Pembrolizumab Plus Lenvatinib Misses Primary End Points in Unresectable HCC


While treatment with pembrolizumab and lenvatinib vs lenvatinib alone seemed to have survival benefit in patients with unresectable hepatocellular carcinoma, the primary end points of the trial were missed.

Though the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) resulted in improvement in overall survival (OS) and progression-free survival (PFS) when compared with lenvatinib alone in patients with unresectable hepatocellular carcinoma (HCC), these results did not meet statistical significance and missed the primary end points of the phase 3 LEAP-002 trial (NCT03713593), according to a press release from Merck.

The median OS of the lenvatinib monotherapy arm of the LEAP-002 trial was longer than what was observed in previously reported clinical trials evaluating lenvatinib alone in unresectable HCC but were not statistically significant.

Further, the safety profile of pembrolizumab plus lenvatinib stayed consistent with previously reported data on the combination. Data is expected to be reported at an upcoming medical conference.

“Our joint clinical development program Keytruda plus Lenvima is designed to address unmet needs for some of the most challenging-to-treat types of cancer, like hepatocellular carcinoma,” said Gregory Lubiniecki, MD, vice president of Global Clinical Development at Merck Research Laboratories, in the press release. “We remain confident in the potential of this combination based on the body of evidence we’ve seen to date and will continue to investigate its role across multiple types of cancer.”

The multicenter, randomized, double-blinded, active-controlled, phase 3 LEAP-002 trial consisted of 794 patients with unresectable HCC. Investigators aimed to evaluate the safety and efficacy of lenvatinib plus pembrolizumab vs lenvatinib in combination with placebo as first-line therapy in this patient population.

In both arms of the study, patients were given 8 mg/kg or 12 mg/kg of oral lenvatinib, and the experimental arm also received 200 mg of pembrolizumab by intravenous infusion on day 1 of every 21-day cycle up to a maximum of 35 cycles. Lenvatinib was administered until progressive disease or unacceptable toxicities were observed.

Primary end points of the trial were PFS and OS with secondary end points consisting of objective response rate, duration of response, disease control rate, adverse events, and time to disease progression.

Enrollment in the trial was open to patients 18 years of age and older with a diagnosis of HCC confirmed by radiology, histology, or cytology. Patients were required to have Barcelona Clinic Liver Cancer Stage C disease or B disease that is not amenable to locoregional treatment options or refractory to locoregional treatments, a Child-Pugh class A liver score, life expectancy of over 3 months, and an ECOG performance status of 0-1. Additionally, patients with hepatitis B were eligible for enrollment as long as their virus was well controlled.

Previously in 2018, the FDA granted approval to lenvatinib as the first-line treatment for patients with HCC based on data from the phase III REFLECT trial. Additionally, the FDA approved the combination of lenvatinib and pembrolizumab for select patients with endometrial cancer in July 2021, and granted approval to the combination as treatment for patients with renal cell carcinoma in the first-line, in August, 2021.

“Aiming for further improvement in the treatment of patients with unresectable HCC, we selected [lenvatinib] monotherapy, a standard of care option, as the control arm of the LEAP-002 trial,” Corina Dutcus, MD, senior vice president of Clinical Research, Oncology at Eisai Inc, concluded. “While results evaluating the combination are not what we had hoped for, we will continue to contribute to the care of patients with unresectable HCC by applying valuable knowledge from the LEAP-002 trial.”

Merck and Eisai provide update on phase 3 LEAP-002 trial evaluating KEYTRUDA® (pembrolizumab) plus LENVIMA® (lenvatinib) versus LENVIMA monotherapy in patients with unresectable hepatocellular carcinoma. News release. Merck. August 3, 2022. Accessed August 4, 2022.
Safety and efficacy of lenvatinib (E7080/MK-7902) in combination with pembrolizumab (MK-3475) versus lenvatinib as first-line therapy in participants with advanced hepatocellular carcinoma (MK-7902-002/E7080-G000-311/LEAP-002). Updated July 27, 2022. Accessed August 4, 2022.
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