Merck and Eisai announced results from the Phase 3 LEAP-012 trial, revealing that Keytruda (pembrolizumab) plus Lenvima (lenvatinib) in combination with transarterial chemoembolization (TACE) significantly improved progression-free survival (PFS) compared to TACE alone in patients with unresectable, non-metastatic hepatocellular carcinoma (HCC). The late-breaking data were presented at the European Society for Medical Oncology (ESMO) Congress 2024.
After a median follow-up of 25.6 months, the Keytruda plus Lenvima regimen with TACE reduced the risk of disease progression or death by 34% (HR=0.66 [95% CI, 0.51-0.84]; p=0.0002) compared to TACE alone. The median PFS was 14.6 months (95% CI, 12.6-16.7) for the combination therapy versus 10.0 months (95% CI, 8.1-12.2) for TACE alone. Although overall survival (OS) data are not yet mature, a trend toward improvement was observed (HR=0.80 [95% CI, 0.57-1.11]; p=0.0867).
Clinical Significance
"Hepatocellular carcinoma is one of the leading causes of cancer-related deaths worldwide, highlighting the need for new treatment options," said Dr. Josep Llovet, Director of the Liver Cancer Program and Professor of Medicine at the Icahn School of Medicine at Mount Sinai. "These findings from the LEAP-012 trial demonstrate the potential of pembrolizumab plus lenvatinib in combination with TACE to extend progression-free survival for patients diagnosed with unresectable, non-metastatic disease."
Rising Incidence of HCC
Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, Merck Research Laboratories, noted, "Global incidence rates for hepatocellular carcinoma are expected to rise by more than 50 percent over the next two decades, and there have been limited advances for patients with unresectable, non-metastatic forms of disease." He added that these results underscore their commitment to exploring therapeutic options for patients, including in earlier stages of the disease.
Safety Profile
Treatment-related adverse events (TRAEs) were observed in 98.7% of patients receiving the Keytruda plus Lenvima combination with TACE, compared to 84.6% of those receiving TACE alone. Grade 3 or 4 TRAEs occurred in 71.3% and 31.1% of patients, respectively. TRAEs led to death in 1.7% of patients in the combination arm versus 0.4% in the TACE alone arm. Discontinuation of both study drugs due to TRAEs occurred in 8.4% versus 1.2% of patients, respectively. Serious adverse events were observed in 33.3% of patients receiving the combination therapy versus 12.4% receiving TACE alone.
Study Design
LEAP-012 is a multicenter, randomized, double-blind Phase 3 trial evaluating Keytruda plus Lenvima in combination with TACE versus dual placebo plus TACE for unresectable, non-metastatic HCC. The primary endpoints are PFS and OS. Secondary endpoints include objective response rate, duration of response, disease control rate, and time to progression. The study randomized 480 patients 1:1 to receive:
- Keytruda (400 mg intravenously every six weeks) plus Lenvima (12 mg or 8 mg orally once a day based on body weight) in combination with TACE.
- Placebo plus TACE.
Treatment continued until protocol-specified discontinuation criteria were met, with Keytruda administered for up to two years. After two years, Lenvima could be administered as a single agent until discontinuation criteria were met.
About Hepatocellular Carcinoma
HCC accounts for approximately 90% of primary liver cancer cases. Liver cancer is a leading cause of cancer-related deaths worldwide, with incidence rates expected to rise. In 2022, there were over 865,000 new cases and 757,000 deaths globally. The five-year relative survival rate in the U.S. is 22% based on data from 2013-2019.
