The autosomal dominant hereditary disorder VHL disease is characterized by germline inactivating mutations in the VHL gene and constitutive activation of the HIF-2α transcription factor, which drives tumor growth. VHL disease is associated with benign and malignant tumors, including clear cell renal cell carcinoma (ccRCC), pancreatic neuroendocrine tumors, central nervous system hemangioblastomas, and retinal lesions. Although surgery is the standard of care for patients with VHL, systemic therapies are an urgent unmet need and could ultimately reduce the need for surgery. MK-6482, a potent, selective, small molecule HIF-2α inhibitor, was evaluated for efficacy in the treatment of VHL-associated tumors in this open-label phase 2 study (NCT03401788).

Eligible patients were aged ≥18 years, had VHL diagnosis based on germline VHL alteration, ≥1 measurable solid RCC tumor, no RCC tumors ≥3 cm that required immediate surgery, no prior systemic anticancer therapy, and ECOG PS 0 or 1. Patients must not have received radiotherapy or undergone surgery for VHL disease within 4 weeks before enrollment. Patients received MK-6482 120 mg orally once daily until progression, intolerable toxicity, or investigator/patient decision to withdraw. For RCC tumors, CT/MRI was performed at baseline, within 7 days before the week 13 visit, and every 12 weeks thereafter. For non-RCC tumors, radiologic imaging and ophthalmic evaluations were performed at baseline and only performed during study treatment if lesions had been previously documented and were present at baseline. Primary end point: ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent review committee (IRC). Secondary end points: ORR in non-RCC tumors and safety.

As of June 1, 2020, 56 of 61 enrolled patients (92%) remain on treatment with a minimum of 60 weeks’ follow-up. All patients had ccRCC, 100% had pancreatic lesions, 70% had CNS hemangioblastomas, and 26% had retinal lesions evaluable by IRC. For ccRCC, ORR was 36% (95% CI, 24-49%) and an additional 7 (11%) unconfirmed responses (documented at single time point and pending confirmation at data cutoff) were reported. All responses were PRs. For non-RCC tumors, per IRC, ORR was 64% (4 CRs) in pancreatic lesions and 30% (5 CRs) in CNS hemangioblastomas. Of 16 patients with evaluable retinal lesions at baseline, 11 (69%) showed improvement per IRC. Treatment-related AEs were reported by 98% of patients: 13% had grade 3 TRAEs. There were no grade 4 or 5 TRAEs. Five patients discontinued treatment: 3 patient decisions, 1 TRAE (grade 1 dizziness), 1 death (acute fentanyl toxicity).

MK-6482 demonstrated durable efficacy in patients with VHL disease–associated ccRCC, pancreatic lesions, and hemangioblastomas by targeting the underlying pathophysiology of the disease; the safety profile is favorable.