Approval based on results from the Phase 3 LITESPARK-011 trial evaluating WELIREG in combination with LENVIMA compared to cabozantinib for the treatment of patients with advanced ccRCC following treatment with a PD-1/PD-L1 inhibitor
WELIREG plus LENVIMA is the first approved combination of a HIF-2 alpha inhibitor and a multi-targeted VEGFR-TKI for these patients
RAHWAY, N.J. & NUTLEY, N.J.--(BUSINESS WIRE)--$MRK #MRK--Merck (NYSE: MRK), known as MSD outside of the United States and Canada, and Eisai today announced the U.S. Food and Drug Administration (FDA) has approved the dual oral regimen of WELIREG® (belzutifan), Merck’s first-in-class oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, plus LENVIMA® (lenvatinib), the orally available multiple receptor tyrosine kinase inhibitor (TKI) discovered by Eisai, for the treatment of adult patients with advanced renal cell carcinoma with a clear cell component (ccRCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.
The approval is based on data from the Phase 3 LITESPARK-011 trial. Results from a pre-specified interim analysis showed treatment with WELIREG plus LENVIMA led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS), one of the dual primary endpoints, compared to cabozantinib, reducing the risk of disease progression or death by 26% (HR=0.74 [95% CI, 0.61-0.89]; p=0.001) in patients with advanced ccRCC following a PD-1 or PD-L1 inhibitor. WELIREG plus LENVIMA resulted in a median PFS of 14.6 months (95% CI, 11.1-16.6) versus 10.6 months (95% CI, 9.2-11.1) with cabozantinib. WELIREG plus LENVIMA also demonstrated a statistically significant improvement in objective response rate (ORR), a key secondary endpoint, with an ORR of 53% (95% CI, 47-58) versus 40% (95% CI, 35-45) for cabozantinib (p=0.0002). Data for duration of response (DOR), another secondary endpoint, were also reported. At the final analysis, overall survival (OS), the study’s other primary endpoint, did not meet statistical significance for patients who received WELIREG plus LENVIMA versus cabozantinib. These results will be presented at the upcoming European Society for Medical Oncology (ESMO) Congress 2026 in Madrid, Spain.
The WELIREG prescribing information contains a boxed warning that exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception. WELIREG can render some hormonal contraceptives ineffective. WELIREG can cause severe anemia that can require a blood transfusion. Monitor for anemia before initiation of and periodically throughout treatment with WELIREG. WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen or hospitalization. Monitor oxygen saturation before initiation of and periodically throughout treatment with WELIREG. Serious cardiac dysfunction, including heart failure with reduced left ventricular ejection fraction (LVEF), and cardiomyopathy, can occur with WELIREG in combination with LENVIMA. The safety of WELIREG in combination with LENVIMA has not been established in patients with LVEF below 50%. Monitor patients for symptoms or signs of heart failure and if present, reassess LVEF. Withhold and resume at a reduced dose upon recovery to baseline or Grade 1 or permanently discontinue WELIREG in combination with LENVIMA based on severity. For more information, see “Selected Safety Information” below.
Adverse reactions, some of which can be serious or fatal, may occur with LENVIMA, including hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QTc interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, impaired wound healing, osteonecrosis of the jaw and embryo-fetal toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception, and based on the severity of the adverse reaction, LENVIMA should be interrupted, reduced and/or discontinued. For more information, see “Selected Safety Information” below.
“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,” said Dr. Robert Motzer, Principal Investigator and Genitourinary Medical Oncologist, Memorial Sloan Kettering Cancer Center. “With this FDA approval of belzutifan plus lenvatinib, we have a new treatment option for patients who progress following treatment with anti-PD-1/PD-L1 therapy – an important development for patients and the physicians who care for them.”
“By bringing together two therapies that each target different pathways, WELIREG plus LENVIMA is now the first approved regimen of its kind, offering a new treatment option for certain patients with advanced renal cell carcinoma who have progressed after anti-PD-1/PD-L1 therapy,” said Dr. M. Catherine Pietanza, Vice President, Global Clinical Development, Merck Research Laboratories. “This approval represents real progress for patients and further reinforces the importance of a HIF-2α inhibitor plus TKI combination as a new treatment approach for these patients.”
