Long-term follow-up of LEAP-002: Lenvatinib monotherapy compared with pembrolizumab

The phase 3 LEAP-002 study was designed to compare the efficacy and safety of lenvatinib/lenvatinib plus pembrolizumab with lenvatinib monotherapy as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Because the study did not meet its primary endpoints of overall survival (OS) at the final analysis and progression-free survival (PFS) at the interim analysis, a new report due in 2024 details the results of an additional 12 months of follow-up.

The randomized, double-blind study enrolled 794 patients, of whom 395 received lenvatinib pluspembrolizumab and 399 received lenvatinib plus placebo (placebo group). Patients weighing <60 kg received 8 mg of lenvatinib daily, and patients weighing ≥60 kg received 12 mg of lenvatinib daily. 200 mg of pembrolizumab was administered intravenously every 3 weeks. The study has two primary endpoints, includingOS and PFS, as well as secondary endpoints of objective response rate (ORR) and duration of response (DOR).

At data cutoff on June 6, 2023, the median follow-up was 43.6 months (Range: 37.3-52.6 months), with 25 patients (3.2%) still receiving treatment. The median OS was 21.1 months and 19.0 months (hazard ratio[HR], 0.836; 95% CI, 0.713-0.981). The OS rates in the pembrolizumab group and placebo group were 16.4% and 9.7%, respectively, at 24 months, 14.1% and 3.3% at 36 months, and 22.4% and 15.3% at 48 months.

The median PFS rate was 8.2 months in the pembrolizumab group and 8.1 months in the placebo group (HR, 0.810; 95% CI, 0.692-0.949). The PFS rates were 16.4% and 9.7% in the pembrolizumab group and placebo at 24 months, and 14.1% and 3.3% in the placebo group at 36 months. The ORR in the pembrolizumab group was 26.3%, and the median DOR was 16.6 months; In the placebo group,ORR was 17.5%, and median DOR was 10.4 months.

The incidence of grade 3 to 5 treatment-related adverse events (TRAE) was 62.8% in the pembrolizumab group and 58.0% in the placebo group. No other deaths related to TRAE have been reported. The most common TRAEs of any grade in the pembrolizumab group compared with placebo were hypertension, diarrhea, and hypothyroidism. At the end of the study, 46.6% of patients in the pembrolizumab group and 55.4% of patients in the placebo group had received more than one systemic anti-cancer treatment.

Based on an additional 12 months of follow-up, the endpoints of OS and PFS remained consistent with the primary analysis in both treatment arms, with no new signals observed. Lenvatinib monotherapy is the standard first-line treatment for advanced HCC, with a median OS rate of 19 months. Lenvatinib plus pembrolizumab will be further studied as a complement to intra-arterial chemoembolization for mid-stage HCC in the ongoing Phase 3 LEAP-012 study.