Advertisement

HIF2A Inhibitor for von Hippel-Lindau Disease–Associated Renal Cell Carcinoma


Advertisement
Get Permission

In an international trial, treatment with MK-6482, a small-molecule inhibitor of hypoxia-inducible factor (HIF)-2a, was well tolerated and resulted in clinical responses for patients with von Hippel-Lindau disease–associated renal cell carcinoma (RCC).

Eric Jonasch, MD

Eric Jonasch, MD

The results of the phase II trial were shared in today’s Genitourinary Cancer Oral Abstract Session during the ASCO20 Virtual Scientific Program by principal investigator Eric Jonasch, MD, Professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center (Abstract 5003).

von Hippel-Lindau Disease–Associated RCC

von Hippel-Lindau disease is a rare inherited mutation of the VHL gene. RCC affects approximately 40% of people with von Hippel-Lindau disease and is one of the most common causes of disease-related death.

The VHL mutation causes cells to lose their ability to respond to oxygen levels properly and leads to a buildup of HIF proteins inside the tumor cell. This process incorrectly signals that the cells are starved of oxygen, causing the formation of blood vessels and driving tumor growth. The inactivation of the VHL tumor-suppressor protein is also observed in more than 90% of sporadic RCC tumors. MK-6482 directly targets HIF-2a, hindering cancer cell growth, spread, and abnormal blood vessel development.

Treatment of von Hippel-Lindau disease–associated renal tumors consists of active surveillance until surgery is required for tumors larger than 3 cm to prevent metastatic disease. Repeated surgical procedures can carry significant complications as many patients develop renal insufficiency.

“Therapy options that can delay or avoid the need for surgery by decreasing tumor size are needed,” said Dr. Jonasch. “This agent could profoundly change the way we manage lesions in patients with von Hippel-Lindau disease.”

Methods

As of data cut-off, the single-arm clinical trial had enrolled 61 adult patients with a germline mutation diagnosis of von Hippel-Lindau disease, no prior systemic cancer therapy, measurable nonmetastatic RCC tumors, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Patients received MK-6482 orally once daily until disease progression, unacceptable toxicity, or investigator’s or patient’s decision to withdraw. Tumor size was evaluated at screening and every 12 weeks thereafter. No patients had progressive disease on treatment and 58 patients (95.1%) remain on treatment.

Results

KEY POINTS

  • The trial met its primary endpoint and showed an objective response rate in RCC tumors per RECIST by independent review. The confirmed response rate was 27.9%. When also considering the eight patients with unconfirmed response, the objective response rate was 41.0%.
  • Additionally, 86.9% of patients had a decrease in the size of their target lesions.
  • Most treatment-related adverse events were grade 1 or 2.

The trial met its primary endpoint and showed an objective response rate in RCC tumors per RECIST by independent review. The confirmed response rate was 27.9%. When also considering the eight patients with unconfirmed response, the objective response rate was 41.0%. Additionally, 86.9% of patients had a decrease in the size of their target lesions. The median time to response was 5.5 months.

Most treatment-related adverse events were grade 1 or 2. Grade 3 adverse events occurred in 9.8% of patients. There were no grade 4 or 5 treatment-related adverse events reported. The most common adverse events were anemia (86.9%), fatigue (57.4%), headache (36.1%), dizziness (31.1%), and nausea (24.6%). Anemia was safely managed with long-acting erythropoietin injections.

“Patients with von Hippel-Lindau disease are at risk of developing several types of cancer and other tumors, and there are currently no approved therapies,” said Dr. Jonasch in a statement. “We are encouraged by the results of this clinical trial and look forward to seeing further study of MK-6482 as we work to make this treatment option available for patients with von Hippel-Lindau disease.”

“MK-6482 was well tolerated and had few side effects,” he continued. “This is the first therapeutic agent that has shown the efficacy and safety required to make it a real option for the management of patients with von Hippel-Lindau disease.”

Future studies to be considered include testing whether MK-6482 can prevent the development of new lesions in patients with von Hippel-Lindau disease.

Disclosure: Funding for this research was provided by Peloton Therapeutics, Inc., a wholly owned subsidiary of Merck & Co., Inc. For full disclosures of the study authors, visit coi.asco.org.

 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
Advertisement

Advertisement



Advertisement