Background: Patients (pts) with AFP-producing G/GEJ adenocarcinoma generally respond poorly to first-line standard chemotherapy. We aimed to assess the efficacy and safety of first-line camrelizumab plus apatinib given concurrently with chemotherapy, followed by camrelizumab plus apatinib in AFP-producing G/GEJ adenocarcinoma pts. Methods: In this open-label, single-arm, multi-center, phase 2 trial (NCT04609176), pts with aged ≥18 years, clinical stage III-IV, unresectable/recurrent or metastatic G/GEJ adenocarcinoma with no prior systemic therapy, serum AFP > 2×ULN or AFP positive by the IHC staining method were enrolled. Pts received 4 cycles of standard S-1 plus oxaliplatin (SOX) and camrelizumab (200mg, iv, d1, q3w) plus apatinib (250mg, po, qd). Pts without disease progression then continued to receive camrelizumab plus apatinib for up to 24 months, or until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1; secondary endpoints included the duration of response (DoR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. Results: A total of 36 pts were enrolled and received treatment between Dec 4, 2020 and Aug 4, 2023. 35 pts were evaluable for tumor response. Median age was 63 years (range: 28, 78), with 30 pts (83.3%) were male. 13 pts (36.1%) presented with GEJ. 34 pts (94.5%) were diagnosed with stage IV. 20 pts (55.6%) had distant lymph node involvement, 18 (50.0%) had liver metastasis, 8 (22.2%) had peritoneal metastasis, and 2 (5.6%) had lung metastasis. Median serum AFP level was 739.8 ng/ml (range: 77.7, 321847.0). At data cut-off (Sep 1, 2023), the median follow-up duration was 6.4 months (range: 0.7, 27.0). Efficacy was assessed in the FAS population (n = 36). 2 pts showed complete response (CR, all confirmed), 22 had partial response (PR, 18 confirmed) and 7 had stable disease (SD). In consequent, the unconfirmed ORR was 66.7% (24/36) and DCR was 86.1% (31/36), with a confirmed ORR of 55.6% (20/36). The median PFS and OS were still immature. However, the estimated 12-month PFS rate was 42.1%. Any grade treatment-related adverse events (TRAEs) occurred in 33 pts (91.7%) and grade ≥ 3 in 13 (36.1%) pts. The most common grade ≥ 3 TRAEs were decreased neutrophil count (13.9%), hypertension (8.3%) and diarrhea (5.6%). 16 pts (44.4%) experienced immune-related adverse events (irAEs) of any grade. No new safety signals were reported. Conclusions: In AFP-producing G/GEJ adenocarcinoma pts who had not previously received systemic therapy, camrelizumab plus apatinib with SOX followed by camrelizumab plus apatinib showed promising antitumor activity and acceptable safety profile. Clinical trial information: NCT04609176.