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

Modeling autosomal dominant erythrocytosis due HIF-2α E398K mutation reveals novel mechanism of erythropoiesis control (ASH 2025) - "We plan to determine this by studyingthe effect of FDA-approved HIF-2α inhibitor belzutifan in vivo and in vitro in this family, in another EPAS1-mutated family with thromboses (PMID:31289208), and in Chuvash erythrocytosis (PMID:14726398). Weplan to determine whether belzutifan not only, as we anticipate, corrects erythrocytosis and itsphlebotomies induced iron deficiency, but also normalizes expression of prothrombotic genes.Grant support: Czech Science Foundation, 24-11730S and GAUK 238121 (VZ, LL) and VA Merit grants JTP."

Cardiovascular • Hematological Disorders • Polycythemia Vera • Pulmonary Embolism • Targeted Protein Degradation • Thrombosis • CD34 • EGLN1 • EPAS1 • GYPA • JAK2 • SH2B3

HIF2α pathway aberrations across tumour types: A rare but actionable entity with high germline conversion (ESMO Asia 2025) - "Background: Knowledge of HIF2α pathway variants beyond VHL-associated RCC is limited, but emerging inhibitors like belzutifan and casdatifan highlight this rare, targetable group... HIF2α aberrations are rare (1–2%) outside VHL-RCC but span diverse cancer types. Excluding VHL ccRCC, high germline conversion rates on and off tumour, suggest germline assessment should be considered. Identifying this cohort of patients opens up therapeutics/trials options in addition to hereditary implications."

Clear Cell Renal Cell Carcinoma • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • EPAS1 • SDHA • VHL

Patient-reported outcomes in LITESPARK-005: a timely step toward patient-centered metrics in advanced renal cell carcinoma. (PubMed, Chin Clin Oncol) - No abstract available

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

From surgery to systemic therapy: long-term lessons of belzutifan in von Hippel-Lindau disease. (PubMed, Transl Androl Urol) - No abstract available

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

From surgery to systemic therapy in von Hippel-Lindau disease: insights from extended follow-up of LITESPARK-004. (PubMed, Transl Androl Urol) - No abstract available

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

Second-line therapies of Metastatic Renal Cell Carcinoma (mRCC) after 1st line immune-combinations (ICI-combos) (Meet-URO 33 study) (EMUC 2025) - "According to the ICI-combo type, 36% of patients treated with Pembrolizumab + Axitinib, 32% with Nivolumab + Ipilimumab, 11% with Nivolumab + Cabozantinib and 9% with Pembrolizumab + Lenvatinib started a 2nd line therapy...Drug combinations (Lenvatinib + Everolimus/Belzutifan) rise as emerging therapies, especially in younger and prognostically unfavorable patients. Further survival and response analyses are planned."

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

Intracranial Metastasis of Renal Cell Carcinoma Exhibiting Mullerian Differentiation: A Case Report (SNO 2025) - "The new plan is to stop nivolumab and cabozantinib and to start belzutifan 120 mg daily based on results from a recent clinical trial involving advanced renal cell carcinoma patients. Despite the uniqueness of the pathology of this patient's malignancy, nivolumab, cabozantinib, and radiotherapy appear to reduce the burden of advanced renal cell carcinoma and associated brain metastases, even if from gynecologic/mullerian origin."

Case report • Clinical • Brain Cancer • Genito-urinary Cancer • Gynecologic Cancers • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Intracranial Metastasis of Renal Cell Carcinoma Exhibiting Mullerian Differentiation: A Case Report (WFNOS 2025) - "The new plan is to stop nivolumab and cabozantinib and to start belzutifan 120 mg daily based on results from a recent clinical trial involving advanced renal cell carcinoma patients. Despite the uniqueness of the pathology of this patient’s malignancy, nivolumab, cabozantinib, and radiotherapy appear to reduce the burden of advanced renal cell carcinoma and associated brain metastases, even if from gynecologic/mullerian origin."

Case report • Clinical • Brain Cancer • Genito-urinary Cancer • Gynecologic Cancers • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Near-infrared carbon dots enable ultra-sensitive fluorometric detection of belzutifan: a novel approach for real-time therapeutic drug monitoring in cancer treatment. (PubMed, Anal Methods) - "The method demonstrated successful clinical validation through analysis of plasma samples from rats, achieving excellent correlation with reference LC-MS/MS methods while providing real-time therapeutic drug monitoring capabilities. This represents the first fluorometric approach for belzutifan quantification and establishes a new paradigm for anticancer drug monitoring that combines the advantages of carbon dot nanotechnology with clinically relevant near-infrared detection, offering significant potential for point-of-care therapeutic drug monitoring in oncology practice."

