Final analysis of the phase 3 LEAP-002 study did not demonstrate an overall survival benefit of addition of pembrolizumab to first-line lenvatinib in patients with advanced hepatocellular carcinoma. However, the study supports the role of lenvatinib as a standard first-line treatment for aHCC.

Systemic therapy options for advanced stages of HCC have rapidly expanded in the past years. For example, the REFLECT study demonstrated lenvatinib in first-line to be non-inferior to sorafenib regarding OS [1]. In addition, pembrolizumab has shown favourable results as a second-line therapy [2,3]. In a phase 1 study, the combination of lenvatinib plus pembrolizumab demonstrated promising anti-tumour activity and manageable safety as first-line therapy in unresectable HCC [4]. The global, randomised, double-blind, phase 3 LEAP-002 study (NCT03713593) evaluated the efficacy and safety of lenvatinib plus pembrolizumab versus lenvatinib plus placebo as first-line therapy for aHCC. Dr Richard Finn (David Geffen School of Medicine, CA, USA) presented the results of the final analysis of LEAP-002 [5].

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

The median OS in patients treated with lenvatinib/pembrolizumab was 21.2 months (which is comparable to the phase 1 study) versus 19.0 months in patients with monotherapy lenvatinib (HR 0.840; P=0.0227). This difference is not statistically significant according to the pre-specified efficacy boundaries. OS was comparable in all pre-specified subgroups. The median PFS at time of the final analysis was 8.2 versus 8.1 months (HR 0.834). At 24 months, 16.7% of patients treated with lenvatinib/pembrolizumab were progression-free versus 9.3% of patients treated with lenvatinib/placebo. Disease control rate was 81.3% in the lenvatinib/pembrolizumab arm (26.1% objective response rate [ORR]) versus 78.4% (17.5% ORR) in the lenvatinib/placebo arm. Duration of response was 16.6 months and 10.4 months, respectively.

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

Based on these results, Dr 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 the REFLECT study, which supports its role as a standard first-line treatment for advanced HCC.”

  1. Kudo M, et al. Lancet 2018;391:1163–1173.
  2. Finn RS, et al. J Clin Oncol. 2020;38:193–202.
  3. Qin SK, et al. J Clin Oncol. 2022;40(suppl 4):383–383.
  4. Finn RS, et al. J Clin Oncol. 2020;38:2960–2970.
  5. 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, Paris, France, 09–13 September.


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