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Mini Oral - Genitourinary tumours, non-prostate

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

Date

18 Sep 2020

Session

Mini Oral - Genitourinary tumours, non-prostate

Presenters

Ramaprasad Srinivasan

Citation

Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325

Authors

R. Srinivasan1, F. Donskov2, O. Iliopoulos3, W..K. Rathmell4, V.K. Narayan5, B.L. Maughan6, S. Oudard7, T. Else8, J.K. Maranchie9, S.J. Welsh10, S. Thamake11, E.K. Park11, R.F. Perini11, W..M. Linehan12, E. Jonasch13

Author affiliations

  • 1 Urologic Oncology Branch Department, National Cancer Institute, 20892 - Bethesda/US
  • 2 Oncology, Aarhus University Hospital, 8000 - Aarhus/DK
  • 3 Hematology/oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston/US
  • 4 Hematology/oncology, Vanderbilt University Medical Center, Nashville/US
  • 5 Medical Oncology, University of Pennsylvania, Philadelphia/US
  • 6 Internal Medicine, University of Utah, Salt Lake City/US
  • 7 Immunothérapie Et Traitement Antiangiogénique En Pathologie cancérologique, Hopital European George Pompidou, 75015 - Paris/FR
  • 8 Internal Medicine, University of Michigan, Ann Arbor/US
  • 9 Urology, University of Pittsburgh, Pittsburgh/US
  • 10 Medical Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge/GB
  • 11 Medical Oncology, Merck & Co., Inc., Kenilworth/US
  • 12 Urologic Oncology, Center for Cancer Research, National Cancer Institute, Bethesda/US
  • 13 Oncology, The University of Texas M. D. Anderson Cancer Center, 77030 - Houston/US
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Resources

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Abstract LBA26

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.

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