Update on Phase III LEAP-012 trial in unresectable, non-metastatic hepatocellular carcinoma – Eisai + Merck

Eisai and Merck & Co., Inc., (known as MSD outside of the United States and Canada) announced results from that Phase III LEAP-012 trial evaluating Lenvima (lenvatinib), the orally available multiple receptor tyrosine kinase inhibitor (TKI) discovered by Eisai, plus Keytruda (pembrolizumab), the anti-PD-1 therapy from Merck, in combination with transarterial chemoembolization (TACE) for the treatment of patients with unresectable, non-metastatic hepatocellular carcinoma (HCC).

At a pre-specified interim analysis, Lenvima plus Keytruda in combination with TACE did not achieve statistical significance for overall survival (OS), one of the study’s primary endpoints, compared to TACE alone. The likelihood of reaching the protocol-specified threshold for statistical significance for OS at a future analysis was evaluated by Eisai and Merck & Co., Inc., Rahway, NJ, USA and considered to be low. On this basis, the study will be closed, and the companies are informing investigators of this decision.

The safety profile of the Lenvima plus Keytruda-based regimen was consistent with that observed in previously reported studies evaluating the combination and in earlier analyses of LEAP-012. Further analysis of the data is ongoing. Eisai and Merck will work with investigators to share the results with the scientific community.

As reported previously, Lenvima plus Keytruda in combination with TACE met the study’s other primary endpoint of progression-free survival (PFS) and demonstrated a statistically significant and clinically meaningful improvement compared to TACE alone. Data from this first interim analysis, which served as the final analysis for the endpoint of PFS, were presented at the European Society for Medical Oncology (ESMO) Congress 2024 and published in The Lancet. With additional follow-up at subsequent analyses, PFS remained consistent.

“Although the progression-free survival results from this study are encouraging, unfortunately, the addition of Keytruda plus Lenvima to TACE did not show the overall survival benefit we hoped,” said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, MSD Research Laboratories. “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 hepatocellular carcinoma, an aggressive and challenging-to-treat cancer.”

“The overall survival findings from LEAP-012, along with the previously reported improvement in progression-free survival, provide important insights for treating unresectable, non-metastatic hepatocellular carcinoma,” said Dr. Corina Dutcus, Senior Vice President, Oncology Global Clinical Development Lead at Eisai. “For years, TACE has been a standard of care for these patients, yet many experience disease progression within twelve months. With LEAP-012, we sought to make a meaningful difference for this patient population. Lenvima 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.”

In July 2025, Lenvima plus Keytruda in combination with TACE was approved in China to treat unresectable non-metastatic HCC. The Lenvima plus Keytruda combination is approved in the U.S., the European Union (EU), Japan and other countries for the treatment of advanced renal cell carcinoma (RCC) and certain types of advanced endometrial carcinoma. Results from the LEAP-012 trial do not affect the current approved indications for the Lenvima plus Keytruda combination, including the approval of Lenvima plus Keytruda in combination with TACE in China to treat unresectable non-metastatic HCC.

Lenvima monotherapy is approved for the treatment of patients with unresectable HCC in more than 80 countries and regions, including in the U.S., the EU, China and Japan.

Keytruda is approved as a monotherapy for the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1 containing regimen in the U.S. and as a monotherapy for the treatment of patients with HCC who have been previously treated with sorafenib or oxaliplatin-containing chemotherapy in China.

About LEAP-012

LEAP-012 is a multicenter, randomized, double-blind Phase III trial (ClinicalTrials.gov, NCT04246177) evaluating Lenvima plus pembrolizumab in combination with TACE versus dual placebo plus TACE for the treatment of patients with unresectable, non-metastatic HCC. The primary endpoints are PFS as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) modified to follow a maximum of 10 target lesions, and with a requirement that new intrahepatic lesions must meet LI-RADS 5 criteria, and OS. Secondary endpoints include objective response rate, duration of response, disease control rate, and time to progression as assessed by BICR per above-mentioned RECIST v1.1 and Modified Response Evaluation Criteria in Solid Tumors (mRECIST), as well as PFS as assessed by BICR per mRECIST and safety.

The study randomized 480 patients 1:1 to receive:

i) Lenvima (12 mg [for participants with screening body weight ≥60 g] or 8 mg [for participants with screening body weight <60 kg] orally once a day) plus pembrolizumab (400 mg IV every six weeks [Q6W]) in combination with TACE (conducted as a background procedure of chemotherapeutic and embolic agents injected via hepatic artery 2-4 weeks after start of study intervention, and after the first tumor assessment scan and ≥1 month after the first TACE); or

ii) oral placebo administered once a day plus IV placebo administered Q6W in combination with TACE.

All study drugs were continued until protocol-specified discontinuation criteria. pembrolizumab was administered for up to two years (approximately 18 doses). After completing two years of combination therapy, Lenvima may have been administered as a single agent until protocol-specified discontinuation criteria were met.