Pembrolizumab/Lenvatinib Combo Misses Survival End Points in Unresectable HCC

The addition of pembrolizumab (Keytruda) to lenvatinib (Lenvima) did not significantly improve overall survival (OS) or progression-free survival (PFS) over lenvatinib alone when used in the frontline treatment of patients with unresectable hepatocellular carcinoma (HCC), missing the dual primary end points of the phase 3 LEAP-002 trial (NCT03713593).¹

Although a trend toward improved survival was observed with the doublet over the monotherapy, they did not reach statistical significance per the prespecified statistical plan. Notably, the median OS in the control arm was noted to be longer than what had previously been observed with single-agent lenvatinib in this disease.

Moreover, the toxicity profile observed with the doublet proved to be consistent with what has previously been reported with the regimen.

Additional data from LEAP-002 are anticipated to be shared at an upcoming medical meeting.

“Our joint clinical development program for [pembrolizumab] plus [lenvatinib] is designed to address unmet needs for some of the most challenging-to-treat types of cancer, like HCC,” Gregory Lubiniecki, MD, vice president of Global Clinical Development at Merck Research Laboratories, stated 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 across multiple types of cancer.”

The multicenter, double-blinded, active-controlled, phase 3 trial enrolled patients who were at least 18 years of age and 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 not amenable to or refractory to locoregional therapy.

Patients also needed to have a Child-Pugh class A liver score, at least 1 measurable lesion per RECIST v1.1 criteria and confirmed by blinded independent central review (BICR), an ECOG performance status of 0 or 1, and a predicted life expectancy that was longer than 3 months.

A total of 794 patients were randomized 1:1 to receive intravenous (IV) pembrolizumab at 200 mg on day 1 of each 3-week cycle in combination with oral lenvatinib at 12 mg once daily in those who weighed at least 60 kg, or oral lenvatinib at 8 mg once daily in those who weighed 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 dual primary end points of the trial were PFS per BICR assessment and RECIST v1.1 criteria, and OS. Key secondary end points comprised objective response rate per 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 that lenvatinib was noninferior but not statistically superior to sorafenib (Nexavar) in terms of OS.³ The median OS with lenvatinib was 13.6 months vs 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 over sorafenib, at a median of 7.3 months vs 3.6 months, respectively (HR, 0.64; 95% CI, 0.55-0.75).

Single-agent lenvatinib has also been approved for the frontline treatment of patients with unresectable HCC in Europe and China, as well as for those with unresectable HCC in Japan.

References

1. 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 3, 2022. https://bit.ly/3OWOtOu
2. 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). ClinicalTrials.gov. Updated July 27, 2022. Accessed August 3, 2022. https://clinicaltrials.gov/ct2/show/NCT03713593
3. FDA approves lenvatinib for unresectable hepatocellular carcinoma. News release. FDA. August 16, 2018. Accessed August 3, 2022. https://bit.ly/3d6xLPy