Comprehensive Safety and Efficacy Evaluation of Immunotherapy Combination Approaches Versus Tyrosine Kinase Inhibitor Monotherapy as First-Line Treatment of Hepatocellular Carcinoma: A Network and Individual Patient Data (IPD) Meta-Analysis

Background: Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and a significant cause of global cancer-related mortality, with the majority of patients diagnosed at advanced or unresectable stages. Historically, tyrosine kinase inhibitor (TKI) monotherapies such as sorafenib and lenvatinib served as the primary systemic standard of care. However, the emergence of immune checkpoint inhibitor (ICPI)-based combinations has significantly transformed the treatment landscape. We aim to perform a comparative analysis of ICPI-based combination treatment versus TKI monotherapy among advanced HCC patients. Methods: This study utilized a reconstructed individual patient data (IPD) pooled analysis derived from nine phase 3 randomized clinical trials, adhering to PRISMA-IPD reporting guidelines. A total of 6161 patients were included in the analysis, which categorized treatment into five primary strategies: ICPI monotherapy, ICPI plus bevacizumab, dual ICPI therapy (duplet), ICPI plus TKI, and TKI monotherapy as the control group. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and the incidence of grade 3 or higher adverse events (AEs). Results: The analysis demonstrated that ICPI-based combinations provided a significant survival advantage over TKI monotherapy. Key hazard ratios (HRs) for OS compared to TKIs were 0.76 (95% CI: 0.67–0.85, p < 0.001) for dual ICPI, 0.76 (95% CI: 0.68–0.85, p < 0.001) for ICPI plus TKI, and 0.70 (95% CI: 0.61–0.81, p < 0.001) for ICPI plus bevacizumab. Median OS was numerically highest for ICPI plus TKI at 19.68 months and dual ICPI at 19.58 months compared to 14.84 months for the TKI group. Among FDA-approved regimens, nivolumab plus ipilimumab (NivoIpi) achieved the longest median OS of 24.08 months. From a safety standpoint, the ICPI plus TKI group had the highest incidence of grade 3/4 AEs at 69.1%. Conversely, TKI monotherapy showed a 50.1% incidence, while dual ICPI therapy exhibited the most favorable safety profile at 32.7%. Conclusions: ICPI-containing combination therapies are superior to TKI monotherapy for the first-line treatment of advanced HCC, providing marked improvements in survival outcomes. Dual ICPI therapy represents the most balanced approach between efficacy and safety, achieving high survival with the lowest rates of severe toxicity. Among approved options, NivoIpi exhibited a numerically favorable survival signal, while DurvaTreme offered the highest tolerability, supporting a personalized treatment approach based on individual patient risk factors and hepatic reserve.