Efficacy of Second-line Lenvatinib for Hepatocellular Carcinoma After Early Progression on Atezolizumab–Bevacizumab

Background/Aim: Atezolizumab plus bevacizumab (Ate+Bev) is widely used as first-line therapy for unresectable hepatocellular carcinoma (HCC). However, a subset of patients experience early disease progression, often detected at the first radiologic assessment around 6 weeks. Evidence guiding second-line therapy in this subgroup is limited, and the clinical value of lenvatinib after early progressive disease (PD) remains unclear. Patients and Methods: We retrospectively analyzed 36 patients with unresectable HCC who received lenvatinib after failure of first-line Ate+Bev. Patients were stratified by early PD, defined as radiologic progression at the scheduled 6-week assessment after starting Ate+Bev. Outcomes included antitumor response, progression-free survival (PFS), and overall survival (OS). Results: Objective response rate (ORR) and disease control rate (DCR) assessed by RECIST 1.1 were comparable between patients with and without early PD (ORR: 28.6% vs. 13.8%; DCR: 85.7% vs. 86.2%; p=0.342). Median PFS was also similar between groups [5.2 months (95% confidence interval=1.9-NA) vs. 6.1 months (3.7-7.5); p=0.307]. In multivariate analyses adjusting for Child–Pugh class, Barcelona Clinic Liver Cancer (BCLC) stage, and reduced starting dose, early PD was not significantly associated with either PFS or OS, whereas Child–Pugh class A was independently associated with improved OS. Correlation between first- and second-line PFS was weak and non-significant (r=0.077, p=0.682). Conclusion: Lenvatinib demonstrated comparable antitumor activity and survival outcomes even in patients with early PD on first-line Ate+Bev, indicating that early radiologic progression does not necessarily signify refractoriness to subsequent systemic therapy. These findings support lenvatinib as a viable second-line option regardless of early Ate+Bev response, particularly in patients with preserved liver function. Larger prospective studies are needed to confirm these observations.