Advantage of Scheduled Upfront Lenvatinib Administration Followed by Transarterial Chemoembolization Therapy Over Lenvatinib Monotherapy in Patients With Unresectable Intermediate‐Stage Hepatocellular Carcinoma: A Multicenter Cohort Study

BACKGROUND AND AIM: Combining systemic chemotherapy with transarterial chemoembolization (TACE) has demonstrated improved outcomes, with promising results for the efficacy of lenvatinib pretreatment combined with TACE in single-arm studies involving patients with hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy of a scheduled upfront lenvatinib combined with a TACE regimen in patients with HCC, representing both the first study to comparatively analyze this approach and to focus specifically on patients unsuitable for TACE. METHODS: We conducted a multicenter retrospective study between 2018 and 2024, enrolling 41 patients with unresectable Barcelona Clinic Liver Cancer intermediate-stage HCC who were considered unsuitable for TACE owing to factors such as exceeding the up-to-7 criteria, having infiltrative HCC, or multiple asynchronous recurrent HCC. Of these patients, 25 received upfront lenvatinib administration prior to TACE (LEN-TACE group), followed by continuous lenvatinib and on-demand TACE, and 16 received lenvatinib monotherapy. RESULTS: Radiological evaluation revealed significantly higher complete response (CR) and objective response rates (ORR) in the LEN-TACE group than in the lenvatinib group. The median overall survival (OS) was not reached in the LEN-TACE group, whereas it was 16.2 months in the lenvatinib monotherapy group, indicating a significantly superior OS in the LEN-TACE group (hazard ratio [HR]: 2.99; 95% CI: 1.01-8.95; p = 0.0496). Superiority in both PFS and OS was also observed in the propensity score-matched (PSM) cohort for the LEN-TACE group. CONCLUSION: Scheduled upfront lenvatinib combined with TACE is superior to lenvatinib monotherapy for intermediate-stage HCC, particularly in patients unsuitable for TACE.