FDA Grants New Designations to MK-6482 in RCC and VHL Disease

The FDA has granted a Breakthrough Therapy designation to MK-6482, a novel HIF-2alpha inhibitor, as treatment of patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) who have non-metastatic tumors that measure less than 3 centimeters in size, unless immediate surgery is needed. The FDA has also granted an Orphan Drug designation to MK-6482 for the treatment of VHL disease alone.¹

The 2 designations were announced in a press release from drug developer, Merck.

“These designations for MK-6482 support the potential of targeting HIF-2α in certain patients with VHL disease, who currently have limited treatment options and face an increased risk for benign tumors as well as several types of cancer, including RCC,” noted Scot Ebbinghaus, MD, vice president, Clinical Research, Merck Research Laboratories, in a statement.

A phase 2 open-label clinical trial of MK-6482 for the treatment of VHL-association clear-cell RCC (NCT03401788) served a basis for both FDA designations.

In 61 patients, the coprimary end points assessed included objective response rate (ORR) and RCC tumors per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). The secondary end points were ORR in non-RCC lesion, duration of response (DOR) in RCC and non-RCC lesions, and safety. Patient tumors were evaluated at the time of screening and every 12 weeks following screening. Eligible patients had a diagnosis of VHL disease, at least 1 measurable RCC tumor, and ECOG performance status of 0 or 1, no prior systemic anticancer treatment, and no metastatic disease.²

The ORR in all patients with 27.9% (95% CI, 17.1%-40.8%). The best response was a partial response (PR), and PRs were observed in 17 patients (27.9%). Forty-three patients (70.5%) had stable disease, and 8 patients (13.1%) had unconfirmed PRs. No patients in the study had progressive disease, and 1 patient was not evaluable for response.

The changes in RCC lesions from baseline per Independent Central Review(ICR) was an 86.9%decrease in size.

The ICR median time to response was 23.7 months (range, 11.6-61.0). The median DOR was not reached (range, 9.1-39.0). Overall, the median linear growth, which explained the longitudinal change from baseline in target RCC lesion per ICR was +3.63 mm per year (range, 3.06-10.91) prior to treatment. After treatment, the median linear growth rate was -6.40 mm per year (range, 23.32-4.48).

All 61 patients were included in the safety analysis of the study. Adverse events (AEs) of any grade occurred in 100% of patients, and treatment-related AEs occurred in 59 patients (96.7%). Of the AEs observed, 19.7% were grades 3 to 5 in severity. Grade 3 treatment-related AEs were seen in 6 patients (9.8%) and grade 4-5 treatment-related AEs were not seen. A total of 2 patients (3.3%) discontinued treatment due to an AE, and there was no discontinuation caused by treatment-related AEs. One patient in the study died, which was not treatment-related.

The most common any-grade AEs experienced by patients in the study were anemia (86.9%), fatigue (57.4%), headache (36.1%), dizziness (31.3%), and nausea (24.6%). Grade 3 AEs included anemia (3.3%), fatigue (4.9%), arthralgia (1.6%), and weight gain (1.6%).

Overtime (approx. 73 weeks), all patients eventually showed increase in hemoglobin levels. Increases appeared higher in patients who did not have a blood transfusion or external EPO compared with patients who did.

Non-RCC tumors also derived benefit from MK-6482 in the study. A baseline MRI from 1 patient in the study showed shrinkage in a left cerebellar hemangioblastoma at week 24 compared with baseline. In another patient with a spinal hemangioblastoma, a decrease in tumor size from baseline to the 24-week mark was also observed.

In a presentation of these data during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, Eric Jonasch, MD, concluded that the results were promising for treatment-naïve patients with VHL-associated RCC. In addition, MK-6482 was well tolerated with a favorable safety profile.

“MK-6482 is an active and well-tolerated therapy for VHL disease-associated RCC,” stated Jonasch.

The 61 patients in the study had a median age of 41 years (range, 19-66) and were predominantly male. ECOG performance status was assessed at baseline, and 50 patients (82.0%) had a score of 0, 10 (16.4%) had a score of 1, and 1 (1.6%) had a score of 2.

Fifty-five patients (90.2%) underwent a prior surgery, and the previous surgery was a partial nephrectomy for 32 patients (52.5%). The non-RCC disease sites evaluated in the study included central nervous system hemangioblastoma (80.3%), pancreatic lesions (50.8%), retinal lesions (27.9%), epididymal cystadenomas (16.4%), adrenal lesions (4.9%), endolymphatic sac tumors (1.6%), and 3.3% of patients had other disease sites.

MK-6482 is an investigational, novel, potent, selective, oral inhibitor of HIF- 2α. In addition to the phase 2 study presented at ASCO 2020, the agent is being investigated in a phase 3 study (NCT04195750), and a phase 1/2 dose-escalation and dose-expansion study (NCT02974738).¹

The Breakthrough Therapy designation granted to the drug will allow expedited development and review of data by the FDA.

_References:

_{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. News release. Merck. July 29, 2020. Accessed July 29, 2020. https://bit.ly/2PiHvXT}

_{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. 2020: 38 (suppl; abstr 5003). doi: 10.1200/JCO.2020.38.15_suppl.5003}