Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC).

Author:

Srinivasan Ramaprasad1,Donskov Frede2,Iliopoulos Othon3,Rathmell Wendy Kimryn4,Narayan Vivek5,Maughan Benjamin L.6,Oudard Stephane7,Else Tobias8,Maranchie Jodi K.9,Welsh Sarah Joanne10,Roy Ananya11,Liu Yanfang11,Perini Rodolfo F.11,Linehan W. Marston1,Jonasch Eric12

Affiliation:

1. Center for Cancer Research, National Cancer Institute, Bethesda, MD;

2. Aarhus University Hospital, Aarhus, Denmark;

3. Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA;

4. Vanderbilt-Ingram Cancer Center, Nashville, TN;

5. University of Pennsylvania, Philadelphia, PA;

6. University of Utah, Salt Lake City, UT;

7. Hôpital Européen Georges Pompidou, Paris, France;

8. University of Michigan, Ann Arbor, MI;

9. University of Pittsburgh, Pittsburgh, PA;

10. Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom;

11. Merck & Co., Inc., Kenilworth, NJ;

12. The University of Texas MD Anderson Cancer Center, Houston, TX;

Abstract

4555 Background: Inactivation of VHL leads to aberrant stabilization and accumulation of HIF-2α, which drives tumor growth. Patients (pts) with VHL disease are at risk for ccRCC, pancreatic neuroendocrine tumors (pNETs), and hemangioblastomas. Repeated surgeries are often needed to control ccRCC and other VHL disease manifestations. Prior results of this ongoing open-label phase 2 study (NCT03401788) showed activity with belzutifan in VHL disease. Updated results are presented. Methods: Adults with germline VHL alterations, measurable and localized/nonmetastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS 0 or 1 received belzutifan 120 mg once daily until progression, intolerable toxicity, or decision to withdraw. The primary end point is ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent review committee (IRC). Secondary end points include DOR, time to response (TTR), PFS, and safety. Results: As of June 1, 2020, 61 pts enrolled. Most pts (82%) had ECOG PS 0, and the median number of prior tumor reduction procedures (eg, partial nephrectomy, craniotomy, radiation therapy) per pt was 5 (range, 0-15). Lesions outside the kidney (non-RCC tumors) evaluable by IRC included pNETs (33%) and CNS hemangioblastomas (82%). Median follow-up was 69 wk (range, 18-105), median duration of treatment was 68 wk (range, 8-105), and 56 pts (92%) remain on therapy. There were 22 confirmed responses (ORR, 36% [95% CI, 24-49]) and 7 (11%) unconfirmed responses (documented at 1 time point, to be confirmed at subsequent time point); all were PRs. In pts with confirmed PR, median DOR was not reached (range, 12+ to 62+ wk), median TTR was 31 wk (range, 12-61), and 56 pts (92%) had some reduction in the sum of all target lesion diameters. PFS rate at 52 wk was 98% (95% CI, 89-100). For non-RCC tumors, ORR was 80% (16/20; 1 CR) in pNETs and 32% (16/50; 1 CR) in CNS hemangioblastomas. Of 16 pts with evaluable retinal hemangioblastomas at baseline, 11 (69%) showed improvement per IRC. In those 16 pts, 29 eyes were monitored for retinal hemangioblastomas: 16 eyes (55%) showed improvement, 12 (41%) were stable, and no evaluation was available for 1 eye (3%). All 61 pts (100%) had at least one AE. The most common all-cause AE was anemia (90%), which is considered an on-target toxicity. Treatment-related AEs (TRAE) were reported by 60 pts (98%), and 8 pts (13%) had a grade 3 TRAE. No pts had grade 4/5 TRAEs. One pt discontinued treatment because of a TRAE (grade 1 dizziness). Conclusions: Belzutifan demonstrates clinical benefit and has a favorable safety profile in patients with VHL disease–associated ccRCC, pNETs, and hemangioblastomas. Clinical trial information: NCT03401788.

Funder

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

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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1. Evolution of the HIF targeted therapy in clear cell renal cell carcinoma;Cancer Treatment Reviews;2023-12

2. Precision medicine in gastroenteropancreatic neuroendocrine neoplasms: Where are we in 2023?;Best Practice & Research Clinical Endocrinology & Metabolism;2023-09

3. Systemic Therapy for Pancreatic Neuroendocrine Tumors;Clinical Colorectal Cancer;2023-03

4. The road to systemic therapy in von Hippel-Lindau (VHL) disease: Are we there yet?;European Journal of Cancer;2023-03

5. Surgical Management of Hereditary Kidney Cancer Syndromes;Integrating Multidisciplinary Treatment for Advanced Renal Cell Carcinoma;2023

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