FDA Approves WELIREG Plus LENVIMA for Previously Treated Advanced Clear Cell Renal Cell Carcinoma
Merck, known as MSD outside the United States and Canada, and Eisai announced that the U.S. Food and Drug Administration (FDA) has approved WELIREG® (belzutifan) in combination with LENVIMA® (lenvatinib) for adults with advanced renal cell carcinoma (RCC) with a clear cell component (ccRCC) following treatment with a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.
The FDA approval, dated September 24, 2026, is based on results from the Phase 3 LITESPARK-011 trial, which evaluated the dual oral regimen against cabozantinib in patients with previously treated advanced ccRCC. (U.S. Food and Drug Administration)
The decision expands the treatment options available for patients whose advanced kidney cancer has progressed following an anti-PD-1 or PD-L1 therapy. WELIREG is an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor developed by Merck, while LENVIMA is an orally available multiple receptor tyrosine kinase inhibitor (TKI) discovered by Eisai.
According to the companies, WELIREG plus LENVIMA represents the first approved combination of a HIF-2α inhibitor and a multi-targeted vascular endothelial growth factor receptor (VEGFR)-TKI for this patient population. (Eisai)
Phase 3 Trial Demonstrated Progression-Free Survival Benefit
The approval was supported by a pre-specified interim analysis from LITESPARK-011, a randomized, open-label Phase 3 study involving 747 patients with advanced ccRCC.
Patients were randomized to receive either WELIREG at 120 mg once daily in combination with LENVIMA at 20 mg once daily, or cabozantinib at 60 mg once daily. Eligible patients had locally advanced or metastatic ccRCC that had progressed on or after a PD-1 or PD-L1 inhibitor, or progressed within six months of completing adjuvant therapy with a PD-1 inhibitor. (U.S. Food and Drug Administration)
Progression-free survival (PFS), one of the study’s dual primary endpoints, was significantly improved with the WELIREG-LENVIMA combination.
At the interim analysis, treatment with WELIREG plus LENVIMA reduced the risk of disease progression or death by 26% compared with cabozantinib. The hazard ratio was 0.74, with a 95% confidence interval of 0.61 to 0.89 and a p-value of 0.001.
Median PFS was 14.6 months for patients receiving WELIREG plus LENVIMA, compared with 10.6 months for those treated with cabozantinib.
The findings build on earlier results from LITESPARK-011. In February 2026, Merck and Eisai reported a 30% reduction in the risk of disease progression or death at an earlier interim analysis, with median PFS of 14.8 months versus 10.7 months for cabozantinib. The companies subsequently continued follow-up, leading to the regulatory review and September approval. (Eisai)
Objective Response Rate Also Improved
The combination also produced a statistically significant improvement in objective response rate (ORR), a key secondary endpoint of the study.
The ORR was 53% among patients treated with WELIREG plus LENVIMA, compared with 40% among those receiving cabozantinib. The difference was statistically significant, with a p-value of 0.0002.
The companies also reported duration-of-response data as part of the LITESPARK-011 results. However, at the final analysis, overall survival (OS), the study’s other primary endpoint, did not meet the threshold for statistical significance for WELIREG plus LENVIMA compared with cabozantinib.
The LITESPARK-011 results are scheduled to be presented at the upcoming European Society for Medical Oncology (ESMO) Congress 2026 in Madrid, Spain.
The FDA’s review specifically identified PFS and ORR as important efficacy findings supporting the approval. The agency described LITESPARK-011 as an open-label, randomized, active-controlled trial in 747 patients with advanced ccRCC. (U.S. Food and Drug Administration)
New Treatment Option After PD-1 or PD-L1 Therapy
Advanced ccRCC is commonly treated using combinations involving immunotherapy and targeted therapies. However, disease progression following PD-1 or PD-L1 therapy can create a need for additional treatment approaches.
Dr. Robert Motzer, Principal Investigator and Genitourinary Medical Oncologist at Memorial Sloan Kettering Cancer Center, said the approval provides another treatment option for patients whose disease progresses after anti-PD-1/PD-L1 therapy.
“While there has been much progress in the first-line treatment of advanced kidney cancer, we have limited options to offer patients if the disease progresses after treatment with a PD-1/PD-L1 immunotherapy,” Motzer said.
He added that the approval of belzutifan plus lenvatinib represents an important development for patients and physicians managing advanced kidney cancer.
The two drugs act through different biological pathways. Belzutifan inhibits HIF-2α, a transcription factor involved in cellular responses to low oxygen and the biology of clear cell RCC. Lenvatinib inhibits multiple receptor tyrosine kinases involved in tumor growth and angiogenesis.
