Phase II Study of the Oral HIF-2α Inhibitor MK-6482 for Von Hippel-Lindau Disease-Associated Renal Cell Carcinoma
Open accessAbstract
5003 Background: Patients (pts) with Von Hippel-Lindau disease (VHL) are at risk for several cancers, including clear cell renal cell carcinoma (ccRCC). Inactivation of VHL results in constitutive activation of the HIF-2α transcription factor, which drives tumor growth. MK-6482, a potent, selective, small molecule HIF-2α inhibitor, has shown favorable safety and antitumor activity in a phase 1/2 study. We present initial results of the open-label phase 2 study of MK-6482 for treatment of VHL-associated ccRCC (NCT03401788). Methods: Adult pts with a pathogenic germline VHL variation, measurable localized/nonmetastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS of 0/1 received MK-6482 120 mg orally once daily until progression, intolerable toxicity, or investigator/pt decision to withdraw. Primary end point was ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent radiology review. Secondary end points were DOR, time to response (TTR), PFS, and safety and tolerability. Results: As of December 6, 2019, 61 pts were enrolled; median (range) age was 41 years (19-66) and most pts were male (52.5%) and had ECOG PS of 0 (82.0%). The most common lesions outside the kidney (non-RCC tumors) were CNS hemangioblastomas (80.3%) and pancreatic lesions (50.8%). Median (range) duration of treatment was 9.9 mo (1.9-18.2) and 95.1% of pts remain on therapy. Three pts discontinued (AE, n = 1; death [fentanyl toxicity], n = 1; pt decision, n = 1). There were 17 confirmed responses (ORR, 27.9% [95% CI, 17.1-40.8%]) and 8 (13.1%) unconfirmed (documented at 1 timepoint and to be confirmed at subsequent timepoint) responses; all responses were PRs. Of 61 pts, 53 (86.9%) had decrease in size of target lesions. In 17 pts with confirmed response, median (range) DOR was not reached (2.1-9.0 mo) and median (range) TTR was 5.5 mo (2.7-14.0). Responses were also observed in CNS, retinal, and pancreatic lesions. Median PFS was not reached; 12-mo PFS rate was 98.3%. Treatment-related AEs (TRAEs) occurred in 96.7% of pts, mostly grade 1 (44.3%) or grade 2 (42.6%) and primarily (≥20%) anemia (83.6%; considered an on-target-toxicity), fatigue (49.2%), and dizziness (21.3%). Grade 3 TRAEs occurred in 9.8% of pts, primarily fatigue (4.9%) and anemia (3.3%). There were no grade 4 or 5 TRAEs. One pt discontinued because of a TRAE (dizziness). Conclusions: MK-6482 showed promising efficacy and tolerability in pts with VHL-associated ccRCC and responses in other VHL-related lesions. These data support further investigation of MK-6482 in VHL disease. Clinical trial information: NCT03401788 .
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MK6482 was used clinically in VHL syndrome related renal cell cancer with promising activity.
“MK6482 was used clinically in VHL syndrome related renal cell cancer with promising activity [90].”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [90]
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- Authors
- Jonasch, E., Donskov, F., Iliopoulos, O., Rathmell, W. K., Narayan, V., Maughan, B. L., Oudard, S., Else, T., Maranchie, J. K., Welsh, S. J., Thamake, S., Park, E. K., Zojwalla, N. J., Perini, R. F., Linehan, W. M., & Srinivasan, R.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Aarhus University Hospital (DK)
- Harvard University (US)
- Vanderbilt University (US)
- University of Pennsylvania (US)
- University of Utah (US)
- Hôpital Européen Georges-Pompidou, Paris, France;
- University of Michigan (US)
- University of Pittsburgh (US)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- National Cancer Institute (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2020-05-20
- Volume
- 38
- Issue
- 15_suppl
- Pages
- 5003-5003
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W3029264785
- Cited by
- 42
- References
- 0
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 17 · 2020: 11
- Type
- conference abstract
- Language
- en
- Open access
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- HIF-2α inhibitor, von Hippel-Lindau disease, clear cell renal cell carcinoma, oral targeted therapy, objective response rate, disease-free survival, progression-free survival, safety and tolerability, hemangioblastoma, pancreatic tumors, treatment discontinuation
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