Welireg (belzutifan) / Merck (MSD) - LARVOL DELTA

Quality-adjusted time without symptoms/toxicity (Q-TWiST) analysis of belzutifan versus everolimus in previously treated advanced renal cell carcinoma (RCC): LITESPARK-005 (ESMO 2025) - No abstract available

Metastases • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Belzutifan Plus Lenvatinib For Chinese Participants (pts) With Previously Treated Advanced Clear Cell Renal Cell Carcinoma (ccRCC): Updated Results of Cohort 1 of the LITESPARK-010 Study (ESMO 2025) - No abstract available

Clinical • Metastases • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor

PMDA regulatory update on approval and revision of the precautions for use of anticancer drugs in Japan; nivolumab plus ipilimumab for hepatocellular carcinoma, fedratinib for myelofibrosis, talquetamab for multiple myeloma, and belzutifan for tumors associated with von Hippel-Lindau disease and renal cell carcinoma. (PubMed, Int J Clin Oncol) - No abstract available

Japanese regulatory • Journal • Genito-urinary Cancer • Hematological Malignancies • Hepatocellular Cancer • Multiple Myeloma • Myelofibrosis • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome

Belzutifan-Associated Hypoxia: A Review of the Novel Therapeutic, Proposed Mechanisms of Hypoxia, and Management Recommendations. (PubMed, Int J Mol Sci) - "As the cause of hypoxia is not well understood, this review also discusses possible mechanisms of hypoxia based on preclinical studies of the HIF pathway and HIF-2α inhibitors. Finally, this review proposes monitoring and management recommendations for clinicians prescribing belzutifan to ccRCC patients."

Journal • Review • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Hematological Disorders • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1

A Study of Belzutifan (MK-6482) and Metformin in Healthy Adult Participants (MK-6482-039) (clinicaltrials.gov) - P1 | N=14 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open

Belzutifan for Advanced Pancreatic Neuroendocrine Tumors (panNETs): Results From Cohort A2 of the Phase 2 LITESPARK-015 Study (ESMO 2025) - No abstract available

Metastases • P2 data • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor

Belzutifan demonstrates durable activity in VHL disease tumors. Vivek Narayan, MD, MS @PennMedicine joins @PBarataMD @caseccc to discuss five-year follow-up data on belzutifan for VHL disease-associated renal cell carcinoma. #WatchNow > http://bit.ly/46ryQLr

LITESPARK-015: Belzutifan in advanced pheochromocytoma and paraganglioma (ESMO 2025) - No abstract available

Metastases • Oncology • Solid Tumor

A Study of Belzutifan (MK-6482) and Metformin in Healthy Adult Participants (MK-6482-039) (clinicaltrials.gov) - P1 | N=14 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1 trial

Renal surgery following HIF-2α antagonist therapy: Surgical indications, outcomes and growth kinetics. (PubMed, Urol Oncol) - "Renal surgery after or during exposure to a HIF-2α antagonist is safe and feasible, with rates of both transfusions and complications commensurate with the reported literature from standard renal surgery. GRs of index renal tumors that eventually needed surgical intervention did not show a significant difference before, during, and after therapy. Tumors exhibiting a positive GR on drug may represent the indication that drives early surgical intervention prior to the tumor reaching the 3 cm threshold. A median washout time of 10 days from last dose of HIF-2α antagonist to surgery was safe and well tolerated."

Journal • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1

Impact of Belzutifan on Pancreatic Cystic Lesions and Neuroendocrine Tumors in Patients with Von Hippel-Lindau Disease. (PubMed, Clin Gastroenterol Hepatol) - No abstract available

Journal • Neuroendocrine Tumor • Oncology • Solid Tumor • Von Hippel-Lindau Syndrome

Successful Use of Targeted HIF-2α Inhibition in EPAS1-Mutated Congenital Erythrocytosis. (PubMed, Pediatr Blood Cancer) - "The therapy has been well tolerated, and her hemoglobin was restored to normal levels without the need for additional phlebotomy. Thus, belzutifan represents a novel strategy for addressing EPAS1-variant driven polycythemia."

Journal • Cardiovascular • Hematological Disorders • Hypertension • Ischemic stroke • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • EPAS1

Belzutifan for advanced clear cell renal cell carcinoma (ccRCC) after a PD-(L)1 inhibitor and ≥2 VEGFR-TKIs in LITESPARK-005 (ESMO 2025) - No abstract available

Metastases • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor

SREBP1 Induces Resistance to HIF-2α antagonist in Clear Cell Renal Cell Carcinoma (UAA 2025) - "In this study, we found the gene SREBP1, which is involved in inducing resistance to HIF-2α antagonists in ccRCC, and confirmed that co-administration of its inhibitors fatostatin and belzutifan has an anticancer effect. Establishment of belzutifan-resistant ccRCC cell lines and generation of xenograft model."

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Metabolic Disorders • Oncology • Solid Tumor • EPAS1

Welireg Plus Cabometyx Shows Tumor Control in Kidney Cancer Trial (Cure Today) - "'Treatment with Welireg showed meaningful clinical activity and disease control across doses,' wrote presenting study author, Dr. Toni K. Choueiri...said during the presentation."

