Purpose <p>Combining paclitaxel with antiangiogenic agents has demonstrated improved efficacy as second-line treatment for advanced gastric cancer. Surufatinib, a multi-kinase inhibitor with antiangiogenic and immunomodulatory properties, has exhibited synergistic effects with chemotherapy in preclinical studies.</p> Methods <p>This single-arm phase 2 trial enrolled patients aged 18–75 with HER2-negative unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma who had failed first-line therapy. All received surufatinib 250&#xa0;mg once daily plus paclitaxel 150mg/m² every 3 weeks for up to 6 cycles, followed by maintenance surufatinib until progression, intolerable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.</p> Results <p>Thirty-five patients were enrolled. Among 32 tumor response-evaluable patients, the ORR and DCR were 25.0% (95% confidence interval [CI]: 11.5, 43.4) and 87.5% (95% CI: 71.0, 96.5), respectively. Median PFS was 5.7 (95% CI: 4.7, 6.9) months and median OS was 10.8 (95% CI: 7.0, 17.2) months. In 26 patients with prior immunotherapy exposure, the median OS was 14.4 (95% CI: 8.5, not estimable) months. Overall, treatment-related adverse events of grade ≥ 3 occurred in 19 (54.3%) patients, with neutropenia (40.0%), leukopenia (34.3%), and hypertension (11.4%) being the most commonly observed.</p> Conclusions <p>Surufatinib plus paclitaxel showed promising efficacy and manageable safety as second-line treatment for advanced gastric cancer, especially in patients who had failed prior immunotherapy.</p> Clinical trial number <p>ChiCTR2200063336, registered in the Chinese Clinical Trial Registry on September 5, 2022.</p>