“Patients facing advanced renal cell carcinoma need treatment options at every stage of their journey, and the complexity of managing this disease over time makes every treatment decision meaningful,” said Dr. Corina Dutcus, Senior Vice President, Oncology Global Clinical Development Lead at Eisai. “Combination approaches with LENVIMA have shaped the treatment landscape for advanced RCC from frontline therapy through later lines, and this FDA approval builds on that legacy by introducing WELIREG plus LENVIMA – the first and only approved combination following a PD-1/PD-L1 inhibitor. At Eisai, our science is driven by the humanity of the patients we serve, and, alongside Merck, we are proud to continue advancing combination treatment options with LENVIMA for the kidney cancer community.”
LENVIMA is approved in the U.S., European Union (EU), Japan, and other regions in combination with multiple agents for the treatment of RCC. In the U.S., it is approved for the following indications:
- LENVIMA, in combination with KEYTRUDA® (pembrolizumab) or KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph), is approved for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
- LENVIMA, in combination with everolimus, is approved for the treatment of adult patients with advanced RCC following one prior anti-angiogenic therapy.
Lenvatinib is approved as KISPLYX for advanced RCC in the EU.
WELIREG is approved in the U.S., EU, Japan, and other regions as a monotherapy and in combination treatment options for the treatment of RCC. In the U.S., it is approved for the following indications:
- WELIREG, as monotherapy, is approved for the treatment of adult patients with advanced ccRCC following a PD-1 or PD-L1 inhibitor and a VEGF-TKI.
- WELIREG, in combination with KEYTRUDA or KEYTRUDA QLEX, is approved for the adjuvant treatment of adult patients with ccRCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
Dr. Motzer has provided consulting and advisory services for Merck and Eisai.
Study design and additional data from LITESPARK-011
LITESPARK-011 is a randomized, open-label Phase 3 trial (ClinicalTrials.gov, NCT04586231) evaluating WELIREG in combination with LENVIMA compared to cabozantinib for the treatment of patients with advanced ccRCC. Eligible patients include participants with locally advanced or metastatic ccRCC who have progressed on or after a PD-1 or PD-L1 inhibitor, or within 6 months of completing adjuvant therapy with a PD-1 inhibitor. The study excluded patients with hypoxia, active CNS metastases and clinically significant cardiac disease within 6 months before first dose of study intervention. The trial enrolled 747 patients who were randomized to receive WELIREG (120 mg orally once daily) plus LENVIMA (20 mg orally once daily) or cabozantinib (60 mg orally once daily). The major efficacy endpoints were PFS per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by blinded independent central review (BICR) and OS. Additional efficacy endpoints included ORR by BICR using RECIST v1.1.
The median duration of exposure to WELIREG was 15.8 months (range: 1 day to 50.6 months) and the median duration of exposure to LENVIMA was 14.5 months (range: 1 day to 50.6 months).
Serious adverse reactions occurred in 54% of patients treated with WELIREG in combination with LENVIMA. Serious adverse reactions in ≥2% of patients included hypoxia (6%), pneumonia (5%), hyponatremia (3.2%), acute kidney injury (3%), hemorrhage (2.7%), anemia (2.7%), cardiac failure (2.4%) and diarrhea (2.4%).
Fatal adverse reactions occurred in 5% of patients who received WELIREG in combination with LENVIMA, including sepsis (0.8%), pneumonia (0.5%), pneumonitis (0.5%), respiratory failure (0.5%) and one case (0.3%) each of acute cholecystitis, acute respiratory distress syndrome, pulmonary edema, embolic cerebral infarction, hemorrhage, postoperative wound complication, thrombotic microangiopathy and upper respiratory tract infection.
Permanent discontinuation of WELIREG due to an adverse reaction occurred in 17% of patients. Adverse reactions which resulted in permanent discontinuation of WELIREG in >0.5% of patients included hypoxia (2.2%), pneumonia (1.1%), fatigue (0.8%), hyponatremia (0.8%), pneumonitis (0.8%) and respiratory failure (0.8%).
