562 Background: Systemic therapy for hepatocellular carcinoma (HCC) has rapidly evolved, and immune checkpoint inhibitor (ICI)-based regimens are now widely used as first-line treatment. However, in patients at risk of gastrointestinal bleeding or those contraindicated for ICIs, tyrosine kinase inhibitors (TKIs) such as sorafenib (SOR) and lenvatinib (LEN) remain clinically important options. While randomized trials and retrospective studies have compared these agents, prospective real-world data are limited. This study aimed to evaluate outcomes of SOR and LEN as first-line therapy for unresectable HCC (uHCC) in a multicenter prospective observational setting. Methods: One hundred sixty-seven patients with uHCC initiating SOR (n=32) or LEN (n=135) at 20 institutions of the Kyushu Study Group of Clinical Cancer (KSCC) were enrolled. Eligible patients had no prior systemic therapy. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Tumor response was assessed by RECIST v1.1 and mRECIST. To adjust for baseline differences, inverse probability of treatment weighting (IPTW) based on propensity scores was applied. Results: In the unadjusted cohort, OS was significantly longer in the SOR group than in the LEN group (median 35.1 vs. 15.7 months, HR 0.49, p=0.0088). However, after IPTW adjustment, OS was comparable (HR 1.13, 95% CI 0.68–1.88). Median PFS was 4.8 months for SOR and 5.4 months for LEN. IPTW-adjusted analysis showed significantly shorter PFS with SOR (median 4.1 vs. 5.5 months, HR 1.50, p=0.047). ORR was significantly higher in the LEN group compared with the SOR group (RECIST v1.1: 30.7% vs. 7.8%, p=0.045; mRECIST: 43.3% vs. 14.7%, p=0.036). DCR was also numerically superior with LEN. Grade ≥3 adverse events occurred in 31.3% (SOR) and 45.2% (LEN), with hand-foot syndrome and proteinuria being the most frequent severe toxicities, for SOR and LEN respectively. Conclusions: This prospective multicenter observational study demonstrated that SOR and LEN achieve comparable OS in the real-world first-line treatment of uHCC. LEN showed superior PFS and tumor response, while SOR maintained favorable tolerability. These findings highlight the continued clinical relevance of both TKIs and emphasize the importance of individualized therapy selection based on tumor burden, biomarker profiles, and patient-specific tolerability. Clinical trial information: 000038867 .
Ogasawara et al. (Sat,) studied this question.