FDA grants novel HIF-2α inhibitor accelerated regulatory pathway in renal cell carcinoma

The FDA has granted a breakthrough therapy designation to MK-6482 for the treatment of patients with von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC) with nonmetastatic renal cell carcinoma tumors less than 3 centimeters in size, unless immediate surgery is required, according to Merck (MSD), the company developing the HIF-2α inhibitor.1

The breakthrough designation was based on data from a phase 2 trial in which MK-6482 induced a confirmed objective response rate (ORR) of 27.9% in patients with VHL disease–associated RCC.2 The ORR consisted of all partial responses. An additional 70.5% of patients reached stable disease.

Based on the same findings, the FDA also granted MK-6482 an orphan drug designation for the treatment of patients with VHL disease. The breakthrough and orphan designations will expedite the development and regulatory review of MK-6482.

“These designations for MK-6482 support the potential of targeting HIF-2α in certain patients with von Hippel-Lindau disease, who currently have limited treatment options and face an increased risk for benign tumors as well as several types of cancer, including renal cell carcinoma,” Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, stated in a press release.

The phase 2 study included 61 patients with a median age of 41 years (range, 19-66). All patients had a diagnosis of VHL disease, based on germline mutation, and at least 1 measurable RCC tumor. Patients had not received prior systemic anticancer treatment. About half (47.5%) of patients were female and 82% had an ECOG performance status of 0.

Overall, 90.2% of patients had prior surgery, including 52.5% who had partial nephrectomy. Sites of non-RCC disease included CNS hemangioblastoma (80.3%), pancreatic lesions (50.8%), retinal lesions (27.9%), epididymal cystadenomas (16.4%), adrenal lesions (4.9%), and endolymphatic sac tumors (1.6%).

Patients received MK-6482 at 120 mg orally once daily. Tumors were evaluated at screening and then every 12 weeks.

At the data cutoff date, treatment was ongoing in 95.1% of patients. Three patients had discontinued treatment, 1 each due to patient decision, an adverse event (AE), and death.

At a minimum follow-up of the 36 weeks, 86.9% (n = 53) of patients had a decrease in the size of target lesions. The median time to response was 23.7 weeks (range, 11.6-61) and the median duration of response had not been reached.

Regarding safety, 96.7% of patients experienced at least 1 treatment-related AE of any grade. Grade 3 treatment-related AEs occurred in 9.8% of patients and there were no grade 4/5 treatment-related AEs. All-cause grade 3 AEs included 2 cases of anemia, 3 cases of fatigue, 1 case of dyspnea, and 1 case of increased weight.

An ongoing phase 3 trial (NCT04195750) is comparing MK-6482 with everolimus (Afinitor) in patients with advanced renal cell carcinoma.

References

1. FDA Grants Breakthrough Therapy Designation to Merck’s Novel HIF-2α Inhibitor MK-6482 for Treatment of Certain Patients With Von Hippel-Lindau Disease- Associated Renal Cell Carcinoma. Published online July 29, 2020. https://bit.ly/39Cqv88. Access July 29, 2020.

2. Jonasch E, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma. J Clin Oncol 38: 2020 (suppl; abstr 5003). doi: 10.1200/JCO.2020.38.15_suppl.5003