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

Final study analysis did not show benefit in advanced hepatocellular carcinoma, but lenvatinib's role as standard first-line treatment in aHCC was supported.

Study included 794 patients with advanced HCC, Child-Pugh class A, and without prior systemic treatment

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 OS1. In addition, pembrolizumab has shown favourable results as a second-line therapy2,3. 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 HCC4.

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-0025.

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. 

Pre-specified statistical significance not met

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.