Real-world outcomes of first-line lenvatinib versus sorafenib in advanced HCC.

e16228 Background: Lenvatinib and sorafenib are approved first-line tyrosine kinase inhibitors for patients with unresectable or metastatic hepatocellular carcinoma (HCC). Although randomized trials demonstrated non-inferior survival, differences in toxicity and tolerability may influence real-world outcomes. While immune-checkpoint inhibitor combinations are now preferred first-line therapy, TKIs remain essential for patients with contraindications to immunotherapy. Methods: We conducted a retrospective cohort study using the TriNetX Research Network. Adults (≥18 years) with advanced HCC initiating first-line lenvatinib or sorafenib were identified. The index date was treatment initiation. The primary outcome was overall survival (OS). Secondary outcomes included hospitalization, emergency department (ED) visits, ascites/paracentesis, hepatic encephalopathy, and hypertension. One-to-one propensity score matching was performed adjusting for age, sex, and baseline comorbidities. Cox proportional hazards models were used. Results: A total of 16,588 patients were identified (5,292 lenvatinib; 11,296 sorafenib). After propensity score matching, 2,514 patients were included in each cohort. Baseline characteristics were well-balanced, including age (65.8 vs 66.0 years), sex (78% male), hypertension (51.8% both), ascites (19.4% vs 18.7%), and hepatic encephalopathy (3.7% vs 3.6%). No significant difference in overall survival was observed between lenvatinib and sorafenib (median 519 vs 501 days; HR 1.03, 0.95-1.11; p = 0.51), suggesting time-varying treatment effects (proportional hazards p = 0.007), with survival probability at end of follow-up favoring sorafenib (20.57% vs 4.15%). Mortality risk was slightly higher with lenvatinib (51.0% vs 48.0%; risk difference 3.1% CI 0.3-5.8%; p = 0.031). No significant differences were observed in hospitalization (34.6% vs 36.9%; p = 0.37), ED visits (31.3% vs 32.9%; p = 0.37), ascites/paracentesis (24.4% vs 22.1%; p = 0.086), GI bleeding (14.7% vs 14.4%; p = 0.82), variceal bleeding (4.2% vs 3.8%; p = 0.56), or hepatorenal syndrome (5.5% vs 5.0%; p = 0.44). Lenvatinib was associated with significantly higher rates of hepatic encephalopathy (7.4% vs 5.7%; RR 1.30, 95% CI 1.05-1.61; p = 0.018), acute kidney injury (22.2% vs 19.7%; RR 1.12, 95% CI 1.00-1.26; p = 0.046), and new-onset or worsening hypertension (25.8% vs 18.4%; RR 1.4, 95% CI 1.20-1.64; p < 0.001). Conclusions: In this propensity score-matched analysis, lenvatinib and sorafenib demonstrated equivalent median overall survival in advanced HCC. However, lenvatinib was associated with significantly higher rates of hepatic encephalopathy, acute kidney injury, and new-onset hypertension, which may inform treatment selection. Limitations include the retrospective design, potential residual confounding, and limited availability of detailed tumor staging and performance status.