The U.S. Food and Drug Administration (FDA) has issued a complete response letter stating that it will not approve the combination of Keytruda (pembrolizumab) plus Lenvima (lenvatinib) as a first-line treatment for people with advanced unresectable hepatocellular carcinoma (HCC).
According to a press release, the decision was made on the basis that there isn’t evidence this treatment combination is meaningfully more effective than other approved treatments.
Keytruda, developed by Merck (known as MSD outside the U.S. and Canada), is an immune checkpoint inhibitor that works to prevent a mechanism used by cancer cells to evade immune responses. It specifically targets the PD-1 receptor at the surface of immune T-cells, and prevents it from binding to the PD-L1 protein on cancer cells, removing the brakes from immune cells.
Eisai‘s Lenvima is an oral inhibitor of specific cellular enzymes known as kinases, which are associated with blood vessel formation, tumor growth, and progression.
Both medications are approved separately to treat various cancer types, and their combination was approved last year for the treatment of certain advanced endometrial cancers.
The FDA also granted the designation of breakthrough therapy to this combination as a potential first-line treatment for HCC, the most common type of liver cancer, that was not suitable for localized treatment.
This designation was based findings from KEYNOTE-524/Study 116 (NCT03006926), a Phase 1b clinical trial designed to assess the safety and effectiveness of the Lenvima-Keytruda combo in patients with advanced or inoperable HCC who had not received prior systemic therapy.
The Eisai-sponsored trial enrolled 104 participants, all of whom were treated with Keytruda (administered intravenously at a dose of 200 mg every three weeks) in combination with Lenvima, given orally once per day at a dose of 8 mg or 12 mg, depending on the individual’s body weight.
The primary goals were to determine the combination’s safety and tolerability, as well as the proportion of patients responding to the treatment and the duration of such responses. Secondary assessments included the time patients lived without signs of disease progression and overall survival.
Updated data, presented at this year’s American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program, showed that 36% of patients responded to the Keytruda-Lenvima combination, including 1% complete responses (no detectable cancer following treatment). Responses lasted a median of 12.6 months.
Also, patients lived a median of 8.6 months without signs of cancer progression, and their median overall survival was 22.6 months.
Severe or worse treatment-related adverse events (side effects) occurred in 67% of participants, and led to discontinuation in 6% of them. The most common adverse events related to treatment were blood pressure (36%), diarrhea (35%), and fatigue (30%). There were three treatment-related deaths.
These data were used to support Merck’s and Eisai’s application seeking accelerated approval of the treatment combination for HCC. But between the application being submitted and a decision being made, the FDA approved another treatment combination for unresectable HCC: Tecentriq (atezolizumab) plus Avastin (bevacizumab), both sold by Genentech.
That approval was based on results from IMbrave150 (NCT03434379), a global Phase 3 trial that evaluated the combination in people with HCC who also had inoperable or advanced tumors and had not been treated before with systemic therapy.
In total, 501 participants were enrolled and received either Tecentriq, another immune checkpoint inhibitor, plus Avastin, which blocks blood vessel growth, and Nexavar (sorafenib), a standard treatment for liver cancer.
Because this trial had a control group, researchers were able to estimate how much patients benefitted from the combination compared with standard treatment. In this trial, the Tecentriq-Avastin combo reduced the risk of death by 42%, and the risk of disease progression or death by 41%, compared with Nexavar.
The FDA’s complete response letter regarding the application for the Keytruda-Lenvima combo stated “that Merck’s and Eisai’s 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.”
The companies plan to work with the FDA on appropriate next steps. An ongoing Phase 3 clinical trial, LEAP-002 (NCT03713593), is further evaluating the treatment combo, versus Lenvima plus a placebo, as first-line treatment for HCC.
