2026 ASCO GU: Two Positive Trials for Belzutifan Combination Therapy
This is a research highlight from the 2026 ASCO Genitourinary Cancers Symposium (ASCO GU), held recently in San Francisco, California.
Belzutifan (Welireg, made by Merck), the most recently approved kidney cancer drug (2021 and 2023) that uses a new biological method to treat disease, has progressed to clinical trials using it in combination with existing immunotherapy and targeted therapies at different times during treatment.
Two such trials presented positive results during ASCO GU suggesting some patients may have potential new treatment options to choose from in the course of their kidney cancer disease management.
Overall survival data were still immature and not reported during the presentation of either trial results and significant side effects remained a consistent feature of treatment, which means thoughtful patient selection and a thorough discussion of treatment implications is critical.
The phase 3 Litespark-022 trial was designed to see if a combination of the immunotherapy pembrolizumab plus belzutifan was superior to treatment with pembrolizumab alone in the adjuvant setting – meaning after kidney cancer patients had undergone surgery.
Belzutifan is a hypoxia-inducible factor (HIF-2a) inhibitor that acts on the cellular mechanisms by which cells adapt to varying levels of oxygen in the environment. HIF-2a activity can be disrupted in renal cell carcinoma (RCC) and for some patients, a HIF-2a inhibitor can effectively impact kidney cancer activity.
After 1 year of follow up, patients with clear cell renal cell carcinoma who had a nephrectomy and were at increased risk for recurrence of their disease experienced a 28% reduced risk of disease recurrence or death when given the pembrolizumab plus belzutifan combination compared with pembrolizumab alone.
Primary investigator Dr. Toni Choueiri of the Dana-Farber Cancer Institute in Boston, noted Litespark-022 was the first phase 3 trial to show belzutifan provides benefit after surgery, receiving applause from the crowd. He suggested the combination regimen could become a new standard of care for kidney cancer patients at risk for recurrence after surgery.
Side effects remained a significant part of the adjuvant treatment regimen. Serious side effects (grade 3 or higher) occurred in 52.5 percent of the pembrolizumab plus belzutifan group compared with 30.2% in the pembrolizumab group. The most common side effects were anemia, liver complications, and hypoxia, consistent with the known side effects for these medications.
Discussing the trials, Katy Beckermann, MD, PhD, of Tennessee Oncology said: “In the historical context of KEYNOTE-564, which was the first study in kidney cancer to show both positive DFS and overall survival (OS) outcomes with pembrolizumab versus placebo in the adjuvant setting, LITESPARK-022 is an exciting study that builds on top of those results. LITESPARK-022 represents the first randomized phase 3 adjuvant trial conducted with an active-control arm, and the first trial to demonstrate that a DFS benefit compared to pembrolizumab is clinically meaningful.”
The Litespark-011 was another phase 3 trial investigating belzutifan, this time in combination with a targeted therapy – the VEGF receptor-tyrosine kinase inhibitor lenvatinib. The combination was compared with cabozantinib in advanced RCC patients whose disease progressed after anti-PD-L1 or anti-PD-1 immunotherapy.
An interim analysis after 17 months showed that the lenvatinib plus belzutifan combination reduced the risk of disease progression or death by 30% compared with cabozantinib. There was a difference of 4.1 months of survival favoring the lenvatinib plus belzutifan regimen. Patients on the combination treatment also had higher objective response rate to treatment and nearly double the duration of response.
Litespark-011 was the first trial to show that a combination of targeted therapy plus a HIF-2a improved outcomes for patients who progress after immunotherapy.
The presence of serious side effects was similar between treatment groups although the types of side effects differed consistent with the type of treatment used. In the lenvatinib plus belzutifan group, rates of anemia, proteinuria, vomiting, hypoxia, and cardiac dysfunction were higher while rates of diarrhea, hand-foot syndrome, stomatitis, and elevated liver enzymes were higher in the cabozantinib group.
While the statistically positive results of both trials indicate the potential for additional treatment options for some kidney cancer patients, experts continue to be mindful of the toxicities of these treatments, the cost, the need for additional therapy, and await additional data on survival.
