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.
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.”