Addition of pembrolizumab to lenvatinib does not improve OS in advanced HCC

The final analysis of the phase 3 LEAP-002 study did not demonstrate an overall survival (OS) benefit of the addition of pembrolizumab to first-line lenvatinib in patients with advanced hepatocellular carcinoma (HCC). However, the study supports the potential usefulness of lenvatinib as a standard first-line treatment for advanced HCC.

Systemic therapy options for advanced stages of HCC have rapidly expanded in the past years. The REFLECT trial (NCT01761266) demonstrated lenvatinib in first-line to be non-inferior to sorafenib regarding OS [1]. In a phase 1 study, lenvatinib plus pembrolizumab demonstrated promising anti-tumour activity as first-line therapy in unresectable HCC [2]. The current global, randomised, double-blind, phase 3 LEAP-002 trial (NCT03713593), presented by Prof. Richard Finn (David Geffen School of Medicine, CA, USA) evaluated the efficacy of lenvatinib plus pembrolizumab versus lenvatinib plus placebo as first-line therapy for advanced HCC [3].

The trial randomised 794 patients with advanced HCC, Child-Pugh class A, and without prior systemic treatment 1:1 to lenvatinib plus pembrolizumab or lenvatinib plus placebo. The dual primary endpoints were progression-free survival (PFS) and OS. Pre-specified efficacy boundaries were one-sided P=0.002 for PFS at the interim analysis (pre-specified final PFS analysis) and 0.0185 for OS at the final analysis.

Median OS in patients treated with lenvatinib plus pembrolizumab was 21.2 months (comparable to the phase 1 study) versus 19.0 months in patients with monotherapy lenvatinib (HR 0.840; P=0.0227). This difference was not statistically significant according to the pre-specified efficacy boundaries.

The median PFS at the time of the final analysis was 8.2 versus 8.1 months (HR 0.834). At 24 months, 16.7% of participants treated with lenvatinib plus pembrolizumab were progression-free versus 9.3% of patients treated with lenvatinib plus placebo. The disease control rate was 81.3% in the lenvatinib plus pembrolizumab arm (26.1% objective response rate [ORR]) versus 78.4% (17.5% ORR) in the lenvatinib plus placebo arm. The duration of response was 16.6 and 10.4 months, respectively.

Overall, 44.1% of patients treated with lenvatinib plus pembrolizumab received subsequent systemic anti-cancer treatment (34.9% tyrosine kinase inhibitor, 14.4% immunotherapy, 3.5% chemotherapy). Of all patients treated with lenvatinib plus placebo, 52.1% received subsequent systemic therapy (40.1% tyrosine kinase inhibitor, 22.8% immunotherapy, 3.3% chemotherapy).

Based on these results, Prof. Finn concluded that “this study does not meet its pre-specified statistical significance for OS and PFS. Nonetheless, median OS in the lenvatinib monotherapy arm was longer than what was observed in REFLECT (14.5 months), which supports its role as a standard first-line treatment for advanced HCC.”

1. Kudo M, et al. Lancet 2018;391(10126):1163–1173.
2. Finn RS, et al. J Clin Oncol. 2020;38(26):2960–2970.
3. Finn RS, et al. Primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC). Abstract LBA34, ESMO Congress 2022, 09–13 September, Paris, France.

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Posted on 16 November 20226 September 2023