Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease

Urology experts, including UPMC Department of Urology physician Jodi K. Maranchie, MD, collaborated to report the results of a clinical trial in The New England Journal of Medicine involving a new medical treatment, belzutifan, for renal cell carcinoma associated with von Hippel-Lindau (VHL) disease.

Belzutifan is now approved by the Food and Drug Administration not only for treatment of patients with VHL-associated renal cell carcinoma but also for patients with VHL-associated hemangioblastomas of the central nervous system (CNS) and pancreatic neuroendocrine tumors that do not necessitate immediate surgery.

“This study has gone beyond our expectations,” says Dr. Maranchie. “We’ve seen that not only are we able to shrink and stabilize renal masses that were previously growing, but over the two years of the study period, the vast majority of this cohort did not develop any new tumors and did not require any invasive procedures, which was markedly different from the two years prior to inclusion in the trial.”

Patients with VHL disease have a high incidence of renal cell carcinoma owing to VHL gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α).

In this phase 2, open-label, single-group trial, experts investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. Researchers also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan.

After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%).

“The drug is very well tolerated,” Dr. Maranchie says. “The primary side effect is anemia, which is manageable with treatment. It appears to be a medication that patients can stay on for years.”
Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease.

Read more about this clinical trial on PubMed.

Collaborators not affiliated with the University of Pittsburgh:

Eric Jonasch, MD
MD Anderson Cancer Center

Frede Donskov, MD
Southern Denmark University Hospital

Othon Iliopoulos, MD
Massachusetts General Hospital

W. Kimryn Rathmell, PhD, MD
Vanderbilt University Medical Center

Vivek K. Narayan, MD, MS
Hospital of the University of Pennsylvania

Benjamin L. Maughan, MD, PharmD
Huntsman Cancer Institute

Stephane Oudard, MD, PhD
Georges Pompidou Hospital

Tobias Else, MD
University of Michigan

Sarah J. Welsh, MD
University of Cambridge

Sanjay Thamake, PhD
Turning Point Therapeutics

Eric K. Park, MD
Santa Teresa Community Hospital

Rodolfo F. Perini, MD
Hospital of the University of Pennsylvania

W. Marston Linehan, MD
Center for Cancer Research

Ramaprasad Srinivasan, MD, PhD
Center for Cancer Research