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ABSTRACT
Introduction
Von Hippel-Lindau (VHL) disease is an inherited autosomal dominant syndrome caused by a germline mutation and/or deletion of the VHL gene. Inappropriate hypoxia-inducible factor (HIF)-mediated transcription of proangiogenic and metabolic genes leads to the development of tumors and cysts in multiple organs. Surgery is a standard treatment for localized tumors with a risk of metastasis or organ dysfunction. Repeated surgeries cause substantial morbidity and have a major impact on quality of life. There is an urgent need to develop effective and safe systemic treatments for VHL disease manifestations. The small-molecule HIF 2 alpha inhibitor MK-6482 (belzutifan) has demonstrated significant efficacy in VHL disease related renal cell carcinomas, hemangioblastomas, and pancreatic neuroendocrine tumors while demonstrating an acceptable safety profile.
Areas covered
This paper reviews the development of the HIF-2 alpha inhibitor, MK-6482, and discusses preliminary results of ongoing phase I/II studies in renal cell carcinoma (RCC) and VHL disease. An examination of ongoing clinical development of MK-6482 and perspectives on potential future developments and challenges are offered.
Expert opinion
Because of its favorable safety profile, its clear efficacy in VHL disease, promising findings in sporadic, advanced RCC, and convenient oral formulation, MK-6482 is expected to become a leading treatment for VHL disease. Among other currently available oral agents, we believe that MK-6482 will be a preferred treatment for VHL-associated RCC.
Article highlights
The small-molecule HIF 2 alpha inhibitor MK6482 (belzutifan) showed preclinical anti-neoplastic activity in Von Hippel Lindau (VHL) mutated or deficient models
MK6482 has demonstrated significant efficacy in VHL disease related renal cell carcinomas, hemangioblastomas, and pancreatic neuroendocrine tumors.
MK6482 has demonstrated significant efficacy in heavily pretreated metastatic renal cell carcinoma patient population.
MK6482 has an acceptable safety profile in VHL disease patients and in metastatic renal cell carcinoma patients.
This box summarizes key points contained in the article.
Declaration of interest
E Jonasch has received research support from Aravive, Arrowhead, Merck, and Novartis, and has received consulting fees from Aravive, Eisai, Exelixis, Merck, NiKang, Novartis, and Pfizer.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose
Abbreviations
| AE | = | adverse events |
| ARNT | = | aryl hydrocarbon receptor nuclear translocator |
| ASCO | = | American Society of Clinical Oncology |
| bHLH | = | basic helix–loop–helix |
| CNS | = | central nervous system |
| CR | = | complete response |
| DOR | = | duration of response |
| EPO | = | erythropoietin |
| ESMO | = | European Society for Medical Oncology |
| GLUT | = | glucose transporter |
| HIF1a | = | hypoxia-inducible factor 1 alpha |
| HIF2a | = | hypoxia inducible factor-2 alpha |
| HRE | = | hypoxia-response element |
| MTD | = | Maximum tolerable dose |
| IMDC | = | International Metastatic RCC Database Consortium |
| ODDD | = | oxygen-dependent degradation domain |
| ORR | = | objective response rate |
| PAS | = | Per-ARNT-Sim |
| PD | = | pharmacodynamic |
| PDGF | = | platelet derived growth factor |
| PFS | = | progression-free survival |
| PHD | = | prolyl hydroxylase |
| PK | = | pharmacokinetic |
| PR | = | partial response |
| pVHL | = | VHL protein |
| RBX1 | = | Ring-Box 1 |
| RCC | = | renal cell carcinoma |
| RP2D | = | recommended phase 2 dose |
| SBDD | = | structure-based drug design |
| VCB | = | pVHL, elongin B, elongin C |
| VEGF | = | vasculare endothelial growth factor |
| VHL | = | Von Hippel-Lindau |
Box 1. Drug Summary Box
Box 1. Drug summary box