Results from the LITESPARK-011 clinical trial show that a two-pronged approach to stopping blood vessel growth is an effective way to treat people with advanced clear cell renal cell carcinoma (ccRCC) that has returned after immunotherapy treatment.

The combination of belzutifan and lenvatinib help control advanced ccRCC better than a commonly used treatment called cabozantinib. The research was presented at the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, which took place February 26 to 28 in San Francisco.

“There is no clear standard of care for patients with advanced kidney cancer after they’ve tried immune checkpoint inhibitor-based immunotherapy. Recent trials aimed at improving outcomes in these patients have not been successful.

This is the first trial to show that a new combination treatment program worked better than the current therapy in this patient population,” said lead study author Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center.

Cabozantinib and lenvatinib are vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) that block tumour blood vessel growth. Belzutifan is a new targeted therapy that prevents the growth of blood vessels in a different way than VEGFR TKIs. Belzutifan blocks a protein called hypoxia-inducible factor 2 alpha (HIF-2 alpha) and is promising because most ccRCC tumours have a genetic change that turns on the HIF-2 alpha protein.

The drug attaches to the HIF-2 alpha protein and stops it from working. This blocks the growth of blood vessels and keeps the tumor cells from growing and spreading.

The phase 3 LITESPARK-011 study included 747 adults with advanced ccRCC who had previously been treated with immunotherapy. They were divided into 2 groups:

1. 371 received belzutifan and lenvatinib (combination group).
2. 376 received cabozantinib (control group).

After a median follow-up of about 29 months, the study results showed that:

• The cancer shrank or disappeared in about 53% of people who took belzutifan and lenvatinib, compared to about 40% of those who took cabozantinib.
• For people with cancer that responded to treatment, the belzutifan and lenvatinib combination kept the disease under control for a median of 23 months compared to about 12 months with cabozantinib.
• People taking belzutifan and lenvatinib went a median of about 15 months before the cancer showed signs of growth, compared to about 11 months in people who took cabozantinib.
• While the combination treatment kept the cancer stable longer, there isn’t yet enough data to know if it helps patients live longer overall.
• Side effects occurred in about 8 in 10 people in both groups.
• A reduction in red blood cells (anaemia), diarrhoea, and high blood pressure (hypertension) were the most common side effects in the group that received belzutifan and lenvatinib.
• Diarrhoea and a skin condition called hand-foot syndrome commonly occurred with cabozantinib treatment.
• There were 2 treatment-related deaths in the combination group and 1 in the control group.

"This phase 3 data shows that a combination approach—specifically belzutifan and lenvatinib—may have selected benefits versus traditional monotherapy with cabozantinib. Importantly, the safety profile shows a trade-off in specific adverse events. However, the prolonged delay in cancer growth in patients with advanced clear cell renal cell carcinoma that recurred despite previous immunotherapy treatment support this combination as a potential new option for care," said Sumanta Kumar Pal, MD, FASCO, an ASCO Expert in kidney cancer and Co-director of the Kidney Cancer Program at City of Hope.

Researchers will continue to collect data to see how long the cancer is controlled in both groups and to determine if people who got belzutifan and lenvatinib live longer than those who got the control therapy.

Investigators are planning future studies to see if other combinations of medicines that block VEGFR TKIs and hypoxia inducible factors (HIFs) are even more successful.

The LITESPARK-011 trial was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc.

Source: ASCO