Ramaprasad Srinivasan, M.D., Ph.D. of the NIH National Cancer Institute speaks about the ESMO 2020 abstract Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC): Update on RCC and non-RCC disease.
VHL autosomal dominant genetic disorder is characterized by germline inactivating VHL gene mutations and constitutive activation of the transcription factor HIF-2 alpha that stimulates tumor development. In this open-label phase II study (NCT03401788), MK-6482, a potent, selective, small-molecule HIF-2 alpha inhibitor, was evaluated for efficacy for the treatment of VHL-associated tumors.
Qualified patients (pts) were ⁇ 18 years of age and were diagnosed with VHL based on germline VHL shift, ⁇ 1 detectable solid RCC tumor, no previous systemic anticancer treatment, and ECOG PS 0 or 1. Pts obtained MK-6482 120 mg once daily orally before escalation, unacceptable toxicity, or withdrawal decision by the investigator/pt. Primary endpoint: independent review committee (IRC) ORR per RECIST v1.1 of VHL-associated ccRCC tumors. Secondary endpoints: ORR in tumors other than RCC, DOR, and protection.
As of 1 June 2020, 56 of 61 (92 percent) enrolled pts remain on care with a follow-up duration of at least 60 wks. All pts had ccRCC, 100% had pancreatic lesions, 70% had CNS hemangioblastomas, and 26% had IRC assessable retinal lesions. For ccRCC, ORR was 36% (95 % CI, 24-49%) and IRC recorded an additional 7 (11%) unconfirmed responses (documented at a single point of time and awaiting confirmation at data cutoff); all responses were PRs. DOR was not achieved in confirmed responses (NR; range, 12-62 wks). The PFS level was 98 percent at 52 wks (95 percent CI, 89-100 percent). The ORR was 64 percent (4 CRs) in pancreatic lesions and 30 percent (5 CRs) in CNS hemangioblastomas for non-RCC tumors per IRC; the median DOR was NR (range, 11-71 wks) in pts with pancreatic lesions and NR (range, 12-72 wks) in pts with hemangioblastoma of the central nervous system. 11 (69 percent) of 16 pts with evaluable retinal lesions at baseline showed improvement per IRC. 98 percent of pts registered treatment-related AEs; 13 percent had grade 3 TRAEs. No grade 4-5 TRAEs were present. (patient decision [n=3], medication-related adverse effect [n=1; grade 1 dizziness], and death [n=1; acute opioid toxicity]) 5 pts discontinued medication.
MK-6482 continued to show promising antitumor activity against and was well tolerated by VHL-associated RCC and non-RCC tumors.
Identification of Clinical Trial