Patients with advanced kidney cancer that no longer responds to immunotherapy have a new option for treatment — a drug combination now approved by the U.S. Food and Drug Administration (FDA).
The drug belzutifan (Welireg®) was approved in combination with lenvatinib (Lenvima®) for patients with a type of kidney cancer called clear cell renal cell carcinoma (ccRCC). This is the most common type of kidney cancer in adults, accounting for about 80% of cases.
The approval, announced on September 24, 2026, was based on a clinical trial led by genitourinary medical oncologist Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center (MSK). Findings from that international phase 3 trial, called LITESPARK-011, were published in The Lancet on August 12, 2026.
“When a patient’s cancer stops responding to immunotherapy, it’s a really difficult time,” Dr. Motzer says. “We’ve had limited options to offer in that situation. Anytime there is a new treatment approved, it’s exciting news.”
What did the phase 3 trial of belzutifan and lenvatinib find?
The trial compared the belzutifan-lenvatinib combination with another drug, called cabozantinib (Cabometyz®), which is one of the current standard treatments for patients with advanced kidney cancer. All three drugs are taken as pills.
- The trial enrolled 747 patients from multiple countries.
- All the patients had advanced kidney cancer that had continued to grow after receiving immunotherapy drugs called checkpoint inhibitors.
- Patients received either the belzutifan-lenvatinib combination or cabozantinib.
- Patients on the combination therapy lived on average more than seven months longer than those on the standard treatment — 34.9 months versus 27.6 months.
- On average they also lived about four months longer without their cancer progressing — 14.8 months versus 10.7 months.
- The responses lasted about twice as long with the combination as they did with cabozantinib.
How does the combination of belzutifan and lenvatinib work in renal cell carcinoma?
In ccRCC, a protein called HIF-2α acts like a stuck “on” switch — driving tumor growth and triggering the formation of new blood vessels that feed the tumor.
Belzutifan blocks HIF-2α, turning off tumor growth while also blocking the signals driving blood vessel growth.
Lenvatinib blocks other proteins in blood vessels to further prevent new growth.
This dual approach targets the same pathway from two sides simultaneously, creating a more complete blockade.
Similarly, cabozantinib also targets blood vessel growth, but in a different way. These types of drugs, known as angiogenesis inhibitors, are commonly used in kidney cancers because kidney tumors are known to be highly dependent on new blood vessel formation for their growth.
What are the side effects of belzutifan + lenvatinib?
Nearly every patient in the trial — 99% — experienced side effects.
- Anemia (low red blood cell counts) was most frequent.
- The most common serious side effect was high blood pressure, which affected about one-third of patients.
- These are both well-known side effects of drugs that target blood vessels.
- Other side effects included fatigue and gastrointestinal problems like nausea and diarrhea.
“We want patients to go into this treatment with the understanding that it can have serious side effects,” Dr. Motzer says. “That’s the reality of treating advanced cancer with these kinds of powerful drugs. Fortunately, at MSK we have a team of specialists who are experienced in supporting patients through these challenges.”
A full list of side effects for belzutifan is available here.
A full list of side effects for lenvatinib is available here.
Evolving treatment for clear cell kidney cancer
Belzutifan had previously been approved to treat ccRCC in combination with pembrolizumab (Keytruda®), a type of immunotherapy. It was originally developed to treat patients with von Hippel-Lindau (VHL) syndrome, an inherited genetic disorder associated with several types of cancer, including kidney cancer.
Lenvatinib also was already approved to treat RCC — in combination with different drugs.
“Every new option we can offer to patients with advanced cancer matters enormously to them and their families,” Dr. Motzer says. “For many of them, this combination could make a meaningful difference.”
Funding and disclosures
Merck Sharp & Dohme, a subsidiary of Merck & Co., provided funding for the Lancet study, and study authors included Merck employees. Dr. Motzer reported receiving funding from Merck Sharp & Dohme and AstraZeneca, and relationships with Exelixis, EMD Serono, Eisai, Incyte, Bristol Myers Squibb, Pfizer, Janssen, Astellas, Novartis, and Bayer.
Dr. Motzer holds the Jack and Dorothy Byrne Chair in Clinical Oncology.
Key Takeaways
- The FDA has approved the combination of belzutifan and lenvatinib for patients with advanced clear cell renal cell carcinoma, the most common form of kidney cancer, when it has stopped responding to immunotherapy.
- Patients taking the new drug combination lived more than seven months longer than those on the current standard treatment, cabozantinib, according to a phase 3 clinical trial.
- The combination therapy attacks tumor growth in two ways simultaneously. Belzutifan blocks a protein that drives tumor growth, and lenvatinib blocks blood vessel formation that feeds the tumor.
- Nearly all patients experienced side effects. Anemia was the most common, and high blood pressure affected about one-third of patients.