LBA26 - 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

Background

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. MK-6482, a potent, selective, small molecule HIF-2α inhibitor, was evaluated for efficacy for treatment of VHL-associated tumors in this open-label phase II study (NCT03401788).

Methods

Eligible patients (pts) were aged ≥18 yrs and had a VHL diagnosis based on germline VHL alteration, ≥1 measurable solid RCC tumor, no prior systemic anticancer therapy, and ECOG PS 0 or 1. Pts received MK-6482 120 mg orally once daily until progression, intolerable toxicity, or investigator/pt decision to withdraw. 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, DOR, and safety.

Results

As of June 1, 2020, 56 of 61 (92%) enrolled pts remain on treatment with a minimum of 60 wks follow-up. All pts 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 by IRC; all responses were PRs. DOR in confirmed responses was not reached (NR; range, 12-62 wks). The PFS rate at 52 wks was 98% (95% CI, 89-100%). For non-RCC tumors, per IRC, the ORR was 64% (4 CRs) in pancreatic lesions and 30% (5 CRs) in CNS hemangioblastomas; median DOR was NR (range, 11-71 wks) in pts with pancreatic lesions and NR (range, 12-72 wks) in pts with central nervous system hemangioblastomas. Of 16 pts with evaluable retinal lesions at baseline, 11 (69%) showed improvement per IRC. Treatment-related AEs were reported by 98% of pts; 13% had grade 3 TRAEs. There were no grade 4-5 TRAEs. Five pts discontinued treatment (patient decision [n=3], treatment-related adverse event [n=1; grade 1 dizziness], and death [n=1; acute fentanyl toxicity]).

Conclusions

MK-6482 continued to demonstrate promising antitumor activity against VHL-associated RCC and non-RCC tumors and was well tolerated.

Clinical trial identification

NCT03401788.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

R. Srinivasan: Advisory/Consultancy, Non-remunerated: Peloton; Research grant/Funding (institution), Funds to institution to partly defray costs of clinical trials: Calithera Biosciences; Research grant/Funding (institution), Funds to institution to partly defray costs of clinical trials: Peloton/Merck. F. Donskov: Honoraria (institution): Pfizer, Ipsen. W.K. Rathmell: Research grant/Funding (self): Incyte. V.K. Narayan: Research grant/Funding (self): Merck; Research grant/Funding (self): Janssen; Research grant/Funding (self): BMS; Research grant/Funding (self): Modra. B.L. Maughan: Research grant/Funding (self): Exelixis, Bavarian-Nordic, Clovis, BMS; Travel/Accommodation/Expenses: Dava Oncology. S. Oudard: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer, Pfizer, BMS, MSD, Sanofi, Astellas, Janssen, Novartis, Roche, AstraZeneca; Honoraria (self): Ipsen. T. Else: Research grant/Funding (self): Corcept, Strongbridge; Advisory/Consultancy: Corcept, HRA. J.K. Maranchie: Research grant/Funding (self): Merck, Peleton, Roche. S.J. Welsh: Travel/Accommodation/Expenses: Ipsen, MedImmune; Speaker Bureau/Expert testimony: Pfizer. S. Thamake: Shareholder/Stockholder/Stock options: Peloton Therapeutics Inc.; Travel/Accommodation/Expenses, Full/Part-time employment: Merck. E.K. Park: Full/Part-time employment: Merck & Co., Inc. R.F. Perini: Advisory/Consultancy, Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: MSD. All other authors have declared no conflicts of interest.