FDA Issues Complete Response Letter for Pembrolizumab plus Lenvatinib in Unresectable HCC

Merck and Eisai announced that the FDA issued a complete response letter to its accelerated approval applications for the combination use of pembrolizumab plus lenvatinib to treat patients with unresectable hepatocellular carcinoma.

The FDA issued a complete response letter to Merck and Eisai for their applications requesting accelerated approval of pembrolizumab (Keytruda) plus lenvatinib (Lenvima) as a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC), according to a press release.

The letter explained that Merck and Eisai’s accelerated approval request did not show sufficient evidence that the pembrolizumab plus lenvatinib combination represents a “meaningful advantage” over the already available therapies to treat unresectable or metastatic HCC with no prior systemic therapy for advanced disease.

The accelerated approval applications were submitted following data from the phase 1b KEYNOTE-524/Study 116 trial presented at the 2020 American Society of Clinical Oncology Virtual Program. The trial showed statistically significant efficacy in the single-arm setting, and the data was supported by a breakthrough therapy designation from the FDA in July of 2019.

Ahead of the PDUFA dates for Merck and Eisai’s accelerated approval applications, another combination therapy was approved based on the data from a randomized, controlled trial demonstrating positive overall survival.

The applications for accelerated approval that were initially submitted by Merck and Eisai no longer fulfilled the requirements for this approval, therefore both companies plan to work with the FDA to take the appropriate steps toward approval. One of those steps consists of conducting a well-controlled clinical trial to show statistically significant evidence of a clinical benefit for this combination.

In accordance with the FDA, the phase 3 LEAP-002 clinical trial, evaluating the pembrolizumab plus lenvatinib combination to treat unresectable HCC, is fully enrolled and underway. Moreover, Merck and Eisai are continuing to monitor the combination of pembrolizumab plus lenvatinib to treat 13 different tumor types across 18 clinical trials.

In March of 2018, the companies of Merck and Eisai entered into a collaboration to co-develop and co-distribute lenvatinib. Under this agreement, the companies will develop, manufacture, and commercialize the drug as both a monotherapy and in combination with Merck’s pembrolizumab. Currently, the companies are jointly analyzing the combination in clinical trials through the LEAP program.

Pembrolizumab is an anti-PD-1 therapy that increases the body’s ability to identify and fight tumor cells. Lenvatinib is a kinase inhibitor that works by inhibiting the kinase activities of vascular endothelial growth factor receptors.


Merck and Eisai Receive Complete Response Letter for KEYTRUDA® (pembrolizumab) plus LENVIMA® (lenvatinib) Combination as First-Line Treatment for Unresectable Hepatocellular Carcinoma [news release]. Kenilworth, New Jersey and Woodcliff Lake, New Jersey. Published July 8, 2020. https://www.businesswire.com/news/home/20200708005239/en/. Accessed July 8, 2020.