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TACE plus pembrolizumab and lenvatinib did not improve OS vs TACE alone in patients with unresectable HCC.
The addition of pembrolizumab (Keytruda) and lenvatinib (Lenvima) to transarterial chemoembolization (TACE) failed to result in a statistically significant improvement in overall survival (OS) vs TACE alone in patients with unresectable, nonmetastatic hepatocellular carcinoma (HCC), according to findings from a prespecified interim analysis of the phase 3 LEAP-012 trial (NCT04246177).1
Prior to the announcement, an analysis was performed to determine the likelihood of the study reaching the protocol-specified threshold for statistical significance for OS. Because the chances were low, the study sponsors decided to close the study. With respect to safety, the adverse effect profile of the regimen was in line with what had been reported from other trials and prior analyses from LEAP-012.
The data will be further evaluated while sponsors work with investigators to share the results with the medical community.
“Although the progression-free survival [PFS] results from this study are encouraging, unfortunately, the addition of [pembrolizumab] plus [lenvatinib] to TACE did not show the OS benefit we hoped,” Gregory Lubiniecki, MD, vice president of Global Clinical Development at Merck Research Laboratories, stated in a news release. “We are grateful to the patients and investigators for their important contributions to this study, and our commitment is unwavering as we pursue new therapeutic options for people living with HCC, an aggressive and challenging-to-treat cancer.”
Previously reported findings shared during the 2024 ESMO Congress and subsequently published in The Lancet illustrated that the trial met one of its primary end points: PFS.2,3
“The OS findings from LEAP-012, along with the previously reported improvement in PFS, provide important insights for treating [patients with] unresectable, nonmetastatic HCC,” Corina Dutcus, MD, senior vice president and Oncology Global Clinical Development Lead at Eisai, added in the news release.1
LEAP-012 was a multicenter, randomized, double-blind phase 3 trial designed to evaluate the activity of TACE plus pembrolizumab and lenvatinib vs TACE plus a dual placebo in patients with unresectable, nonmetastatic HCC.
The primary end points were blinded independent central review (BICR)–assessed PFS per RECIST 1.1 criteria and OS. Secondary end points were BICR-assessed objective response rate, duration of response, disease control rate, and time to progression per RECIST 1.1 and mRECIST criteria, BICR-assessed PFS per mRECIST criteria, and safety.
A total of 480 patients were randomly assigned 1:1 to receive 400 mg of intravenous (IV) pembrolizumab every 6 weeks (Q6W) plus either 12 mg of lenvatinib for patients with screening body weight of 60 kg or greater or 8 mg for patients with screening body weight of less than 60 kg, orally once daily, plus TACE, which was injected via hepatic artery 2 to 4 weeks after beginning study therapy, after the first tumor assessment scan, and at least 1 month after the first TACE; or IV placebo administered Q6W plus oral placebo and TACE.
All study drugs were given until protocol-specified discontinuation criteria were met. Pembrolizumab was given for up to 2 years, at which point lenvatinib could be administered as monotherapy until protocol-specified discontinuation criteria were met.
Findings published in The Lancet with median follow-up of 25.6 months (IQR, 19.5-32.4) revealed that the median PFS was 14.6 months (95% CI, 12.6-16.7) with lenvatinib plus pembrolizumab vs 10.0 months (95% CI, 8.1-12.2) with the dual placebo (HR, 0.66; 95% CI, 0.51-0.84; 1-sided P = .0002).
The 2-year OS rate was 75% (95% CI, 68%-80%) in the lenvatinib plus pembrolizumab arm vs 69% (95% CI, 62%-74%) in the dual placebo arm (HR, 0.80; 95% CI, 0.57-1.11; 1-sided P = .087).
In terms of safety, grade 3 or worse treatment-related AEs (TRAEs) were reported in 71% (n = 169 of 237) of patients in the lenvatinib plus pembrolizumab arm vs 32% (n = 76 of 241) of those in the dual placebo arm. The most frequent TRAEs were hypertension (investigational: 24%, n = 57; vs control: 7%, n = 18, respectively) and decreased platelet counts (11%, n = 27; 6%, n = 15).
Deaths due to TRAEs occurred in 2% (n = 4) of patients in the lenvatinib plus pembrolizumab arm (n = 1 each due to hepatic failure, gastrointestinal hemorrhage, myositis, and immune-mediated hepatitis) and less than 1% (n = 1 case of brain stem hemorrhage).
“For years, TACE has been a standard of care for these patients, yet many experience disease progression within 12 months,” Dutcus added. “With LEAP-012, we sought to make a meaningful difference for this patient population. [Lenvatinib] continues to play an important role as a monotherapy treatment option for patients with unresectable HCC, and as a company with a deep heritage in liver cancer research, Eisai remains committed to advancing the science.”
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