The U.S. Food and Drug Administration (FDA) has granted a Breakthrough Therapy designation for pembrolizumab (Keytruda®), an anti-PD-1 therapy developed by Merck/MSD, in combination with lenvatinib (Lenvima®), an orally available kinase inhibitor discovered and developed by Eisai, for the potential first-line treatment of patients with advanced unresectable hepatocellular carcinoma (HCC) who are not amenable to locoregional treatment.
Pembrolizumab is a humanized antibody used in cancer immunotherapy used to treat patients with melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, or stomach cancer.
Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). The drug also inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation.
This is the third Breakthrough Therapy designation for the pembrolizumab + lenvatinib combination and is based on updated interim results from the Phase 1b trial KEYNOTE-524/Study 116.
An earlier interim analysis was presented during the 2019 annual meeting of the American Association for Cancer Research (AACR) 
Prevalence and mortality
The prevalence and mortality rate of liver cancer have been rising steadily over the past decade. In 2019, it is estimated there will be more than 42,000 new liver cancer cases diagnosed in the U.S. (including intrahepatic bile duct cancer).
Additionally, it is estimated there will be nearly 32,000 deaths from liver cancer in the U.S. Liver cancer — which is often diagnosed at an advanced stage — has one of the highest mortality rates of solid cancers, with a five-year survival rate of about 18%.
Hepatocellular carcinoma is the most common type of liver cancer, accounting for approximately 90% of these cases. The stage of disease at diagnosis largely determines the treatment approach, with potentially curative options, like resection or transplantation, only available for early-stage HCC.
Unresectable HCC, a type of liver cancer that cannot be removed by surgery, has a worse prognosis, with a median survival of less than one year. Unfortunately, approximately 70% of patients are diagnosed too late to be eligible for resection, ablation or transplantation, and there have been limited treatment options available for patients with unresectable disease.
The KEYNOTE-524/Study 116 (NCT03006926) is a multi-center, open-label, single-arm Phase 1b study evaluating the safety and efficacy of the combination of pembrolizumab (200 mg intravenously every three weeks) and lenvatinib (12 mg/day for patients weighing 60 kg or more, and 8 mg/day for patients weighing less than 60 kg) in patients with unresectable HCC, Barcelona Clinic Liver Cancer (BCLC) stage B (not eligible for transarterial chemoembolization [TACE]) or C, Child-Pugh class A, and ECOG performance status (PS) of 0 or 1.
The primary endpoints are tolerability and safety, and the secondary endpoints include overall survival (OS), objective response rate (ORR), progression-free survival (PFS) and time to progression (TTP) using modified Response Evaluation Criteria In Solid Tumors (mRECIST) criteria.
Tumor assessments of complete response (CR) or partial response (PR) were confirmed at least four weeks (or longer) after initial response. The first part of the trial evaluated tolerability by assessing dose-limiting toxicities (DLTs) during the first cycle of treatment in patients for whom no other appropriate therapy was available.
After tolerability was confirmed, additional patients with no prior systemic therapy for unresectable HCC were enrolled in the expansion part of the trial, which is evaluating ORR and duration of response as measured by mRECIST and Response Evaluation Criteria In Solid Tumors (RECIST 1.1) based on independent imaging review (IIR).
Earlier Breakthrough Therapy designations
The first two Breakthrough Therapy designations for the combination were in advanced and/or metastatic renal cell carcinoma and advanced and/or metastatic non-microsatellite instability-high (MSI-H)/proficient mismatch repair (pMMR) endometrial carcinoma, received in January 2018 and July 2018, respectively. The combination of pembrolizumab plus lenvatinib is investigational.
The efficacy and safety of this combination has not been established. The combination of pembrolizumab plus lenvatinib is not approved in any cancer types today.
“As part of our ongoing collaboration with Eisai, we are committed to evaluating the potential of pembrolizumab plus lenvatinib across a number of different types of cancer,” said Jonathan Cheng MD, Vice President, Oncology Clinical Research, Merck Research Laboratories.
“With this Breakthrough Therapy designation from the FDA, we look forward to working with Eisai to potentially build upon our existing indications for this difficult-to-treat cancer, so that we can help patients through a combination approach,” Cheng added.
“We are excited that the FDA has recognized the potential of pembrolizumab plus lenvatinib in combination in advanced unresectable hepatocellular carcinoma not amenable to locoregional treatment with this Breakthrough Therapy designation,” said Takashi Owa, MD, Vice President, Chief Medicine Creation and Chief Discovery Officer, Oncology Business Group at Eisai.
“We are dedicated to working together with Merck to potentially bring another important option to patients,” Owa concluded.
The Breakthrough Therapy designation is intended to expedite development and review of medicines for serious or life-threatening conditions and to qualify for this designation, preliminary clinical evidence must demonstrate that the therapy may provide substantial improvement over currently available therapy on at least one clinically significant endpoint.
A Trial of Lenvatinib Plus Pembrolizumab in Subjects With Hepatocellular Carcinoma – NCT03006926
 Ikeda M, Sung MW, Kudo M, Kobayashi M, Baron AD, Finn RS, Kaneko S, Zhu AX, et al. A Phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): Updated results. In: Proceedings of the 110th Annual Meeting of the American Association for Cancer Research; 2019 March 29 – April 3; Atlanta, GA. Philadelphia (PA): AACR; 2019. Abstract nr CT061 / 18. [Abstract/Poster]