Background: Immune checkpoint inhibitors (ICIs) plus chemotherapy has become the standard first-line regimen for advanced GC/GEJC, but the efficacy still needs to be improved. Fruquintinib is an oral, highly selective VEGFR 1/2/3 inhibitor that has synergistic antitumor effects when combined with ICIs/chemotherapy. Additionally, the phase III study (NCT03223376) of fruquintinib combined with paclitaxel in second-line GC/GEJC has achieved positive topline result. Therefore, this study was aimed to evaluate the efficacy and safety of fruquintinib combined with SOX and toripalimab as a first-line therapy in GC/GEJC. Methods: In this phase Ib/II, open-label trial (NCT05024812), patients (pts) aged 18-75 years who were HER2-negative with no previous anti-tumor therapy were enrolled. The Ib phase employed a 3+3 dose escalation design, pts were treated with fruquintinib 3mg/d, po, d1-14 (dose level; DL1), 4mg/d (DL2), or 5mg/d (DL3) in combination with fixed dose of toripalimab (240mg, iv, d1), oxaliplatin (130 mg/m², iv, d1) and S-1 (40-60mg based on BSA, po, d1-14) every 3 weeks. The primary objective of phase Ib was to determine the DLT in first treatment cycle defining the PR2D. Additional 64 pts were enrolled in the phase II dose expansion stage using RP2D. Primary endpoint of phase II was PFS per RECIST 1.1. Secondary endpoints included ORR, DCR, OS, DOR and safety. Results: At data cut-off (August 31, 2023), 17 pts (9 in phase Ib; 8 in phase II) with median age 65 years old had been enrolled. 59% were male, 100% had ECOG PS 1 and 35% had liver metastasis. 10/17 (59%) pts were PD-L1 CPS ≥1. No DLTs were observed at all three dose levels. Fruquintinib 5mg/d was defined as the RP2D. Of the 16 pts evaluable for tumor response, 9 pts achieved PR, 7 pts achieved SD. The ORR was 56.3% (9/16), the DCR was 100% (16/16). Pts with PD-L1 CPS ＜1 were more likely to achieve better responses (4PR in 6 pts, ORR-66.7%). After a median follow-up of 5.4 months, the median PFS was 9.3 (95% CI: 4.76–NA) months and OS result was not mature. Median DOR was not reached and two responders were estimated to have a response duration ≥8.0 months. Majority of TRAEs were grade 1-2, including neutrophil count decreased (64.3%), white blood cell decreased, hypoproteinemia and platelet count decreased (all were 42.9%). Grade 3 TRAEs included neutrophil count decreased (11.8%), platelet count decreased, impaired liver function, rash, pruritus and mucositis (5.9%, one patient for each). There were no treatment related deaths in the trial. Conclusions: Fruquintinib combined with SOX and toripalimab was well tolerated, with encouraging antitumor activity as first-line treatment for advanced metastatic GC/GEJC, especially in pts with CPS ＜1. The trial is still recruiting, more data including the potential predictive response biomarkers would be further analyzed and reported. Clinical trial information: NCT05024812.