FDA Grants Belzutifan Priority Review for VHL-Associated RCC

The novel, selective hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor belzutifan (MK-6482) was granted a priority review by the FDA for the treatment of patients with von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC) who do not require immediate surgery.

The FDA has set a Prescription Drug User Fee Act target action date of September 15, 2021, for a decision on the new drug application (NDA)’s potential approval.

“Von Hippel-Lindau disease is a rare genetic condition for which there is no systemic treatment option available and is associated with a high risk of cancer development in multiple organs. In fact, up to 70% of patients with VHL develop renal cell carcinoma during their lifetime,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, in a statement. “This priority review validates the important progress we have made to expand and diversify Merck’s oncology pipeline with innovative, new therapeutic approaches. We look forward to working closely with the FDA to bring belzutifan to patients in need.”

HIF-2α and other hypoxia-inducible factors can accumulate in patients who have an inactivated VHL tumor-suppressor protein, leading to cellular proliferation, angiogenesis, and tumor growth. Inactivation of clear cell RCC tumors is found in about 90% or more of clear cell RCC tumors.

Findings from the ongoing, open-label phase 2 Study-004 trial (NCT03401788) supported the NDA, showing a significant response rate of 36.1% (95% CI, 24.2%-49.4%) in patients with VHL disease–associated RCC treated with belzutifan.

The trial is no longer enrolling patients but is continuing to follow-up on the 61 patients in the study. Patients included in the study had VHL disease–associated RCC and at least 1 measurable tumor localized to the kidney who did not require immediate surgery; treatment of 120 mg belzutifan was administered orally once daily until disease progression or unacceptable toxicity.

Those who had previously received treatment with a HIF-2α inhibitor or had received other systemic anticancer therapy as well as those with evidence of metastatic disease or a need for immediate surgery were excluded from participating in the study.

The primary end point of the study is objective response rate (ORR) in VHL disease–associated RCC tumors and secondary end points include duration of response (DOR), time to response (TTR), progression-free survival (PFS), and time to surgery (TTS) in VHL disease–associated RCC tumors as well as ORR, DOR, TTR, PFS, and TTS in non-RCC tumors. Safety and pharmacokinetics were also reviewed in the study.

The median age of enrolled patients was 41 years (range, 19-66) with the majority of patients being male (52.5%) with an ECOG performance status of 0 (82.0%).

The median duration of treatment, according to prior results of the study, was 9.9 months (range, 1.9-18.2). The confirmed ORR was 27.9% and there were unconfirmed responses in 13.1%; all responses were partial responses. Decrease in tumor lesion size was observed in 86.9%. Responses were also seen in central nervous system, retinal, and pancreatic lesions.2

The median DOR was not reached (range, 2.1-9.0 months) and the median TTR was 5.5 months (range, 2.7-14.0). The median PFS was also not reached and the PFS rate at 1 year was 98.3%.

Treatment-related adverse events (TRAEs) were observed in 96.7% of patients, most of which were grade 1 or 2 in severity; no grade 4 or 5 TRAEs were reported. The most common TRAEs were anemia in 83.6%, which was considered an on-target toxicity; fatigue in 49.2%; and dizziness in 21.3%. Grade 3 TRAEs, primarily fatigue and anemia, were reported in 9.8% of patients. One patient discontinued due to a TRAE of dizziness.

Belzutifan is also being investigated in phase 3 trials as a monotherapy and in combination regimens in patients with RCC.

_References

_{1. Merck Receives Priority Review From FDA for New Drug Application for HIF-2α Inhibitor Belzutifan (MK-6482). News release. Merck. March 16, 2021. Accessed March 16, 2021. https://bit.ly/38NLYM2}

_{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. 2020;38(suppl 15):5003. doi:10.1200/JCO.2020.38.15_suppl.5003}