Comparative effectiveness of immunotherapy versus lenvatinib in advanced hepatocellular carcinoma: A real-world analysis using target trial emulation

Background & Aims: Immunotherapy has emerged as an effective treatment for advanced hepatocellular carcinoma (HCC). We aimed to investigate the real-world effectiveness of immunotherapy compared to lenvatinib in HCC. Approach & Result: From the TriNetX database, we used a target trial emulation framework and identified HCC patients who received first-line treatment with immunotherapy (atezolizumab/bevacizumab or tremelimumab/durvalumab) or lenvatinib between or between August 2018 and December 2023. Overall survival (OS) was compared using Kaplan-Meier analysis and Cox proportional hazards regression. After propensity score matching, 1203 patients were included in each group. Immunotherapy was associated with improved OS versus lenvatinib (median survival: 545 vs. 425 d; hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.76-0.97). Regarding treatment type, atezolizumab plus bevacizumab showed improved survival compared to lenvatinib (n=1070 in each group; HR: 0.87, 95% CI: 0.77-0.99), while the point estimate favored durvalumab plus tremelimumab vs. lenvatinib (HR: 0.81, 95% CI: 0.59-1.12), though this difference was not statistically significant, likely due to small sample size. Regarding etiology, immunotherapy had improved OS compared to lenvatinib in viral hepatitis (n=510 in each group; HR: 0.74, 95% CI: 0.61-0.89) and alcoholic liver disease (n=190 in each group; HR: 0.65, 95% CI: 0.49-0.87), but not in metabolic dysfunction-associated steatotic liver diseases (n=156 in each group; HR: 0.96, 95% CI: 0.70-1.31). Conclusions: In this real-world analysis, immunotherapy was associated with improved OS compared to lenvatinib in advanced HCC, with consistent benefit across most subgroups. These findings support the use of immunotherapy as a first-line treatment for advanced HCC.