Real-world comparative analysis of sorafenib and lenvatinb as first-line systemic therapy in unresectable hepatocellular carcinoma: A multicenter prospective observational study in Japan (KSCC HAMRET Study)

Background Sorafenib and lenvatinib remain important first-line therapies for unresectable hepatocellular carcinoma (uHCC), especially in patients unsuitable for immune checkpoint inhibitors. However, prospective real-world comparative data are limited. Methods This multicenter prospective observational study (KSCC HAMRET) enrolled 167 patients with uHCC at 20 Japanese institutions between February 2020 and October 2021. Patients received sorafenib (n = 32) or lenvatinib (n = 135) and were followed until October 2023. Outcomes included overall survival (OS), progression-free survival (PFS), tumor response, and safety. Inverse probability of treatment weighting (IPTW) adjusted for baseline imbalances. Results In the unadjusted cohort, sorafenib showed longer OS than lenvatinib (median 35.1 vs. 15.7 months; hazard ratio [HR], 0.49; p = 0.0088). After IPTW adjustment, OS was similar (HR, 1.13; 95% confidence interval, 0.68–1.88). Median PFS was 4.8 months for sorafenib and 5.4 months for lenvatinib, with IPTW analysis favoring lenvatinib (HR, 1.50; p = 0.047). Weighted objective response rates were higher with lenvatinib by RECIST v1.1 (30.7% vs. 7.8%; p = 0.045) and mRECIST (43.3% vs. 14.7%; p = 0.036). Disease control rates were also greater with lenvatinib. Grade ≥ 3 adverse events occurred in 31.3% of sorafenib-treated and 45.2% of lenvatinib-treated patients, with hand–foot syndrome and proteinuria being the most common severe toxicities. Conclusions This prospective real-world study showed comparable OS between sorafenib and lenvatinib in first-line uHCC. Lenvatinib demonstrated superior PFS and tumor response, whereas sorafenib had a more favorable tolerability profile. These findings support individualized treatment selection based on tumor burden, biomarkers, and patient factors.