Data from the LITESPARK-022 study supported adding belzutifan (Welireg) to standard adjuvant pembrolizumab for patients with clear cell renal cell carcinoma (RCC) that has a high chance of recurring following nephrectomy.

In this patient population, compared with adjuvant pembrolizumab alone, adjuvant belzutifan plus pembrolizumab led to a statistically significant and clinically meaningful 28% decrease in the risk for recurrence or death.

“LITESPARK-022 is the first adjuvant phase 3 trial in RCC to show a significant benefit for a combination treatment vs an active immunotherapy comparator,” lead investigator Toni Choueiri, MD, medical oncologist at Dana-Farber Cancer Institute, Boston, said in a presentation at the ASCO Genitourinary Cancers Symposium 2026.

The LITESPARK-022 results are “practice changing,” Brian Rini, MD, American Society of Clinical Oncology expert in kidney cancer, with Vanderbilt University Medical Center in Nashville, Tennessee, noted during a press briefing where the results were presented. “Pembrolizumab monotherapy is a standard of care in resected high-risk kidney cancer and this adds to that,” said Rini.

High Unmet Need

Roughly 40% of patients with clear cell RCC treated with adjuvant pembrolizumab experience recurrence or death within 5 years of nephrectomy. “Additional adjuvant therapy options are needed,” Choueiri said.

Belzutifan is a potent, first-in-class hypoxia-inducible factor-2 alpha (HIF-2 alpha) inhibitor shown to be effective in patients with advanced RCC treated with prior immunotherapy and VEGF receptor-TKI therapy.

LITESPARK-022 is testing the potential benefit of adding belzutifan to adjuvant pembrolizumab.

A total of 1841 patients with resected clear cell RCC at an increased risk for recurrence and no prior systemic therapy were randomly allocated (1:1) to pembrolizumab plus belzutifan or pembrolizumab plus placebo. Pembrolizumab was administered at 400 mg every 6 weeks for roughly 1 year, while belzutifan was given at 120 mg daily for up to 54 weeks.

The primary endpoint was investigator-assessed disease-free survival (DFS), with overall survival as a key secondary endpoint.

At the first interim analysis, with a median follow-up of 28.4 months, pembrolizumab plus belzutifan significantly improved DFS over pembrolizumab plus placebo (hazard ratio [HR], 0.72; P = .0003).

At 1 year, DFS was 92% with pembrolizumab plus belzutifan vs 85% with pembrolizumab plus placebo; at 2 years, DFS was 81% vs 69%; and at 30 months, DFS was 76% vs 69%. The DFS benefit with the combination was generally consistent across subgroups, Choueiri said.

Overall survival results remain immature, but there was a trend in favor of adding belzutifan to adjuvant pembrolizumab (HR, 0.78; P = .1220). At this first interim analysis, about 4% of patients in the combination group and 5% in the control group had died. Further follow-up is planned to determine whether the DFS benefit with the combination will translate into a definitive overall survival advantage, Choueiri said.

Safety Profile Consistent With Known Effects of Each Drug

The lead investigator said the safety profile of pembrolizumab plus belzutifan was consistent with the known effects of each individual drug, with low rates of adverse events (AEs) leading to discontinuation (10% with the combination vs 7% with pembrolizumab single agent).

Nearly all patients had a treatment-emergent AE, with more grade 3 or higher events with combination therapy than single agent therapy (42% vs 18%).

Anemia, a known side effect of HIF-2 alpha inhibitors, was more common with belzutifan plus pembrolizumab (84% vs 12%). Most cases of anemia were grade 1-2; grade 3+ anemia occurred in 12% and 0.5%, respectively. This side effect was managed mostly by dose interruption, reduction, or discontinuation (4%) and occasionally by blood transfusion, erythropoiesis-stimulating agent, or both, Choueiri said.

Hypoxia, another known side effect of belzutifan, occurred in 7% of patients taking the drug; about 5% of hypoxia was grade 3+. This side effect was also managed by dose interruption, reduction, or discontinuation and occasionally with oxygen therapy.

Choueiri said AEs did not affect study completion rates, with roughly 70% of patients in both groups completing their full course of therapy.

Rini noted that belzutifan is currently approved as monotherapy in the refractory setting, “but I think most people thought it would work better in earlier settings, including potentially — and as we’re seeing with these data — the much earlier [adjuvant setting].”

The study was funded by Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co. Choueiri and Rini disclosed having relationships with Merck and other pharmaceutical companies.