Belzutifan and Pembrolizumab Combination Improves Disease-Free Survival in Kidney Cancer Patients

Patients with a common form of kidney cancer called clear cell renal cell carcinoma (ccRCC) who have a high risk of recurrence after surgery showed significantly improved disease-free survival when treated with an oral combination regimen that includes belzutifan (Welireg), a HIF-2α inhibitor, given with standard immunotherapy pembrolizumab (Keytruda).

These findings, from the Phase III LITESPARK-022 study, were presented on February 28, 2026, by Dr. Toni Choueiri of Dana-Farber Cancer Institute at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) in San Francisco, California [1]. Previous Dana-Farber research led by Dr. Choueiri showed that pembrolizumab alone reduced the risk of death and disease progression for advanced kidney cancer patients after surgery. Pembrolizumab is an immune checkpoint inhibitor that helps the immune system find and fight cancer cells. While effective, about one in five people who take it will relapse.

Understanding the LITESPARK-022 Trial

The LITESPARK-022 study was designed to combine the immunotherapy with belzutifan to improve the overall survival of patients considered high-risk for kidney cancer relapse. [2]

“A significant percentage of patients with high risk kidney cancer will recur within five years after surgery because microscopic cancer cells can remain undetected,” says Dr. Choueiri, director of the Lank Center for Genitourinary Cancer at Dana-Farber. “We need new therapies that can work together to better prevent the cancer from coming back.”

The HIF-2α inhibitor belzutifan helps to reduce the risk of progression by blocking HIF-2α, which is overabundant in ccRCC cells and drives cancer growth. Dana-Farber’s Dr. William G. Kaelin, Jr., was awarded a Nobel Prize in Physiology or Medicine in 2019 for the science behind the development of belzutifan.

LITESPARK-022 is a global, multicenter, double-blind, randomized, Phase III study that included 1,841 participants with ccRCC [3]. Participating patients underwent surgery to remove the tumor and had no signs of cancer but had an elevated risk of recurrence. Patients were randomized to receive either pembrolizumab and belzutifan after surgery or pembrolizumab and a placebo after surgery.

Key Findings and Results

With a median follow-up of 28.4 months, the combination of pembrolizumab plus belzutifan resulted in a 28% decrease in recurrence (HR=0.72 [95% CI 0.59-0.87]. p=0.0003) compared to pembrolizumab plus placebo [1]. About 81% of participants who took the two-drug regimen were cancer-free, compared to 74% of those who received standard of care.

Side effects were consistent with data from previously reported studies. The study has not yet collected enough information to determine if adding belzutifan helps people live longer overall.

“People at high risk of ccRCC coming back after surgery may have a new option to reduce that risk,” says Dr. Choueiri. “In this study, belzutifan, in combination with pembrolizumab, reduces the chance of recurrence compared with the current standard treatment of pembrolizumab alone.”

Based on these data, the U.S. Food and Drug Administration (FDA) has accepted for priority review supplemental applications for WELIREG in combination with KEYTRUDA or KEYTRUDA QLEX™ for the adjuvant treatment of certain patients with RCC [1].

The trial is sponsored by Merck Sharp & Dohme, a subsidiary of Merck & Co.