Abstract
BACKGROUND: The optimal second-line treatment for unresectable hepatocellular carcinoma (HCC) remains uncertain, given variability in efficacy and safety among available therapies. The comparative effectiveness and safety of second-line treatments for advanced HCC were methodically assessed in this network meta-analysis. METHODS: A thorough search was conducted up until 20 February 2025, across the PubMed, Medline, Embase, Cochrane Central, and Web of Science databases to find randomized controlled trials (RCTs) evaluating second-line monotherapies (such as Ramucirumab, Regorafenib, Pembrolizumab, Cabozantinib, and Apatinib) in adults with advanced HCC. The main results comprised overall survival and progression-free survival; the supplementary results included objective response rate, disease control rate, and the occurrence of adverse events. A Bayesian random-effects network meta-analysis was employed for data synthesis, with interventions rated according to the SUCRA. RESULTS: Eighteen RCTs involving 6,910 patients were analyzed. Ramucirumab (SUCRA: 69.2%), Regorafenib (67.6%), and Pembrolizumab (66.5%) significantly improved OS compared to control (mean difference [MD]: 2.79 months, 2.80 months, and 2.75 months, respectively). Apatinib (SUCRA: 93.0%; MD: 3.08 months), Cabozantinib (84.8%; MD: 2.65 months), and Regorafenib (48.9%; MD: 1.60 months) provided the most significant PFS benefits. Pembrolizumab (OR: 5.71, 95% CI, 2.71-12.04), Cabozantinib (OR: 5.38, 95% CI, 1.81-16.00), and Apatinib (OR: 5.32, 95% CI, 1.69-16.74) achieved superior ORR, while Apatinib, Cabozantinib, and Regorafenib had the highest DCR (OR: 3.92, 3.67, and 3.31, respectively). Pembrolizumab and Ramucirumab exhibited relatively lower incidences of severe adverse events (grade ≥3 AEs). CONCLUSION: Pembrolizumab and Ramucirumab had the most favorable balance of efficacy and tolerability among second-line treatments for advanced HCC and are indicated as optimal therapy alternatives to enhance clinical outcomes. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD420251010308.