Updated results of benmelstobart plus anlotinib combined with SOX in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma with low PD-L1 expression: A single-arm, multicenter phase II clinical trial.

Abstract

4054 Background: While PD-1 inhibitors plus chemotherapy have become standard first-line therapy for advanced HER2-negative gastric/gastroesophageal junction (G/GEJ) adenocarcinoma, patients with low PD-L1 expression (Combined Positive Score (CPS)＜5) derive limited benefit. Anti-angiogenic agents can modulate the tumor immune microenvironment and synergize with immune checkpoint inhibitors. Anlotinib, a multi-targeted tyrosine kinase inhibitor approved in China, offers a promising combination strategy. This study evaluates the efficacy and safety of benmelstobart (a PD-L1 inhibitor) combined with anlotinib and SOX (S-1 plus oxaliplatin) as first-line therapy in patients with advanced G/GEJ adenocarcinoma and low PD-L1 expression. Methods: Patients with HER2-negative, unresectable, locally advanced, or metastatic G/GEJ adenocarcinomas and PD-L1 CPS＜ 5, who had not received prior systemic therapy were included. They received benmelstobart (1200mg, iv, d1, q3w) combined with anlotinib (10mg, po, d1~14, q3w), oxaliplatin (130mg/m 2 , d1, iv, q3w) and S-1 (40mg, po, bid, d1~14, q3w) for 6 cycles as initial therapy. Maintenance therapy with benmelstobart (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) followed for non-progressive disease until PD or unacceptable toxicity occurred. Tumor responses were evaluated by RECIST 1.1 criteria. The target sample size was 37, with ORR as the primary endpoint, and safety, DCR, DoR, PFS, and 1-year OS rate as secondary endpoints. Results: From June 2023 to June 2025, 37 patients were enrolled. At the data cut-off date (December, 2025), the best overall response indicated that there were 31 PR (83.8%) and 6 SD (16.2%). Therefore, the preliminary ORR was 83.8% (95%CI: 68-93.8), DCR was 100% (95%CI: 90.5-100). The preliminary prognostic result exhibited that the median PFS of the 37 patients was 11.3 months (95%CI: 8.07-14.53). The 1-year OS rate was 91.33% (95%CI: 75.46–97.12). Safety was manageable, common TRAEs＞20% included platelet count decreased (54.1%), white blood cell decreased (32.4%), anemia (24.3%). Conclusions: The combination of benmelstobart, anlotinib, and SOX demonstrated promising efficacy with a manageable safety profile as first-line therapy for advanced G/GEJ adenocarcinoma with low PD-L1 expression. These findings warrant validation in larger cohorts. Clinical trial information: NCT06939452 .