Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) combined with antiangiogenic agents have become a standard strategy for advanced hepatocellular carcinoma (HCC). There remains an urgent need for effective biomarkers to guide treatment, with C-reactive protein and alpha-fetoprotein in immunotherapy (CRAFITY) scores and cytokine levels representing promising candidates. OBJECTIVES: We aimed to assess the efficacy, safety, and potential biomarkers of anlotinib plus TQB2450 in patients with advanced HCC. DESIGN: This study was a single-arm, phase Ib trial. Twenty-five patients with advanced HCC were enrolled. METHODS: Patients received an intravenous infusion of TQB2450 (1200 mg, on Day 1) and oral administration of anlotinib (initiated at 10 mg, once a day, from Day 1 to Day 14), which was repeated every 3 weeks. Blood was collected at baseline for serum cytokine analysis. RESULTS: After a median follow-up of 41.80 months, the median progression-free survival (mPFS) was 5.49 months, and the median overall survival (mOS) was 8.94 months. Treatment-related adverse events (TRAEs) occurred in 22 patients, with grade ⩾3 TRAEs observed in 12 patients. Patients who achieved clinical benefit (CB) had higher baseline serum brain-derived neurotrophic factor (BDNF) levels than non-CB patients (median, 227.97 vs 129.26 pg/ml, p = 0.036). High serum BDNF concentrations (⩾153.59 pg/ml) were associated with longer mPFS (9.64 vs 3.52 months, p < 0.001) and mOS (18.14 vs 5.55 months, p = 0.010). A CRAFITY score combining BDNF and Eastern Cooperative Oncology Group (ECOG) score showed superior prognostic performance in patients receiving anlotinib plus TQB2450, which was confirmed in a validation cohort of 36 advanced HCC patients treated with ICIs and antiangiogenic agents. CONCLUSION: Anlotinib plus TQB2450 demonstrated promising efficacy with manageable safety in advanced HCC. Elevated serum BDNF levels might serve as a potential positive prognostic marker and, together with ECOG score, may help complement the CRAFITY score in identifying subgroups that could benefit from ICIs and antiangiogenic therapy. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov (NCT03825705, registered January 31, 2019).