Abstract
PURPOSE: Real-world evidence concerning the triple-combination regimens of radiotherapy (RT), PD-1 inhibitors, and targeted therapy for unresectable hepatocellular carcinoma (uHCC) is limited. This study evaluated the efficacy and safety of this combination and identified predictors of survival. PATIENTS AND METHODS: In this multicenter retrospective study, 122 consecutive patients with uHCC received RT combined with PD-1 inhibitors and targeted therapy were analyzed. Objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS) and treatment-related adverse events (TRAEs) were calculated. Cox regression was used to identify independent prognostic factors. Subgroup analysis explored the association between immunotherapy cycles and overall survival across tumor response stratification. RESULTS: The cohort included 53 patients with extrahepatic metastases and 48 with macrovascular invasion. Patients received RT with a median dose of 45 Gy (range: 32.3-58.5 Gy). Median follow-up was 14.2 months. According to the modified response evaluation criteria in solid tumor (mRECIST), the ORR and DCR were 18.85% and 73.78%, respectively. The median OS was 19.0 months (95% CI: 17.8-23.4 months), and the median PFS was 7.2 months (95% CI: 5.5-10.9 months). TRAEs of any grade occurred in 93 patients (76.23%), with grade 3-4 TRAEs observed in 40 patients (32.79%). No treatment-related death was observed. Multivariate analysis identified elevated AFP and higher mALBI grade as independent risk factors for OS. Higher mALBI grade and neutrophil-to-lymphocyte ratio (NLR) predicted worse PFS. Exploratory analysis suggested extending immunotherapy duration may improve OS in patients with stable disease. CONCLUSION: The triple-combination of RT, PD-1 inhibitors, and targeted therapy demonstrates promising survival benefits and a manageable toxicity profile for uHCC. Baseline AFP, liver function, NLR level are key determinants of survival, supporting the individualized application of this multimodal approach.