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

SUO 2025: LITESPARK-004: 5-Year Follow-up of the Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitor Belzutifan in Von Hippel-Lindau (VHL) Disease–associated Neoplasms (UroToday) - "The overall ORR for RCC was 70%, including a complete response in 7 patients (11%) and a partial response in 36 patients (59%). Since the previous data cutoff (April 3, 2023), the ORR increased from 67% to 70.5%, driven by two additional partial responses. Notably, 93% of participants experienced a reduction in the total sum of RCC target lesion diameters from baseline, underscoring the sustained antitumor activity of belzutifan in this VHL population."

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

Therapeutic response to belzutifan in two cases of sporadic disseminated central nervous system hemangioblastomatosis (SNO 2025) - "She began belzutifan 120 mg daily and experienced symptomatic improvement at two months. These cases suggest that belzutifan may offer a promising noninvasive therapeutic option for patients with sporadic CNS hemangioblastomas, especially in disseminated cases where conventional therapies are limited."

Clinical • CNS Disorders • Hematological Disorders • Von Hippel-Lindau Syndrome • EPAS1 • VHL

Sporadic hemangioblastomatosis: a case of remarkable response to belzutifan in the absence of von Hippel-Lindau syndrome (SNO 2025) - "After 22 months of therapy, she continues to demonstrate sustained clinical and radiographic improvement with excellent quality-of-life. This represents a new potential systemic therapy option for individuals with unresectable sporadic hemangioblastoma."

Clinical • Ataxia • Breast Cancer • Movement Disorders • Musculoskeletal Pain • Palliative care • Pulmonary Embolism • Solid Tumor • Urinary Incontinence • Von Hippel-Lindau Syndrome

Update on Systemic Therapies for Metastatic/Unresectable Pheochromocytomas and Paragangliomas and Future Directions. (PubMed, Cancers (Basel)) - "Radiopharmaceuticals such as 131I-MIBG and 177Lu-DOTATATE continue to play a pivotal role, achieving disease control in many patients. Cytotoxic regimens, particularly temozolomide, remain relevant, with some studies suggesting that SDHB-mutated PPGLs demonstrate a heightened sensitivity associated with MGMT promoter hypermethylation and reduced MGMT expression. Targeted agents are increasingly important: multi-kinase inhibitors such as sunitinib, anlotinib, and cabozantinib have shown meaningful activity. The landmark approval of belzutifan, a HIF-2α inhibitor, in 2025 represents the first oral targeted therapy for advanced/metastatic PPGL, which is particularly relevant for pseudohypoxic Cluster 1 tumors...This review summarizes current evidence and highlights ongoing clinical trials, underscoring a paradigm shift toward precision medicine and rational combination strategies. Collectively, these advances bring cautious optimism that metastatic PPGLs may soon become a..."

IO biomarker • Journal • Review • Endocrine Cancer • Oncology • Solid Tumor • EPAS1 • MGMT • SDHB

Emerging Diagnostics and Therapies in Neuroendocrine Neoplasms: A Critical Review. (PubMed, Cancers (Basel)) - "In treatment, radioligand therapy (PRRT) is used earlier in appropriate receptor-positive disease; cabozantinib improves progression-free survival after prior therapy; and belzutifan offers a biomarker-guided option for malignant pheochromocytoma/paraganglioma...We appraise strengths and limitations of key trials, note issues of access and toxicity, and highlight active areas in development (SSTR antagonists, alpha emitters, and dose-guided PRRT). Our goal is to provide a concise, evidence-based map of the field to support informed clinical judgment and future research priorities."

IO biomarker • Journal • Review • Endocrine Cancer • Neuroendocrine Carcinoma • Neuroendocrine Tumor • Oncology • Solid Tumor • ATRX • DAXX • SSTR

Targeting of HIF2-driven cachexia in kidney cancer. (PubMed, Nat Med) - "Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in patients with ccRCC, including in some who did not exhibit objective tumor shrinkage. Our findings support prospective clinical studies to determine whether HIF2 inhibitors can be leveraged not only for tumor control, but also for the treatment of cancer-associated cachexia in renal cell carcinoma."

Journal • Cachexia • Clear Cell Renal Cell Carcinoma • Endocrine Disorders • Genito-urinary Cancer • Kidney Cancer • Metabolic Disorders • Oncology • Renal Cell Carcinoma • Solid Tumor • PTHLH

Targeted Therapy or Tension: A Case of Tyrosine Kinase Inhibitor-Mediated Hypertensive Crisis in a Patient with Advanced Renal Cell Carcinoma (KIDNEY WEEK 2025) - "Case Description A 71-year-old woman with well-controlled hypertension on lisinopril 20 mg daily and prior RCC treated by radical nephrectomy and short-lived pembrolizumab (stopped for immune polyarthritis) began cabozantinib 40 mg daily for progression...Twelve weeks after stopping cabozantinib, she remained markedly hypertensive despite four agents (lisinopril 40 mg qd, nifedipine 120 mg qd, chlorthalidone 25 mg qd, spironolactone 25 mg qd)...Since then, she has been receiving Belzutifan (HIF-2α inhibitor) without adverse effects. ( Ref Fig1 ) Discussion Grade 1-3 HTN was observed in about 37% of patients in the METEOR Trial (Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma), but frank hypertensive crisis (grade 4) and true resistant hypertension are very uncommon (<1 %). Presentation with hypertensive crisis prompts discontinuation of the TKI therapy."

