ASCO 2020: Phase II Study of the Oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau Disease–Associated Renal Cell Carcinoma

( Von Hippel-Lindau disease (VHL) is an inherited autosomal dominant syndrome which are associated with benign and malignant tumors, including hemangioblastomas, clear cell RCC, pheochromocytoma, serous cystadenomas, and papillary cystadenomas. There are two main types of VHL disease, and type 2B families have a high incidence of RCC. The mean age of onset of RCC for patients with VHL is 44, and it has been estimated that up to 70% of patients surviving to the age of 60 will develop RCC1. For patients with localized disease, surgery is considered to help prevent metastasis but tumors frequently recur and repeated surgeries are often needed.
MK-6482 is a small molecule HIF-2α inhibitor. It has been hypothesized that inactivation of VHL may drive activation of HIF-2α, which in turn drives tumor growth. In a prior phase I/II study of MK-6482 in patients with advanced clear cell RCC, MK-6482 had a favorable side effect profile and resulted in an objective response rate of 24% and disease control rate of 80%. The median PFS in this unselected population was 11.0 months and only 4% of patients had discontinued drug due to adverse effects2. This oral abstract presents data on the safety and efficacy of MK-6482 for patients with a pathogenic germline VHL variation and untreated localized clear cell RCC.
The study schema is shown above. Patients with a diagnosis of VHL based on germline mutation and no prior systemic anticancer therapy were included in the study. Patients also had no metastatic disease. A total of 61 patients enrolled in this study with a median age of 41 years old. In terms of baseline characteristics, 52% were men and the median age was 41, with a range of 19-66. Almost all the patients had prior surgery (90%) and 52% have had partial nephrectomy. 80% of patients also had CNS hemangioblastomas, 50% had pancreatic lesions, 27.9% had retinal lesions, and 16.4% had epididymal cystadenomas.

After a minimum of 36 weeks follow up, the median duration of treatment was 9.98 months and 95% of patients remain on treatment. In terms of objective response, 28% had a confirmed objective response and 13% had an unconfirmed response. 87% of patients had a decrease in tumor size and in the 17 patients with confirmed response. Of note, time to response was 23.7 months and the median duration of therapy had not yet been reached.
Many patients with rapid tumor growth also experienced the fastest response times as shown below whereas patients with more indolent tumors were slower to respond and stabilize.
MK-6482 was well tolerated with only 3% of patients discontinuing due to adverse event. 9.8% of patients had a grade 3 treatment related AE. The most common AE was anemia, followed by fatigue, headache, dizziness, and nausea. In addition to RCC tumor shrinkage, responses were also seen in non-RCC tumors, such as the cerebellar hemangioblastoma below. 
HIF-2α inhibition with MK-6482 was effective and produced durable responses for patients with Von Hippel-Lindau disease. An impressive 95% of patients remain on therapy at the time of this publication. These results are truly incredible and these data support approval of MK-6482 for the treatment of non-metastatic VHL associated RCC. 

Presented by: Eric Jonasch, MD, The University of Texas MD Anderson Cancer Center, Houston, TX

Written by: Jason Zhu, MD, Medical Oncologist, Division of Genitourinary Cancers, Levine Cancer Institute, Twitter: @TheRealJasonZhu, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.

  1. Maher E, Yates J, Harries R, et al. Clinical features and natural history of von Hippel-Lindau disease. QJM: An International Journal of Medicine 1990;77:1151-63.
  2. Choueiri TK, Plimack ER, Bauer TM, et al. Phase I/II study of the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC). American Society of Clinical Oncology; 2020.
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Read: ASCO GU 2020: A Phase I/II Study of the Oral HIF-2 α Inhibitor MK-6482 in Patients with Advanced Clear Cell Renal Cell Carcinoma (ccRCC)