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).
Authors: Srinivasan Ramaprasad , Donskov Frede , Iliopoulos Othon , Rathmell Wendy Kimryn , Narayan Vivek , Maughan Benjamin L. , Oudard Stephane , Else Tobias , Maranchie Jodi K. , Welsh Sarah Joanne , Roy Ananya , Liu Yanfang , Perini Rodolfo F. , Linehan W. Marston , Jonasch Eric 
Published: June 2021

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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.