LEAP-002 Long-term Follow-up: Lenvatinib Monotherapy Versus Lenvatinib With Pembrolizumab

The phase 3 LEAP-002 study began in 2018 to compare the efficacy and safety of lenvatinib plus pembrolizumab against lenvatinib monotherapy as a first-line treatment for patients with advanced hepatocellular carcinoma (HCC).

As the study did not meet its primary end point of overall survival (OS) at final analysis and progression-free survival (PFS) at interim analysis, a new report presented at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium detailed the results following 12 months of additional follow-up.

The randomized, double-blind study recruited 794 patients, with 395 receiving lenvatinib plus pembrolizumab (pembrolizumab arm) and 399 receiving lenvatinib plus placebo (placebo arm). Lenvatinib was administered at 8 mg daily for patients with a body weight <60 kg or 12 mg daily for patients ≥60 kg. Pembrolizumab was administered intravenously at 200 mg every 3 weeks.

The study had dual primary end points, which included OS and PFS, along with a secondary end point of objective response rate (ORR) and duration of response (DOR).

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

The median PFS rate was 8.2 months in the pembrolizumab arm and 8.1 months in the placebo arm (HR, 0.810; 95% CI, 0.692-0.949). The PFS rates for the pembrolizumab and placebo arms were 16.4% versus 9.7% at 24 months and 14.1% versus 3.3% at 36 months.

The ORR in the pembrolizumab arm was 26.3%, and the median DOR was 16.6 months (range, 2.0+ to 45.3+ months). In the placebo arm, the ORR was 17.5% and the median DOR was 10.4 months (range, 1.9-37.0+ months).

Grade 3 to 5 treatment-related adverse event (TRAE) rates were 62.8% in the pembrolizumab arm and 58.0% in the placebo arm. No additional TRAE-related deaths were reported. The most common TRAEs of any grade in the pembrolizumab versus placebo arms were hypertension (43.8% vs 46.8%), diarrhea (40.8% vs 34.2%), and hypothyroidism (40.0% vs 35.9%). More than 1 poststudy systemic anticancer treatment was administered to 46.6% of patients in the pembrolizumab arm and 55.4% of those in the placebo arm.

Based on the results of an additional 12 months of follow-up, the end points of OS and PFS remained consistent with primary analyses in both treatment arms, and no new signals were observed. Lenvatinib monotherapy as a standard-of-care first-line treatment for advanced HCC is supported by a median OS rate of 19 months. Lenvatinib plus pembrolizumab will be further investigated as an addition to transarterial chemoembolization for intermediate-stage HCC in the ongoing phase 3 LEAP-012 study.