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

A Study of Belzutifan (MK-6482) in Combination With Palbociclib Versus Belzutifan Monotherapy in Participants With Advanced Renal Cell Carcinoma (MK-6482-024/LITESPARK-024) (clinicaltrials.gov) - P1/2 | N=210 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting | Trial completion date: Sep 2028 ➔ Jul 2026 | Trial primary completion date: Sep 2028 ➔ Jul 2026

Enrollment closed • Monotherapy • Trial completion date • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

When is belzutifan the right option for von Hippel-Lindau disease-associated hemangioblastomas?-a critical review of LITESPARK-004 results. (PubMed, Transl Cancer Res) - No abstract available

Journal • Oncology • Von Hippel-Lindau Syndrome

Belzutifan's Role in Active Surveillance Versus Treatment for Indolentmetastatic Clear Cell Renal Ccell Carcinoma (BRAVE-RCC) (clinicaltrials.gov) - P2 | N=78 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

New P2 trial • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Leptomeningeal hemangioblastoma: illustrative case. (PubMed, J Neurosurg Case Lessons) - "After resection, hemangioblastoma recurrence with leptomeningeal spread is a rare but dangerous possible complication. Management is complex, yet a combination of pan-CNS radiation therapy, targeted resection, and belzutifan (a small-molecule inhibitor that selectively targets and blocks the function of HIF-2α) may represent an effective treatment combination. https://thejns.org/doi/10.3171/CASE25204."

Journal • Oncology • Von Hippel-Lindau Syndrome • EPAS1

Barriers and challenges for precision medicine and evidence-based oncology in genitourinary tumors in Latin America: insights from the LACOG 1024 survey CIELO. (ASCO 2025) - "Regarding access to therapies, 48.1% of the participants had access to adjuvant pembrolizumab for renal cell carcinoma, 42.7% to olaparib monotherapy for PC, 41.2% to enzalutamide for non-metastatic castration-sensitive PC, 38.2% to adjuvant nivolumab for urothelial carcinoma, and 31.3% to pembrolizumab for non-muscle invasive bladder cancer. Conversely, treatments such as first-line enfortumab vedotin with pembrolizumab (18.3%), erdafitinib (18.3%), Lu 177 vipivotide tetraxetan (9.9%), relugolix (6.9%), and belzutifan (1.5%) faced significant access barriers... To the best of our knowledge, this is the largest survey conducted on this topic to date in LATAM. The results underscore substantial barriers to the adoption of precision medicine, driven predominantly by limited insurance coverage and financial constraints. Enhancing access to advanced diagnostics and therapies is crucial for bringing regional practices in line with global standards and for improving patient..."

Bladder Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

A real-world pharmacovigilance study of belzutifan in renal cell carcinoma and von Hippel-Lindau disease: insights from the FDA adverse event reporting system database. (PubMed, Int J Clin Pharm) - "This study provided the first real-world pharmacovigilance assessment of belzutifan, confirming expected AEs while identifying emerging safety signals. Close monitoring of hematologic, respiratory, hepatic, and neurological toxicities is warranted. Further prospective studies are needed to optimize patient selection and improve AE management."

Adverse events • Journal • Real-world evidence • Endocrine Disorders • Genito-urinary Cancer • Hematological Disorders • Hepatology • Infectious Disease • Liver Failure • Oncology • Pneumonia • Renal Cell Carcinoma • Respiratory Diseases • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1

Design and Development of Hypoxia-Inducible Factor 2α Targeted PET Radiotracers for Kidney Cancer (SNMMI 2025) - "Targeting HIF2α has emerged as a promising therapeutic strategy for metastatic ccRCC as evidenced by the FDA’s approval of belzutifan in December 2023... Synthesis of the precursor to [11C]PT2385 and [18F]PT2385 follows a multistep organic synthesis with 17% and 11 % overall yields. Automated radiosynthesis of [11C]PT2385 and [18F]PT2385 gave ~ 60 mCi of the final product at the end of synthesis (EOS). The radiochemical purity of both [11C]PT2385 and [18F]PT2385 was > 99% as determined by radio-HPLC."

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

Design and Development of Hypoxia-Inducible Factor 2α Targeted PET Radiotracers for Kidney Cancer (SNMMI 2025) - "Targeting HIF2α has emerged as a promising therapeutic strategy for metastatic ccRCC as evidenced by the FDA’s approval of belzutifan in December 2023... Synthesis of the precursor to [11C]PT2385 and [18F]PT2385 follows a multistep organic synthesis with 17% and 11 % overall yields. Automated radiosynthesis of [11C]PT2385 and [18F]PT2385 gave ~ 60 mCi of the final product at the end of synthesis (EOS). The radiochemical purity of both [11C]PT2385 and [18F]PT2385 was > 99% as determined by radio-HPLC."