Permanent discontinuation of LENVIMA due to an adverse reaction occurred in 23% of patients. Adverse reactions which resulted in permanent discontinuation of LENVIMA in >0.5% of patients included fatigue (1.6%), cardiac failure (1.1%), hyponatremia (1.1%), pneumonia (1.1%), decreased ejection fraction (0.8%), increased lipase (0.8%), pneumonitis (0.8%), proteinuria (0.8%) and rash (0.8%).
Dosage interruptions of WELIREG due to an adverse reaction occurred in 69% of patients. Adverse reactions which required dosage interruption in >3% of patients included fatigue (14%), diarrhea (12%), anemia (9%), vomiting (9%), hypertension (9%), nausea (8%), decreased appetite (5%), abdominal pain (4.6%), COVID-19 (4.6%), musculoskeletal pain (4.1%), pneumonia (3.5%), hypoxia (3.5%) and hemorrhage (3.5%).
Dosage interruptions of LENVIMA due to an adverse reaction occurred in 72% of patients. The most common adverse reactions resulting in dosage interruption of LENVIMA (>3%) were fatigue (15%), hypertension (14%), diarrhea (13%), nausea (10%), vomiting (10%), anemia (8%), proteinuria (7%), decreased appetite (6%), COVID-19 (5%), musculoskeletal pain (4.3%), abdominal pain (4.3%), rash (4.3%), pneumonia (3.5%), stomatitis (3.5%) and hemorrhage (3.2%).
Dose reductions of WELIREG due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dose reductions of WELIREG in >2% of patients included fatigue (7%), hypoxia (7%), anemia (6%), diarrhea (3%) and dyspnea (2.4%).
Dose reductions of LENVIMA due to an adverse reaction occurred in 67% of patients. Adverse reactions which required dose reductions of LENVIMA in >2% of patients included fatigue (20%), diarrhea (13%), hypertension (12%), proteinuria (9%), decreased appetite (8%), nausea (6%), rash (6%), vomiting (4.1%), anemia (3.5%), decreased weight (3.5%), abdominal pain (3%), increased alanine aminotransferase (ALT) (2.7%), stomatitis (2.7%), musculoskeletal pain (2.4%) and hypothyroidism (2.2%).
The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients who received WELIREG in combination with LENVIMA were 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.
Clinically relevant adverse reactions occurring in <15% of patients who received WELIREG in combination with LENVIMA included COVID-19 (14%), dysphonia (14%), dysgeusia (14%), urinary tract infection (14%), pruritus (12%), pyrexia (11%) and arrhythmia (9%).
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.
Indications for WELIREG (belzutifan) in the U.S.
von Hippel-Lindau (VHL) disease
WELIREG is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.
Renal Cell Carcinoma with a Clear Cell Component (ccRCC)
WELIREG, in combination with KEYTRUDA or KEYTRUDA QLEX, is indicated for the adjuvant treatment of adult patients with ccRCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
WELIREG, in combination with LENVIMA, is indicated for the treatment of adult patients with advanced ccRCC following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.
WELIREG, as monotherapy, is indicated for the treatment of adult patients with advanced ccRCC following a PD-1 or PD-L1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).
Pheochromocytoma or Paraganglioma (PPGL)
WELIREG is indicated for the treatment of adult and pediatric patients 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL).
Selected Safety Information for WELIREG
Warning: Embryo-Fetal Toxicity
Exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective.
Anemia
WELIREG can cause severe anemia that can require blood transfusion.
Monitor for anemia before initiation of, and periodically throughout, treatment with WELIREG. Transfuse patients as clinically indicated. Withhold, reduce dose, or permanently discontinue WELIREG based on severity.
In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months).
The safety of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established.
In LITESPARK-005, in patients receiving WELIREG for advanced ccRCC (n=372), decreased hemoglobin occurred in 88% of patients with advanced ccRCC and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received ESAs only, and 12% received both transfusion and ESAs.
