Lenvatinib Added to Nivolumab and Ipilimumab Improves Tumor Control and Progression-Free Survival in Unresectable Hepatocellular Carcinoma

Background In CheckMate-9DW, the suboptimal early tumor control of nivolumab–ipilimumab resulted in higher early mortality compared with the sorafenib/lenvatinib arm during the first 12 months. We evaluated whether adding lenvatinib to nivolumab–ipilimumab (NIL) improves outcomes versus nivolumab–ipilimumab (NI). Methods Patients with unresectable HCC treated with NI with or without lenvatinib were retrospectively analyzed. Responses were evaluated by RECIST v1.1, survival outcomes by Kaplan–Meier and inverse probability of treatment weighting (IPTW) adjustment, and multiple sensitivity analyses. Liver function changes were evaluated using the albumin–bilirubin (ALBI) score. Results Among 104 patients, 82 received NI and 22 received NIL. The NIL group demonstrated a higher disease control rate than the NI group (81.8% vs 39.0%; p < 0.01), with similar duration of response (21.4 vs 21.8 months). Median progression-free survival (PFS) was longer with NIL (10.2 vs 3.2 months), but not for overall survival (OS). In the first-line setting, NIL showed a trend toward longer PFS and fewer early deaths within 12 months. After IPTW adjustment and sensitivity analyses, the NIL regimen consistently demonstrated improved PFS (HR 0.44; p < 0.01) without a statistically significant OS benefit. Hypertension, proteinuria and stomatitis were more frequent in the NIL group, while ALBI scores remained stable. Development of immune-related adverse events was associated with improved outcomes. Conclusions This real-world study provides proof-of-concept evidence that incorporating a VEGF inhibitor into dual ICIs therapy is associated with improved tumor control and prolonged PFS, with a potential reduction in early mortality. Prospective studies are warranted to confirm these findings.