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

Granzyme B PET Imaging Enhances Belzutifan and KL201 Combination Therapy Using a Tumor Cell Membrane Nano-Loading Platform for Renal Cell Carcinoma (SNMMI 2025) - "This study successfully developed a tumor cell membrane-based nanoplatform co-delivering Belzutifan and KL201 for the treatment of RCC. The combination therapy enhanced the tumor immunocidal effect by boosting the immune response at the tumor site. The nanoplatforms demonstrated uniform morphology, optimal size, and excellent stability."

Combination therapy • Tumor cell • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Rhabdomyosarcoma • Sarcoma • Solid Tumor • CRY1 • EPAS1 • GZMB

Current status of adjuvant immunotherapy and relapse management in renal cell carcinoma: Insights from a European delphi study. (PubMed, Eur J Cancer) - "This Delphi study provides insights into the evolving role of adjuvant immunotherapy in localized RCC and relapse management. A multidisciplinary approach and periodic review are essential to optimizing treatment strategies."

IO biomarker • Journal • Genito-urinary Cancer • Oncology • Papillary Renal Cell Carcinoma • Renal Cell Carcinoma • Renal Disease • Solid Tumor • KIM1 • PD-L1

ESMO Living Guideline: Renal Cell Carcinoma (ESMO.org) - "Cytoreductive nephrectomy should usually be avoided in advanced RCC. It should only be considered for selected patients with favourable or intermediate-risk disease after multidisciplinary team review [I, B]...Metastasectomy is not routinely recommended within 1 year of nephrectomy [I, D]; however, in patients with oligometastatic disease who have undergone complete resection (M1 and no evidence of disease), adjuvant pembrolizumab [ESMO-MCBS v1.1 score: A] can be offered [II, B]...Zoledronic acid or denosumab can be considered in patients with bone metastases after consideration of individualised risk [IV, C]. Denosumab is less nephrotoxic."

Clinical guideline • Clear Cell Renal Cell Carcinoma • Renal Cell Carcinoma

A Clinical Study of Belzutifan (MK-6482) Alone or With Phenytoin in Healthy Participants (CA46602/MK-6482-035) (clinicaltrials.gov) - P1 | N=14 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion

Synthetic essentiality of TRAIL/TNFSF10 in VHL-deficient renal cell carcinoma. (PubMed, bioRxiv) - "TRAIL was identified as a direct transcriptional target of HIF2α and paradoxically found to be crucial for cell proliferation, primarily by activating the p38 MAPK pathway and facilitating G1/S phase transition. Depletion of endogenous TRAIL or inhibition of HIF2α with belzutifan sensitizes ccRCC cells to recombinant TRAIL, presenting a promising avenue for combination therapy to overcome both TRAIL resistance and belzutifan resistance in treating ccRCC."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • TNFSF10

Management of Advanced Renal Cell Carcinoma. (PubMed, Oncol Res Treat) - "Combination therapy for clear cell RCC is standard in first line therapy and published data also support its use in non-clear cell carcinoma. Local therapies can be considered in selected patients. In sub sequent treatment lines tyrosine kinase inhibitors, mTOR inhibitors and the HIF2-α inhibitor Belzutifan are used."

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

Reducing risks of surgeries and complications in von Hippel-Lindau disease with belzutifan treatment in China. (ASCO 2025) - "The cost-consequence analysis demonstrated that belzutifan initiation could substantially reduce healthcare system resource use and costs associated with VHL-related surgeries and surgical complications, by more than 80% based on trial-observed reductions in VHL-related surgeries."

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

Real-world outcomes and toxicity with belzutifan in the treatment of Von Hippel–Lindau disease: A single centre Canadian experience. (ASCO 2025) - "Our real-world outcomes demonstrate that belzutifan is effective in treatment of VHL disease and generally being well-tolerated. Further research into long-term outcomes, efficacy for other VHL-associated lesions, such as pheochromocytomas and delineation of mechanism of resistance may expand its therapeutic utility."

Clinical • Real-world • Real-world evidence • Anemia • Endocrine Cancer • Fatigue • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1 • VHL

Impact of early imaging-based screening on outcomes in young patients with von Hippel-Lindau disease: A retrospective study. (ASCO 2025) - "Pharmacologic management, including targeted therapies like Belzutifan, delayed lesion progression in pharmacologically managed cases... Early imaging-based screening with MRI and CT effectively identifies subclinical lesions in young patients with VHL, allowing for timely interventions and improved clinical outcomes. These findings highlight the importance of incorporating routine imaging protocols into the management of VHL. While the small cohort size limits generalizability, the study emphasizes the potential of early interventions to significantly enhance disease outcomes."

Retrospective data • Oncology • Von Hippel-Lindau Syndrome

LITESPARK-029: A phase 2, randomized, open-label study of belzutifan plus fulvestrant in participants with estrogen receptor–positive, HER2-negative unresectable locally advanced or metastatic breast cancer after progression on previous endocrine therapy. (ASCO 2025) - P2 | "LITESPARK-029 (NCT06428396) evaluates belzutifan + fulvestrant vs everolimus + fulvestrant or exemestane in pts with estrogen receptor–positive (ER+)/HER2– unresectable locally advanced or metastatic breast cancer. Secondary endpoints include PFS rate per RECIST v1.1 by BICR at 6 and 12 mo, OS, ORR per RECIST v1.1 by BICR, clinical benefit (CR, PR, or stable disease for ≥24 weeks), and safety. The study start date was July 2024."