The combination therefore brings together HIF-2α inhibition with multi-targeted kinase inhibition.
Dr. M. Catherine Pietanza, Vice President of Global Clinical Development at Merck Research Laboratories, said the approval reflects the development of a treatment strategy that combines therapies targeting different pathways.
“By bringing together two therapies that each target different pathways, WELIREG plus LENVIMA is now the first approved regimen of its kind,” Pietanza said.
LITESPARK-011 Study Design
LITESPARK-011, registered as NCT04586231, enrolled patients with locally advanced or metastatic ccRCC whose disease had progressed following PD-1 or PD-L1 treatment or within six months of completing adjuvant PD-1 inhibitor therapy.
The trial excluded patients with hypoxia, active central nervous system metastases and clinically significant cardiac disease within six months before the first dose of study treatment.
Participants were randomized to the WELIREG-LENVIMA combination or cabozantinib. The primary efficacy endpoints were PFS, assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and OS. ORR assessed by blinded independent central review was among the additional efficacy endpoints.
The median duration of exposure to WELIREG was 15.8 months, with exposure ranging from one day to 50.6 months. For LENVIMA, median exposure was 14.5 months, also ranging from one day to 50.6 months.
These exposure data provide context for the safety profile observed during the study and the frequency with which dose interruptions, reductions and discontinuations were required.
Safety Findings With WELIREG and LENVIMA
The combination’s safety profile is an important component of the newly approved treatment.
Serious adverse reactions occurred in 54% of patients treated with WELIREG plus LENVIMA. Serious adverse reactions occurring in at least 2% of patients included hypoxia, pneumonia, hyponatremia, acute kidney injury, hemorrhage, anemia, cardiac failure and diarrhea.
Hypoxia occurred as a serious adverse reaction in 6% of patients, while pneumonia occurred in 5%. Hyponatremia was reported in 3.2%, acute kidney injury in 3%, hemorrhage in 2.7%, anemia in 2.7%, cardiac failure in 2.4% and diarrhea in 2.4%.
Fatal adverse reactions occurred in 5% of patients receiving the combination. Reported fatal events included sepsis, pneumonia, pneumonitis and respiratory failure, as well as individual cases of acute cholecystitis, acute respiratory distress syndrome, pulmonary edema, embolic cerebral infarction, hemorrhage, postoperative wound complication, thrombotic microangiopathy and upper respiratory tract infection.
The prescribing information also carries important warnings for WELIREG. The drug can cause embryo-fetal harm, severe anemia and severe hypoxia. Pregnancy status should be verified before treatment, and patients should be advised regarding effective non-hormonal contraception because WELIREG can make some hormonal contraceptives ineffective.
WELIREG can also cause serious oxygenation problems requiring treatment interruption, supplemental oxygen or hospitalization. Oxygen saturation should be monitored before treatment and periodically during therapy.
When WELIREG is combined with LENVIMA, serious cardiac dysfunction, including heart failure with reduced left ventricular ejection fraction and cardiomyopathy, can occur. The safety of the combination has not been established in patients with LVEF below 50%.
Dose Modifications Were Common
Treatment modifications were frequently required during the trial.
Permanent discontinuation of WELIREG because of an adverse reaction occurred in 17% of patients, while permanent discontinuation of LENVIMA occurred in 23%.
Dose interruptions occurred in 69% of patients for WELIREG and 72% for LENVIMA. Dose reductions were reported in 35% of patients receiving WELIREG and 67% of those receiving LENVIMA.
For WELIREG, common adverse reactions resulting in dose reductions included fatigue, hypoxia, anemia and diarrhea. For LENVIMA, dose reductions were frequently associated with fatigue, diarrhea, hypertension, proteinuria, decreased appetite, nausea, rash and vomiting.
The most common adverse reactions and laboratory abnormalities occurring in at least 25% of patients receiving the combination included decreased hemoglobin, fatigue, increased AST, hypertension, increased ALT, musculoskeletal pain, diarrhea, decreased lymphocytes, decreased sodium, increased creatinine, nausea, hypothyroidism, decreased appetite, decreased platelets, increased potassium, increased lipase, proteinuria, decreased magnesium, decreased calcium, increased activated partial thromboplastin time, rash, vomiting, decreased weight, constipation, abdominal pain and stomatitis.
Other clinically relevant adverse reactions occurring in fewer than 15% of patients included COVID-19, dysphonia, dysgeusia, urinary tract infection, pruritus, pyrexia and arrhythmia.
