Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease

Abstract

Background: Patients with von Hippel-Lindau (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).

Methods: In this phase 2, open-label, single-group trial, we 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. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan.

Results: 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%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl).

Conclusions: 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. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).

Figure 1 (facing page).. Change in Lesions from Baseline, Duration of Treatment, and Tumor-Reduction Procedures.

Panel A shows the maximum change from baseline in target renal tumors. Panel B shows the longitudinal change from baseline in target renal tumors. In Panels A and B, the dashed lines represent a 20% increase in target tumors from baseline and a 30% reduction in target tumors from baseline, which correspond to the definitions of progressive disease and partial response, respectively, according to Response Evaluation Criteria in Solid Tumors, version 1.1. Panel C shows duration of treatment and time to response in patients with renal cell carcinoma. Panel D shows the distribution of tumor-reduction procedures: adrenalectomy, craniotomy, cryoablation, cryotherapy, eye removal, intradural resection, laser ablation, laser surgery, laminectomy, laser photocoagulation, pancreatectomy, partial nephrectomy, radiation therapy, radiofrequency ablation, retinal surgery, total nephrectomy, tumor enucleation, and ventriculoperitoneal shunt placement. In Panel D, the solid line indicates the start of belzutifan treatment, and the red dashed line shows the maximum duration of treatment and the equivalent period before treatment started. Two patients had no tumor-reduction procedures before treatment or while receiving belzutifan.

Figure 2.. Hemoglobin Levels in All Patients over Time.

Dashed lines represent upper and lower boundaries of normal values for women; dotted lines represent upper and lower boundaries of normal values for men. I bars represent standard deviations.