Clinical • Metastases • P2 data • Breast Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • ER • FOXA1 • HER-2

Long-term safety of belzutifan in von Hippel-Lindau syndrome: A single-center experience. (ASCO 2025) - "These findings provide long-term safety data on belzutifan in VHL. While AE were common, dose reductions were effective in maintaining tolerability without compromising disease control. Adverse events in at least 5% of the safety population (25 pts)."

Clinical • Anemia • Genito-urinary Cancer • Hematological Disorders • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome

A phase 1b, open-label, safety, tolerability, and efficacy study of HC-7366 in combination with belzutifan in patients with advanced or metastatic renal cell carcinoma (NCT06234605). (ASCO 2025) - P1 | "in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Sponsor contact: Paulette Mattson pmattson@hibercell.com, 651.312.5831."

Clinical • Combination therapy • Metastases • P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1

Hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan in von Hippel-Lindau (VHL) disease–associated neoplasms: 5-year follow-up of the phase 2 LITESPARK-004 study. (ASCO 2025) - P2 | "After 5 years of follow-up, belzutifan continues to demonstrate durable antitumor activity and a manageable safety profile, consistent with prior reports. Most pts remain on treatment after this period. Results continue to support the use of belzutifan in pts with VHL disease–related RCC, CNS HB, and pNETs who do not require immediate surgery."

P2 data • Anemia • Cerebral Hemorrhage • CNS Disorders • CNS Tumor • Endocrine Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Ophthalmology • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1

ASCO 2025: Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitor Belzutifan in Von Hippel-Lindau (VHL) Disease–associated Neoplasms: 5-Year Follow-up of the Phase 2 LITESPARK-004 Study (UroToday) - P2 | N=50 | LITESPARK-004 (NCT03401788) | Sponsor: Peloton Therapeutics, Inc. | "The median time from first dose to data cutoff was 61.8 months...As of the data cutoff date, 61 participants were treated and 35 were continuing treatment. The median study follow-up was 61.8 months. The primary reason for treatment discontinuation was participant decision...At baseline, all participants had RCC; 50 (82%) had at ≥1 evaluable CNS hemangioblastoma tumor and 20 (33%) had ≥1 pNET. 59 (97%) participants underwent ≥1 VHL disease–related surgical procedure before starting belzutifan...The ORR was 70.5%. A complete response (CR) was observed in 7 (11%) patients and a partial response (PR) in 36 (59%). From the previous data cutoff date of April 3, 2023, to the current data cutoff date of April 1, 2024, the ORR increased from 67% to 70.5% (2 additional partial responses). 93% of participants experienced any reduction from baseline in the total sum of RCC target lesion diameter."

P2 data • Clear Cell Renal Cell Carcinoma • Renal Cell Carcinoma • Von Hippel-Lindau Syndrome

Research on Novel Treatment Approaches and Scientific Advances From Merck’s Broad and Differentiated Oncology Portfolio and Pipeline to be Presented at ASCO 2025 (Merck (MSD) Press Release) - "New and updated data for MK-1084, an investigational KRAS G12C inhibitor, from the colorectal cancer and non-small cell lung cancer cohorts of the Phase 1 KANDLELIT-001 study will be presented; Zilovertamab vedotin and sacituzumab tirumotecan data to highlight progress in Merck’s pipeline of innovative antibody-drug conjugates; Follow-up data for KEYTRUDA (pembrolizumab) and WELIREG (belzutifan), as well as new and updated analyses for KEYTRUDA in earlier stages of cancer, add to the body of evidence supporting the role of these medicines."

Clinical data • Cervical Cancer • Clear Cell Renal Cell Carcinoma • Colorectal Cancer • Diffuse Large B Cell Lymphoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Melanoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Prostate Cancer • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Von Hippel-Lindau Syndrome

Welireg: Newly added patents in Orange Book (Orange Book) - Expiry on Sep 5, 2034

Patent • Genetic Disorders • Genito-urinary Cancer • Kidney Cancer • Neuroendocrine Tumor • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome

Dual Inhibition of HIF-1α and HIF-2α as a Promising Treatment for VHL-Associated Hemangioblastomas: A Pilot Study Using Patient-Derived Primary Cell Cultures. (PubMed, Biomedicines) - "Belzutifan (Welireg™), a selective HIF-2α inhibitor and the only FDA-approved non-surgical option, has shown limited efficacy in CNS-HBs, highlighting the need for alternative therapeutic strategies... These results suggest that the in vitro proliferative dynamics of HB cell cultures may reflect clinical characteristics associated with CNS-HB progression, potentially serving as indicators to predict tumor development in patients with VHL. Furthermore, our findings support the simultaneous targeting of both HIF-1α and HIF-2α isoforms as a promising non-invasive therapeutic strategy."

Journal • Preclinical • Brain Cancer • Oncology • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1 • HIF1A • VHL