Anlotinib combined with benmelstobart as a chemo-free first-line treatment in advanced esophageal squamous cell carcinoma: an exploratory multicenter, single-arm phase II clinical trial

BACKGROUND: No combined antiangiogenic and PD-1/PD-L1 blockade therapy has been investigated as a chemo-free first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). This study evaluates the efficacy and safety of anlotinib combined with benmelstobart as a chemo-free treatment in previously untreated advanced ESCC, and identifies potential predictive biomarkers using next-generation sequencing (NGS). METHODS: ALTER-E-003, a single-arm, open-label phase II trial, enrolled patients with advanced ESCC across five Chinese centers. Patients received oral anlotinib 12 mg daily on days 1-14 per three-week cycle, with benmelstobart 1200 mg infused on day 1 of each cycle for up to 24 months. Thereafter, patients received anlotinib maintenance therapy. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR), and safety. NGS and fluorescent multiplex immunohistochemistry (mIHC) were performed on tumor specimens. RESULTS: Of 53 screened patients, 46 completed the study. The confirmed ORR was 56.5% (95% CI 41.1-71.1), and DCR was 91.3% (95% CI 79.2-97.6). Median PFS was 15.74 months (95% CI 9.03-21.91). Treatment-related adverse events occurred in 93.5% of patients, with 28.3% experiencing grade 3 or higher events. NGS revealed a novel predictive mutational signature (TP53+/FAT1+/NOTCH3-) that was associated with better ORR (65.6% versus 11.1%, P < 0.001), longer median PFS (17.91 versus 5.32 months, P = 0.005) and improved OS (P = 0.006). CONCLUSION: First-line anlotinib-benmelstobart combination demonstrated durable responses and acceptable safety in ESCC patients. Exploratory biomarker analyses identified a TP53+/FAT1+/NOTCH3- mutational signature potentially associated with improved outcomes, though further validation in randomized trials is warranted. TRIAL REGISTRATION: NCT05038813.