In LITESPARK-022, in patients receiving WELIREG in combination with KEYTRUDA for adjuvant treatment for ccRCC (n=915), decreased hemoglobin occurred in 95% of patients and 11% had Grade 3 or higher events. Median time to onset of anemia was 42 days (range: 1 day to 11.1 months). Of the patients with anemia, 5% received transfusions only, 8% received ESAs only, and 1.3% received both transfusion and ESAs.
In LITESPARK-011, in patients receiving WELIREG in combination with LENVIMA for advanced ccRCC (n=370), decreased hemoglobin occurred in 87% of patients and 20% had Grade 3 events or required transfusion. Median time to onset of anemia was 56 days (range: 1 day to 33 months). Of the patients with anemia, 15% of patients received transfusions only, 22% received ESAs only, and 8% received both transfusion and ESAs.
In LITESPARK-015 (n=72), anemia occurred in 96% of patients with PPGL and 22% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 22.1 months). Of the patients with anemia, 20% received transfusions only, 26% received ESAs only, and 6% received both transfusion and ESAs.
Hypoxia
WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization.
Monitor oxygen saturation before initiation of, and periodically throughout, treatment. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a health care provider.
In LITESPARK-004, hypoxia occurred in 1.6% of patients with VHL disease.
In LITESPARK-005, in patients receiving WELIREG as monotherapy for advanced ccRCC, hypoxia occurred in 15% of patients and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months).
In LITESPARK-022, in patients receiving WELIREG in combination with KEYTRUDA for adjuvant treatment for ccRCC, hypoxia occurred in 7% of patients and 5% had Grade 3 or higher events. Of the patients with hypoxia, 47% were treated with oxygen therapy. Median time to onset of hypoxia was 93 days (range: 9 days to 11.7 months).
In LITESPARK-011, in patients receiving WELIREG in combination with LENVIMA for advanced ccRCC, hypoxia occurred in 16% of patients and 12% had Grade 3-4 events. Of the patients with hypoxia, 62% of patients were treated with oxygen therapy. Median time to onset was 63 days (range: 4 days to 25 months).
In LITESPARK-015, hypoxia occurred in 13% of patients with PPGL and 10% had Grade 3 hypoxia. Median time to onset of hypoxia was 35 days (range: 6 days to 23.9 months). Of the patients with hypoxia, 67% were treated with oxygen therapy.
Cardiac Dysfunction with Concomitant Use of WELIREG and LENVIMA
Serious cardiac dysfunction, including heart failure with reduced left ventricular ejection fraction (LVEF), and cardiomyopathy, can occur with WELIREG in combination with LENVIMA. The safety of WELIREG in combination with LENVIMA has not been established in patients with LVEF below 50%.
In patients treated with WELIREG in combination with LENVIMA in the LITESPARK-011 trial, Grade 3 or higher cardiac dysfunction adverse events occurred in 6% of patients. The median time to onset of Grade 3 or higher cardiac dysfunction was 26 weeks (range: 1 to 192 weeks). An absolute decrease in LVEF >20% with or without clinical symptoms occurred in 6% of patients. The median time to onset of LVEF decrease >20% was 29 weeks (range: 2 to 192 weeks).
Consider obtaining a baseline echocardiogram or Multigated Acquisition (MUGA) imaging. Monitor patients for symptoms or signs of heart failure and if present, reassess LVEF. Withhold and resume at a reduced dose upon recovery to baseline or Grade 1 or permanently discontinue WELIREG in combination with LENVIMA based on severity.
Embryo-Fetal Toxicity
Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman.
Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.
Adverse Reactions
Adverse Reactions in LITESPARK-004 (VHL disease)
Serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each).
WELIREG was permanently discontinued due to adverse reactions in 3.
Contacts
Media Contacts:
Merck:
Julie Cunningham
julie.cunningham@merck.com
John Infanti
john.infanti@merck.com
Eisai:
Marie Ronda
marie_ronda@eisai.com
Investor Contacts:
Merck:
Peter Dannenbaum
(732) 594-1579
Steven Graziano
(732) 594-1583
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