Abstract Background and Aim Molecular‐targeted therapies such as sorafenib and lenvatinib have long been used as first‐line treatment for advanced hepatocellular carcinoma (aHCC). However, adverse events or limited therapeutic effects may necessitate the change to another therapeutic option, known as post‐progression therapy. To investigate the significance of post‐progression therapy, we analyzed the outcomes of aHCC patients following first‐line molecular‐targeted therapy in a real‐world study. Methods This retrospective, multicenter study involved patients with aHCC who received sorafenib or lenvatinib as first‐line therapy between January 2011 and September 2021. Results In total, 513 patients were analyzed: 309 treated with sorafenib and 204 with lenvatinib. The overall response and disease control rates were 15 and 50%, respectively, in the sorafenib group and 30 and 75%, respectively, in the lenvatinib group (P < 0.001). Kaplan–Meier analysis revealed no significant differences in progression‐free survival and overall survival (OS) between the two treatments. Multivariate analysis revealed that fibrosis‐4 index, disease control rate, post‐progression therapy, and use of an immune checkpoint inhibitor (ICI) were significantly associated with OS. OS was significantly longer in patients who received post‐progression therapy than in those who did not (log‐rank P < 0.001). Most patients who received an ICI as post‐progression therapy had previously received lenvatinib. Among lenvatinib‐treated patients, OS was significantly longer in patients who received an ICI than in patients received another or no post‐progression therapy (P = 0.004). Conclusion The introduction of newer drugs for post‐progression therapy is expected to prolong survival. ICI‐based regimens appear to be effective after lenvatinib.