Media quote

#KEYMAKER-U03 Trial: Combinatorial therapies for IO-refractory #KidneyCancer. @katy_beckermann @TNOncology joins @PBarataMD @caseccc discussing results that show pembrolizumab plus belzutifan achieved 20% objective response rate with 5.4 months PFS, similar to belzutifan monotherapy. #FullVideo on UroToday > http://bit.ly/4h8H50t

Clinical

Substudy 03C: A Study of Combination Therapies in Participants With Renal Cell Carcinoma With Recurrent Disease During or After Anti-PD-(L)1 Therapy (MK-3475-03C/KEYMAKER-U03) (clinicaltrials.gov) - P1/2 | N=100 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Determining the impact of HIF2a inhibition on T cell function in clear cell renal cell carcinoma (KCRS 2025) - "Belzutifan, a HIF2 a inhibitor, was recently approved as a treatment for refractory, sporadic advanced RCC, and is under investigation in combination with pembrolizumab in the adjuvant (LITESPARK-022) and first-line metastatic (LITESPARK-012) setting...For functional assays, T cells were treated with DMSO (vehicle), tacrolimus (control for effective inhibition of T cell function), or HIF2 a inhibitors (belzutifan or PT2399)...In the settings examined, HIF2 a inhibition did not impair T cell function, suggesting that combination with immune checkpoint inhibitors remains a viable therapeutic strategy pending results of ongoing clinical studies. Ongoing laboratory-based assessment will assess the impact of prolonged HIF2 a inhibition on T cell phenotype, evaluate its effects on direct cytotoxicity using antigen-specific RCC killing assays, and examine potential synergy with anti–PD-1 therapy."

IO biomarker • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD4 • CD8 • EPAS1 • IFNG • IL2 • TNFA

VHL and TP53 mutation status are not associated with response or progression-free survival in metastatic renal cell carcinoma treated with VEGF-targeted therapies (KCRS 2025) - "VEGF-targeted therapy was defined broadly to include newer generation vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs; excluding agents like sunitinib), belzutifan, and VEGF-TKI–based combinations with immunotherapy or everolimus...The most common VEGF-targeted therapies were cabozantinib, lenvatinib, axitinib, and tivozanib, frequently administered in combination with immunotherapy or everolimus...Conclusions In this ctDNA-based analysis of patients with mRCC treated with VEGF-targeted therapies, neither VHL nor TP53 mutation status was associated with meaningful differences in clinical outcomes. These findings align with prior reports and suggest that mutation status alone may not predict efficacy of VEGF-targeted regimens, even in the context of combination therapies."

IO biomarker • Metastases • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • TP53 • VEGFA • VHL

Quantification of Belzutifan in Biological Samples: LC-MS/MS Method Validation and Pharmacokinetic Study in Rats. (PubMed, Biomed Chromatogr) - "Belzutifan and apalutamide (IS) were quantified on a symmetry shield (150 × 4.6 mm, 3.5 μm) column using acetonitrile and buffer (30:70% v/v) as the mobile phase, with a run time of 7 min. The results indicate linearity between 5 and 100 ng/mL concentration with r2 = 0.9997, which proved to be accurate with % recovery between 95.0% and 97.98%, along with other essential metrics within the accepted limits. The pharmacokinetic study demonstrates that the established LC-MS/MS method accurately quantifies the drugs in rat plasma and might be useful for routine quantification of belzutifan in biological matrices."

Journal • PK/PD data • Preclinical • Oncology • Von Hippel-Lindau Syndrome

Development of small molecule inhibitors of hypoxia-inducible factors for cancer therapy. (PubMed, Pharmacol Rev) - "An HIF-2 inhibitor, belzutifan, has recently been approved for the treatment of renal cell carcinoma. Dual HIF-1/2 inhibitors are being developed and are likely to have utility as cancer therapeutics, particularly in combination with immune checkpoint blockade. SIGNIFICANCE STATEMENT: Hypoxia-inducible factor inhibitors represent a powerful new therapeutic approach that has the potential to improve patient survival in many types of cancer when administered in combination with existing therapies."

Journal • Review • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • HIF1A

Physiologically Based Pharmacokinetic Model to Assess the Drug-Drug-Gene Interaction Potential of Belzutifan in Combination With Cyclin-Dependent Kinase 4/6 Inhibitors. (PubMed, JCO Precis Oncol) - P1, P1/2 | "Our simulations predict that belzutifan decreases the exposure of combination therapies metabolized via CYP3A, with the severity of interaction dependent on CYP2C19 and UGT2B17 phenotypes."

Journal • PK/PD data • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • CYP2C19 • UGT2B17

Real-World Efficacy and Safety of Belzutifan in Sporadic Metastatic Renal Cell Carcinoma: A Multicenter Study from The City of Hope Enterprise (KCRS 2025) - "The safety profile remained consistent with previous reports. A key limitation of this study is that belzutifan was frequently initiated late in the disease course which may have limited observed efficacy."

Clinical • IO biomarker • Metastases • Real-world • Real-world effectiveness • Real-world evidence • Anemia • Fatigue • Genito-urinary Cancer • Oncology • Papillary Renal Cell Carcinoma • Pulmonary Disease • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Von Hippel-Lindau Syndrome • VHL

The Impact of Belzutifan on Tumor Reduction Procedures and Healthcare Resource Utilization in Von Hippel–Lindau (VHL) Disease (KCRS 2025) - "The increase in ultrasound utilization, along with a shift from IP to OP care, suggests a transition toward lower-intensity, surveillance-focused management following belzutifan initiation. These findings provide real-world evidence of belzutifan's impact on clinical management in patients with VHL."

HEOR • CNS Tumor • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Pain • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1

LASER – a Phase 2 trial of 177Lu-PSMA-617 as Systemic Therapy for Renal Cell Carcinoma (NCT06964958) (KCRS 2025) - P2 | "The study will employ a Simon's optimal two-stage design, with the aim of detecting an ORR of 25% (similar to ORR of belzutifan in the post-IO/TKI setting). Furthermore, the planned imaging, blood and tissue correlatives will provide unique scientific in-sights into the mechanisms of response and resistance to LuPSMA in RCC, and potentially lead to identification of other therapeutic targets and inform future clinical and translational research evaluating RPT in RCC. Trial Schem."

P2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • CA9 • FOLH1