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Opinion granted based on positive progression-free survival results from the Phase 3 LITESPARK-011 trial If approved, this regimen will be the first and only approved combination of a HIF-2α inhibitor and a multi-targeted VEGFR-TKI in the European Union RAHWAY, N.J.--(BUSINESS WIRE)-- $MRK #MRK --Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending approval of WELIREG ® (belzutifan), Merck’s first-in-class oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, plus 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. This recommendation will now be reviewed by the European Commission (EC) for marketing authorization in the European Union (EU), Iceland, Liechtenstein and Norway. A final decision is expected in the next two months. “Patients with advanced renal cell carcinoma in the European Union have limited treatment options if their disease progresses following anti-PD-1 or anti-PD-L1 therapy,” said Dr. Christina Derleth, vice president, global oncology clinical development, Merck Research Laboratories. “This positive opinion is a meaningful step toward potentially bringing this first-of-its-kind regimen to patients in need in the European Union and underscores the important role of WELIREG plus lenvatinib as a new option in the treatment of renal cell carcinoma.” The recommendation is based on results from the Phase 3 LITESPARK-011 trial. In the study, WELIREG in combination with lenvatinib demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS), one of the study’s dual primary endpoints, 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 whose disease progressed on or after treatment with a PD-1 or PD-L1 inhibitor compared to cabozantinib. Initial results for the trial were presented at the 2026 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium. At the final analysis, overall survival (OS), the study’s other dual primary endpoint, did not meet statistical significance for patients who received WELIREG in combination with lenvatinib compared to cabozantinib. WELIREG in combination with lenvatinib reduced the risk of death by 15% (HR=0.85 [95% CI, 0.70-1.03]) in these patients compared to cabozantinib. Additionally, at the final analysis, the combination showed a continued benefit in objective response rate (ORR), a key secondary endpoint, of 53.1% for WELIREG plus lenvatinib versus 40.2% for cabozantinib. Similarly, WELIREG in combination with lenvatinib improved duration of response (DOR), another secondary endpoint, compared to cabozantinib, with a median DOR of 22.0 months versus 11.9 months, respectively. These results were presented at the European Society for Medical Oncology (ESMO) Congress 2026. In September 2026 , WELIREG in combination with LENVIMA ® (lenvatinib) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with advanced ccRCC following a PD-1 or PD-L1 inhibitor, based on results from the Phase 3 LITESPARK-011 trial. About 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 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. Objective response rate per RECIST v1.1 as assessed by BICR, DOR per RECIST v1.1 as assessed by BICR and safety were additional endpoints. 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 regulatory approvals in certain patients with advanced renal cell carcinoma with a clear cell component (ccRCC) and adjuvant ccRCC in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, 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 in the U.S. von Hippel-Lindau 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 WELIREG, in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, is indicated for the adjuvant treatment of adult patients with renal cell carcinoma with a clear cell component (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 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 erythropoiesis-stimulating agents (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% received transfusions only, 22% received erythropoiesis-stimulating agents (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 with WELIREG. For decreased oxygen saturation with exercise (e.g., pulse oximeter 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 3.3% of patients for dizziness and opioid overdose (1.6% each). Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness. Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%). The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%). Adverse Reactions in LITESPARK-022 (Adjuvant ccRCC) Serious adverse reactions occurred in 30% of patients receiving WELIREG in combination with KEYTRUDA. The most frequently reported serious adverse reactions (≥1%) were pneumonia (2%), hypoxia (1.9%), pneumonitis (1.6%), arrhythmia (1.5%), diarrhea (1.1%), and acute kidney injury (1.1%). Fatal adverse reactions occurred in 1.1% of patients who received WELIREG in combination with KEYTRUDA, including sepsis (0.1%). WELIREG was permanently discontinued due to adverse reactions in 27% of patients. Adverse reactions which resulted in permanent discontinuation of WELIREG in ≥1% of patients included anemia (4%), fatigue (2.2%), rash (2%), increased alanine aminotransferase (ALT) (1.7%), hypoxia (1.6%), diarrhea (1.4%), pneumonitis (1.3%), increased aspartate aminotransferase (AST) (1.1%), and hepatic function abnormal (1%). Dosage interruptions of WELIREG due to an adverse reaction occurred in 52% of patients. Of the patients who received WELIREG in combination with KEYTRUDA, 30% were ≥65 years old and 5% were ≥75 years old. Dose interruptions of WELIREG occurred in 57% of patients ≥65 years of age and in 49% of younger patients. Adverse reactions which required dosage interruption of WELIREG in ≥2% of patients included anemia (25%), fatigue (3.7%), increased ALT (3.5%), diarrhea (3.4%), increased AST (3.4%), COVID-19 (2.6%), hypoxia (2.5%), pyrexia (2.5%), musculoskeletal pain (2.1%), and rash (2.1%). Dose reductions of WELIREG due to an adverse reaction occurred in 34% of patients. Dose reductions of WELIREG occurred in 39% of patients ≥65 years of age and in 32% of younger patients. Adverse reactions which required dose reduction in ≥3% of patients included anemia (17%), hypoxia (3.5%), increased ALT (3.2%), and fatigue (3.1%). The most common (≥25%) adverse reactions, including laboratory abnormalities, in patients who received WELIREG in combination with KEYTRUDA were decreased hemoglobin (95%), increased ALT (57%), fatigue (49%), increased AST (46%), decreased lymphocytes (38%), and increased alkaline phosphatase (29%). Adverse Reactions in LITESPARK-011 (Advanced ccRCC) Serious adverse reactions occurred in 54% of patients who received WELIREG in combination with LENVIMA. Serious adverse reactions in ≥2% of patients included hypoxia (6%), pneumonia (5.0%), 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%). 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%). Dose reductions of WELIREG due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dose reductions in >2% of patients included fatigue (7%), hypoxia (7%), anemia (6%), diarrhea (3%), and dyspnea (2.4%). 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. Adverse Reactions in LITESPARK-005 (Advanced ccRCC) Serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions (≥2%) were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%). WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%), anemia (0.5%), and hemorrhage (0.5%). Dosage interruptions due to an adverse reaction occurred in 39% of patients. Of the patients who received WELIREG, 28% were 65 to 74 years, and 10% were 75 years and over. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%). Dose reductions due to an adverse reaction occurred in 13% of patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. The most frequently reported adverse reactions which required dose reduction (≥1%) were hypoxia (5%) and anemia (3.2%). The most common adverse reactions (≥25%), including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (34%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%). Adverse Reactions in LITESPARK-015 (PPGL) Serious adverse reactions occurred in 36% of patients. The most frequently reported serious adverse reactions (≥2%) were anemia and hypertension (4.2% each) and pyelonephritis, pneumonia, hypoxia, dyspnea and hemorrhage (2.8% each). WELIREG was permanently discontinued due to adverse reactions in 2 patients (2.8%). Adverse reactions which resulted in permanent discontinuation were increased alanine aminotransferase and paraparesis (1.4% each). Dosage interruptions due to an adverse reaction occurred in 40% of patients. Of the patients who received WELIREG, 13% were ≥65 years old and 4.2% were ≥75 years. Adverse reactions which required dosage interruption in >3% of patients were hypoxia, nausea, and fatigue (4.2% each). Dose reductions due to an adverse reaction occurred in 14% of patients. The most frequently reported adverse reaction which required dose reduction was hypoxia (4.2%). The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients were anemia (96%), fatigue (56%), musculoskeletal pain (56%), decreased lymphocytes (54%), increased alanine aminotransferase (51%), increased aspartate aminotransferase (42%), increased calcium (34%), dyspnea (33%), increased potassium (31%), decreased leukocytes (30%), headache (29%), increased alkaline phosphatase (25%), dizziness (26%) and nausea (25%). Contacts Media Contacts: Julie Cunningham julie.cunningham@merck.com AJ Seymour andrew.seymour@merck.com Investor Contacts: Peter Dannenbaum (732) 594-1579 Steven Graziano (732) 594-1583 Read full story here