogenic agents and immunotherapy for this specific subtype remain unknown. This multi-center, single-arm, phase 2 trial (ClinicalTrials.gov NCT04609176) evaluated the antitumor activity, safety, and biomarkers of camrelizumab plus apatinib and S-1 and oxaliplatin (SOX), followed by maintenance treatment with camrelizumab plus apatinib, as a first-line treatment in patients with AFP-G/GEJ adenocarcinoma. Primary endpoint was the confirmed objective response rate (ORR) per RECIST v1.1 in the full analysis set. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response, time to response, and safety. Between December 4, 2020, and August 4, 2023, 36 patients were enrolled and treated. The trial met its primary endpoint with a confirmed ORR of 66.7% (95% CI: 49.0-81.4). The DCR was 88.9% (95% CI: 73.9-96.9). With a median follow-up of 11.7 months (range: 3.2-37.9), the median PFS reached 7.8 months (95% CI: 4.9-12.3) and the median OS reached 18.0 months (95% CI: 10.5-NR). No new safety concerns were identified. In exploratory analysis, patients with durable clinical benefit exhibited higher pre-treatment (PD-1