The U.S. Food and Drug Administration issued a Complete Response Letter to Merck and Eisai over their Lenvima and Keytruda combination for first-line treatment of unresectable hepatocellular carcinoma (HCC).
The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to Kenilworth, New Jersey’s Merck and Tokyo’s Eisai over their Lenvima and Keytruda combination for first-line treatment of unresectable hepatocellular carcinoma (HCC).
Lenvima, which was discovered and developed by Eisai, is a kinase inhibitor of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (IDR) and VEGFR3 (FLT4). It also inhibits other kinases associated with pathogenic angiogenesis, tumor growth, and cancer progression, as well as their other normal cellular functions.
As a monotherapy, the drug has been approved for thyroid cancer in more than 60 countries, including Japan and the U.S., and for unresectable hepatocellular carcinoma in more than 55 countries. It is also approved in combination with everolimus (Novartis’ Afinitor) for renal cell carcinoma after previous antiangiogenic therapy, and in combination with Merck’s Keytruda for advanced endometrial cancer that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) who have disease progression after previous systemic therapy who are not eligible for curative surgery or radiation.
Keytruda is Merck’s blockbuster checkpoint inhibitor, an anti-PD-1 therapy that has been approved for a laundry list of cancer indications by itself or in combination with other drugs. It is involved in more than 1,200 clinical trials in a wide range of cancers and treatment settings.
The companies’ applications, which were seeking accelerated approval status, were based on data from the Phase Ib Study 116/KEYNOTE-524 trial. In the single-arm setting, the data showed clinically meaningful efficacy. It was sufficient enough to garner Breakthrough Therapy designation, but not enough for approval.
The companies note that, “Ahead of the PDUFA action dates of Eisai’s and Merck’s applications, another combination therapy was approved based on a randomized controlled trial that demonstrated overall survival. Consequently, the CRL stated that the applications do not provide evidence that KEYTRUDA in combination with Lenvima represents a meaningful advantage over available therapies for the treatment of unresectable or metastatic HCC with no prior systemic therapy for advanced disease.”
They indicate they plan to work with the agency to determine the appropriate steps, including another clinical trial, to show more evidence of effectiveness and clinical benefit of the combo treatment. To do so, the Phase III LEAP-002 trial evaluating the two drugs as first-line treatment for advanced HCC is already fully enrolled and currently ongoing.
The therapy it failed to beat out, even though this was not a head-to-head trial, is Roche’s Tecentriq-Avastin combination. In a trial compared with Bayer’s standard-of-care Nexavar, the Tecentriq-Avastin combo decreased the risk of death by 42% and the risk of disease progression or death by 41% compared to Nexavar in the Phase III ImBrave150 trial.
On June 2, the FDA approved the combination for unresectable or metastatic HCC in patients who have not had previous systemic therapy.
HCC is an aggressive cancer with limited options for treatment. About 750,000 people worldwide are diagnosed with HCC each year, with almost half of the cases in China. In the U.S., the number of liver cancer cases have more than tripled since 1980 and HCC is the fastest-rising cause of cancer-related death. It is found mostly in people with cirrhosis caused by chronic hepatitis B or C or alcohol use. It typically is diagnosed at an advanced stage. The prognosis for unresectable HCC is poor and has a one-year survival rate of less than 50% after diagnosis.
Merck and Eisai recently presented data at this year’s American Society of Clinical Oncology virtual meeting, showing that the Keytruda-Lenvima combo caused a response in 36% of previously untreated liver cancer patients, and provided sustained response for a median of 12.6 months.
Bristol Myers Squibb recently gained accelerated FDA approval for its Opdivo-Yervoy immuno-oncology treatment for HCC patients who previously received Nexavar.
Merck is also investigating with Bayer whether Keytruda with Stivarga, a follow-on to Nexavar, can work in new liver cancer patients.
