The combination of lenvatinib and pembrolizumab is the current standard of care for ccRCC, however, most patients still experience disease progression. The addition of a third agent may lead to improvement in outcomes.
A phase 3 trial is currently underway to determine the efficacy of the triplet combinations of belzutifan (Welireg), lenvatinib (Lenvima), and pembrolizumab (Keytruda) or lenvatinib, pembrolizumab, and quavonlimab (MK-1308) versus lenvatinib and pembrolizumab alone, for the treatment of advanced clear cell renal cell carcinoma (ccRCC), according to a poster presented at the 2021 International Kidney Cancer Symposium: North America.1
Compared with sunitinib (Sutent), the combination of the PD-1 inhibitor pembrolizumab and the vascular endothelial growth factor receptor tyrosine kinase inhibitor lenvatinib, demonstrated superior survival benefits. However, despite this advance, most patients with advanced ccRCC will experience progressive disease. Adding the anti-cytotoxic T-lymphocyte-associated protein 4, quavonlimab, or the hypoxia-inducible factor 2a inhibitor, belzutifan, may improve survival.
The randomized, parallel assignment, phase 3 trial (NCT04736706) has an estimated enrollment of 1431 patients and an estimated completion date of October 2026. The primary end point of the study is progression-free survival (PFS) per RECIST v1.1 and overall survival (OS). Secondary end points include objective response rate (ORR) per RECIST v1.1, duration of response, and safety and tolerability.2
During the study, patients will be randomized 1:1:1 into 1 of 3 arms. In arm 1 (n = 477), patients will receive pembrolizumab 400 mg, belzutifan 120 mg, and lenvatinib 20mg. Pembrolizumab will be administered intravenously (IV) once every 6 weeks for up to 18 administrations while belzutifan and lenvatinib will be administered once daily until disease progression of discontinuation.
In arm 2 (n = 477), patients will receive a coformulation of pembrolizumab 400mg and quavonlimab 25 mg plus lenvatinib 20 mg. The coformulation will be administered once every 6 weeks by IV for up to 18 administrations. Lenvatinib will be continued once daily until progressive disease or discontinuation.
In arm 3 (n = 477), the control arm, patients will receive pembrolizumab 400 mg plus lenvatinib 20 mg. Pembrolizumab will be administered once every 6 weeks by IV for up to 18 administrations while lenvatinib will be administered until disease progression or discontinuation.
In terms of safety evaluation, adverse events (AEs) will be monitored throughout the entire study and for 90 days after the cessation of treatment. In order to determine efficacy, patients will receive tumor imaging at week 12, then every 6 weeks until week 78, then every 12 weeks thereafter. If bone imaging is positive at baseline, subsequent bone imaging will be done at week 18, then once every 12 weeks through week 78. After week 78, imaging will be performed once every 24 weeks until disease progression. Brain imaging will be conducted after randomization in order to confirm complete response in patients with brain metastases at baseline.1
After treatment is discontinued, a safety follow-up will be performed within 30 days. An additional safety follow-up will be conducted at 60 and 90 days after treatment discontinuation.
The efficacy analysis population will be made up of all randomly assigned patients and PFS and OS will be calculated using a stratified log-rank test. Additionally, hazard radios will be estimated using stratified Cox proportional hazard models. ORR will be calculated within the stratified Miettinen and Nurminen method, with strata weighed by sample size.
Safety will be calculated in all randomly assigned patients who received 1 or more doses of the study treatment and results will be analyzed using a tiered approach. Additionally, the Miettinen and Nurminen method will be used to perform analyses to provide the between-treatment differences in percentages of patients who experienced AEs.
In order to participate, patients must be 18 years of age or older, have locally advanced or metastatic ccRCC with or without sarcomatoid features, measurable disease per RECIST v1.1, no prior systemic therapy for advanced ccRCC, and a KPS score of 70% or more. Patients with a known additional malignancy, central nervous system metastases, radiotherapy 2 weeks or less before the frits dose of study intervention, hypoxia, or clinically significant cardiac disease are not eligible to participate.
The study is currently recruiting in Alabama, California, Connecticut, Florida, Georgia, Illinois, Indiana, Kentucky, Louisiana, Maine, Massachusetts, Michigan, Minnesota, New York, South Carolina, Tennessee, Texas, and Washington.2