Clinical • Metastases • Cardiovascular • Genito-urinary Cancer • Hypertension • Immunology • Oncology • Renal Cell Carcinoma • Renal Disease • Solid Tumor • EPAS1

LITESPARK-033: A Clinical Study of Belzutifan and Zanzalintinib in People With Recurrent Kidney Cancer Following Adjuvant Therapy (MK-6482-033) (clinicaltrials.gov) - P3 | N=904 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P3 trial • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Identification of Degradation Products and a Stability-Indicating RP-HPLC Method for the Determination of Belzutifan in Pharmaceutical Dosage Forms. (PubMed, J Pharm Bioallied Sci) - "Relative standard deviations (RSD) were below 2%, indicating precision and reproducibility. Owing to its simplicity and efficiency, the method is suitable for routine quality control in pharmaceutical laboratories."

Journal • Oncology • Von Hippel-Lindau Syndrome • EPAS1

Belzutifan for Advanced Pheochromocytoma or Paraganglioma. (PubMed, N Engl J Med) - P2 | "Belzutifan showed antitumor activity with durable responses in participants with advanced pheochromocytoma or paraganglioma. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; LITESPARK-015 ClinicalTrials.gov number, NCT04924075.)."

Journal • Hematological Disorders • Oncology • Solid Tumor • EPAS1

Merck and Exelixis reveal their combo study (ApexOnco OncologyPipeline) - "Merck & Co has finally pulled back the curtain on its long-awaited phase 3 trial pairing Welireg against Exelixis’s Cabometyx follow-on zanzalintinib. The study, Litespark-033, has now landed on clinicaltrials.gov, and is set to kick off before the end of the year. This is the first of two phase 3 trials in renal cancer that the partners promised when they signed a deal last year, with silence still surrounding the second. Litespark-033 will evaluate the Welireg/zanzalintinib combo against Cabometyx in the post adjuvant PD-(L)1 setting, mirroring the indication explored in the phase 1/2 trial that started earlier this year."

Trial status • Renal Cell Carcinoma

Therapeutic response to belzutifan in two cases of sporadic disseminated central nervous system hemangioblastomatosis (WFNOS 2025) - "She began belzutifan 120 mg daily and experienced symptomatic improvement at two months. These cases suggest that belzutifan may offer a promising noninvasive therapeutic option for patients with sporadic CNS hemangioblastomas, especially in disseminated cases where conventional therapies are limited."

Clinical • CNS Disorders • Hematological Disorders • Von Hippel-Lindau Syndrome • EPAS1 • VHL

Sporadic hemangioblastomatosis: a case of remarkable response to belzutifan in the absence of von Hippel-Lindau syndrome (WFNOS 2025) - "After 22 months of therapy, she continues to demonstrate sustained clinical and radiographic improvement with excellent quality-of-life. This represents a new potential systemic therapy option for individuals with unresectable sporadic hemangioblastoma."

Clinical • Ataxia • Breast Cancer • Movement Disorders • Musculoskeletal Pain • Palliative care • Pulmonary Embolism • Solid Tumor • Urinary Incontinence • Von Hippel-Lindau Syndrome

MK-6482-012 China Extension: A Study of Pembrolizumab (MK-3475) in Combination With Belzutifan (MK-6482) and Lenvatinib (MK-7902), or Pembrolizumab/Quavonlimab (MK-1308A) in Combination With Lenvatinib, vs Pembrolizumab and Lenvatinib, for Treatment of Advanced Clear Cell Renal Cell Carcinoma (MK-6482-012)-China Extension Study (clinicaltrials.gov) - P3 | N=249 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Dec 2026 ➔ Jun 2027 | Trial primary completion date: Dec 2026 ➔ Jun 2027

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

LITESPARK-004: 5-YEAR FOLLOW-UP OF THE HYPOXIA-INDUCIBLE FACTOR-2α (HIF-2α) INHIBITOR BELZUTIFAN IN VON HIPPEL-LINDAU (VHL) DISEASE–ASSOCIATED NEOPLASMS (SUO 2025) - P2 | "After 5 years of follow-up, belzutifan continues to show durable antitumor activity and a manageable safety profile, which is consistent with prior reports. The results continue to support the use of belzutifan in participants with VHL disease–related RCC, CNS hemangioblastomas, and pNETs who do not require immediate surgery."

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

Cases: Genetic Counseling/Management Hereditary (SUO 2025) - "VHL Case Surgery vs. Welireg, Early Onset Small Mass (Biopsy, Genetics Before/After), Bilateral/Multifocal Workup and Long-Term Management"

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