The phase 3 LEAP-012 trial, presented at the European Society for Medical Oncology (ESMO) Congress 2024, reveals that the combination of lenvatinib (Lenvima; Eisai and Merck), pembrolizumab (Keytruda; Merck Sharp and Dohme), and transarterial chemoembolization (TACE) significantly improves progression-free survival (PFS) in patients with intermediate-stage hepatocellular carcinoma (HCC). This finding offers a potential new treatment option for a patient population with limited therapeutic choices. Hepatocellular carcinoma is a leading cause of cancer-related mortality worldwide, and while TACE has been the standard of care for intermediate-stage HCC for two decades, its efficacy has plateaued, necessitating novel treatment strategies.
The LEAP-012 trial (NCT04246177) is a double-blind, placebo-controlled study that randomized patients with intermediate-stage HCC (1:1) to receive either lenvatinib plus pembrolizumab with TACE or dual placebo with TACE. Key inclusion criteria included confirmed HCC confined to the liver, without portal vein thrombosis or extrahepatic spread, and ineligibility for curative treatments like resection or ablation. The trial's primary endpoints were PFS and overall survival (OS), with secondary endpoints including objective response rate (ORR), duration of response, disease control rate (DCR), time to progression, and safety. A total of 480 patients were enrolled, with 237 assigned to the lenvatinib-pembrolizumab-TACE arm and 243 to the dual placebo-TACE arm.
Significant Improvement in Progression-Free Survival
After a median follow-up of 25.6 months, the first interim analysis demonstrated a significant difference in PFS between the two groups. The median PFS was 14.6 months for the combination arm compared to 10 months for the placebo arm (HR: 0.66; 95% CI: 0.51-0.84; P = 0.0002). This represents a 34% reduction in the risk of disease progression or death. The improvement in PFS was consistent across various pre-specified subgroups.
Overall Survival and Objective Response Rate
While overall survival (OS) data were still immature at the time of the interim analysis, a favorable trend was observed in the combination arm, with a 2-year survival probability of 74.6% compared to 68.6% in the dual placebo arm (HR: 0.80; P = 0.086). However, this difference did not reach statistical significance. The objective response rate (ORR) was significantly higher in the combination arm, with 46.8% of patients achieving a response compared to 33.3% in the placebo arm (P = 0.0005).
Safety and Tolerability
Treatment-related adverse events (AEs) were more frequent in the combination arm, with 71% of patients experiencing grade 3/4 AEs compared to 31% in the placebo arm. Common AEs included hypertension, proteinuria, and elevated liver enzymes, consistent with the known safety profiles of lenvatinib and pembrolizumab. However, the toxicity was considered manageable, with only 8.4% of patients discontinuing both drugs due to AEs and a low incidence (1.7%) of grade 5 toxicity.
Implications for Clinical Practice
According to Angela Lamarca, MD, PhD, MSc, a medical oncologist at the Fundacion Jimenez Diaz University Hospital in Madrid, Spain, the LEAP-012 trial represents a significant step forward in addressing an unmet need in HCC. While cross-trial comparisons should be made cautiously, LEAP-012 demonstrated a more robust reduction in progression risk compared to the EMERALD-1 trial, which evaluated durvalumab and bevacizumab with TACE in a similar patient population.
The LEAP-012 trial suggests that the combination of lenvatinib, pembrolizumab, and TACE can improve PFS and ORR compared to TACE alone, offering a more effective treatment option for patients with intermediate-stage HCC. Further studies are needed to investigate optimal sequencing of therapies and the timing of re-TACE procedures. The oncology community awaits mature OS data and further research to identify biomarkers that can predict response to combination therapies.