Existing RCC Indications for Both Medicines
The FDA decision adds another RCC use for both WELIREG and LENVIMA.
In the United States, LENVIMA is already approved in combination with pembrolizumab for the first-line treatment of adults with advanced RCC. It is also approved with everolimus for adults with advanced RCC following one prior anti-angiogenic therapy.
LENVIMA is approved as KISPLYX for advanced RCC in the European Union.
WELIREG was previously approved in the United States as monotherapy for adults with advanced ccRCC following treatment with a PD-1 or PD-L1 inhibitor and a VEGF-TKI. In June 2026, the FDA also approved WELIREG in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph for adjuvant treatment of adults with ccRCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. (U.S. Food and Drug Administration)
The new approval therefore adds a combination regimen for patients who have previously received PD-1 or PD-L1 therapy.
Continuing Development in Renal Cell Carcinoma
The approval expands Merck’s and Eisai’s collaboration in RCC and adds another treatment strategy to the companies’ LITESPARK clinical development program.
Dr. Corina Dutcus, Senior Vice President and Oncology Global Clinical Development Lead at Eisai, said the approval builds on the company’s experience with LENVIMA-based combinations across different stages of advanced RCC.
The regulatory decision also follows a broader period of development for WELIREG in renal cell carcinoma. Earlier studies have evaluated belzutifan both as monotherapy and in combination with other anticancer agents. FDA previously approved belzutifan for advanced RCC following PD-1/PD-L1 inhibitor and VEGF-TKI treatment based on LITESPARK-005. (U.S. Food and Drug Administration)
For patients with advanced ccRCC whose disease has progressed after PD-1 or PD-L1 treatment, the September 2026 FDA approval establishes WELIREG plus LENVIMA as an additional treatment option. The LITESPARK-011 results provide the clinical basis for the approval, with the combination demonstrating longer PFS and a higher ORR than cabozantinib, while the final OS analysis did not demonstrate a statistically significant difference.
The combination’s safety profile and the need for monitoring, dose modification and potential treatment interruption remain important considerations as the regimen enters clinical use. Further presentation of LITESPARK-011 data at ESMO Congress 2026 is expected to provide additional information about the study and its results.
About renal cell carcinoma
Renal cell carcinoma is the most common type of kidney cancer, with about nine out of 10 kidney cancer diagnoses being RCC. In 2024, there were an estimated 442,570 new cases of kidney cancer and 144,871 deaths from the disease worldwide. Renal cell carcinoma is about twice as common in men as in women. Cases of RCC might be discovered incidentally during imaging tests for other reasons. Approximately 32% of patients with kidney cancer are diagnosed at a regional or metastatic stage. Clear cell renal cell carcinoma, which accounts for about 70% of RCC diagnoses, is the most common subtype.
About Merck’s research in genitourinary cancers
Merck is advancing research aimed at helping transform the treatment landscape and broaden options for people with genitourinary (GU) cancers, including bladder, kidney and prostate cancers. Globally, GU cancers account for an estimated 2.6 million new cancer diagnoses each year, equaling over 1 in 8 of all cancer incidences. Through a robust clinical development program with more than 50 ongoing clinical trials evaluating more than 22,000 patients around the world, Merck is investigating the potential of several portfolio medicines and pipeline assets, leveraging multiple novel combination strategies, across various stages of disease, to help address unmet needs in GU cancers.
About WELIREG® (belzutifan) 40 mg tablets, for oral use
WELIREG, Merck’s first-in-class hypoxia-inducible factor 2 alpha (HIF-2α) inhibitor, is an orally administered small-molecule that in conditions of hypoxia or impairment of VHL protein function, blocks HIF-2alpha and HIF-1beta interaction, which may reduce the transcription and expression of HIF-2α target genes associated with cellular proliferation, angiogenesis and tumor growth. By inhibiting HIF-2α signaling, WELIREG may disrupt key pathways certain tumors may use to adapt to low-oxygen conditions, including those that help promote abnormal blood vessel formation and support tumor survival.
WELIREG has received prior regulatory approvals in certain patients with advanced renal cell carcinoma with a clear cell component (ccRCC) and adjuvant ccRCC in combination with KEYTRUDA, von Hippel-Lindau (VHL) disease-associated tumors and pheochromocytoma or paraganglioma (PPGL). As part of a broader clinical program, Merck continues to research WELIREG for people with RCC and selected solid tumors across different treatment settings, to further understand where WELIREG may provide clinical benefit.