Adding pembrolizumab to lenvatinib did not significantly improve overall survival or progression-free survival compared to lenvatinib alone when used in the first-line treatment of patients with unresectable hepatocellular carcinoma, missing the two primary endpoints of the Phase 3 LEAP-002 trial.
Adding pembrolizumab (Keytruda) to lenvatinib (Lenvima) did not significantly improve overall survival (OS) or progression-free survival (PFS) compared to lenvatinib alone when used in the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) missing both primary endpoints from the phase 3 LEAP-002 trial (NCT03713593).1
Although a trend of improved survival was observed with doublet compared to monotherapy, they did not reach statistical significance according to the predefined statistical plan. Notably, it was noted that the median OS in the control group was longer than previously observed with lenvatinib monotherapy in this disease.
Additionally, the toxicity profile observed with the doublet was found to be consistent with what had previously been reported with the diet.
Additional data from LEAP-002 should be shared at an upcoming medical meeting.
“Our joint clinical development program for [pembrolizumab] more [lenvatinib] is designed to address the unmet needs of some of the most difficult-to-treat types of cancer, such as HCC,” said Gregory Lubiniecki, MD, vice president of global clinical development at Merck Research Laboratories, in a press release. “We remain confident in the potential of this combination based on the body of evidence we have seen to date and will continue to investigate its role in multiple types of cancer.”
The phase 3 multicentre, double-blind, active-control trial enrolled patients aged 18 years or older who had a diagnosis of HCC confirmed by radiology, histology or cytology.2 Patients were required to have Barcelona Clinic Liver Cancer (BCLC) stage C disease or BCLC stage B disease that was unsuitable or refractory to locoregional therapy.
Patients were also required to have a Child-Pugh Class A liver score, at least 1 lesion measurable by RECIST v1.1 criteria and confirmed by blinded independent central review (BICR), an ECOG performance status of 0 or 1 and an expected life expectancy was over 3 months.
A total of 794 patients were randomized 1:1 to receive intravenous (IV) pembrolizumab 200 mg on day 1 of each 3-week cycle in combination with oral lenvatinib 12 mg once daily in those who weighed at least 60 kg, or oral lenvatinib 8 mg once daily in people weighing less than 60 kg; or lenvatinib alone at either of these doses based on weight.
Treatment was continued until disease progression, intolerable toxicity, or up to 35 cycles.
The two primary endpoints of the trial were PFS according to BICR assessment and RECIST v1.1 criteria, and OS. Primary secondary endpoints included objective response rate according to BICR assessment and RECIST v1.1 criteria and duration of response.
In August 2018, the FDA approved lenvatinib monotherapy for the first-line treatment of patients with unresectable HCC based on data from the Phase 3 REFLECT trial (NCT01761266), which showed lenvatinib to be unresectable. inferior but not statistically superior to sorafenib (Nexavar) in terms of OS.3 The median OS with lenvatinib was 13.6 months versus 12.3 months with sorafenib in this patient population (HR, 0.92; 95% CI, 0.79-1.06). However, lenvatinib was found to significantly improve PFS compared to sorafenib, at a median of 7.3 months versus 3.6 months, respectively (HR, 0.64; 95% CI, 0.55-0 ,75).
Lenvatinib monotherapy has also been approved for the first-line treatment of patients with unresectable HCC in Europe and China, as well as for those with unresectable HCC in Japan.
- Merck and Eisai provide an update on the Phase 3 LEAP-002 trial evaluating Keytruda (pembrolizumab) plus Lenvima (lenvatinib) versus Lenvima monotherapy in patients with unresectable hepatocellular carcinoma. Press release. Thanks. August 3, 2022. Accessed August 3, 2022. https://bit.ly/3OWOtOu
- Safety and efficacy of lenvatinib (E7080/MK-7902) in combination with pembrolizumab (MK-3475) compared to lenvatinib as first-line treatment in participants with advanced hepatocellular carcinoma (MK-7902-002/E7080- G000-311/LEAP-002). ClinicalTrials.gov. Updated July 27, 2022. Accessed August 3, 2022. https://clinicaltrials.gov/ct2/show/NCT03713593
- FDA approves lenvatinib for unresectable hepatocellular carcinoma. Press release. FDA. August 16, 2018. Accessed August 3, 2022. https://bit.ly/3d6xLPy