Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma.

Abstract

5003 Background: Patients (pts) with Von Hippel-Lindau disease (VHL) are at risk for several cancers, including clear cell renal cell carcinoma (ccRCC). Inactivation of VHL results in constitutive activation of the HIF-2α transcription factor, which drives tumor growth. MK-6482, a potent, selective, small molecule HIF-2α inhibitor, has shown favorable safety and antitumor activity in a phase 1/2 study. We present initial results of the open-label phase 2 study of MK-6482 for treatment of VHL-associated ccRCC (NCT03401788). Methods: Adult pts with a pathogenic germline VHL variation, measurable localized/nonmetastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS of 0/1 received MK-6482 120 mg orally once daily until progression, intolerable toxicity, or investigator/pt decision to withdraw. Primary end point was ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent radiology review. Secondary end points were DOR, time to response (TTR), PFS, and safety and tolerability. Results: As of December 6, 2019, 61 pts were enrolled; median (range) age was 41 years (19-66) and most pts were male (52.5%) and had ECOG PS of 0 (82.0%). The most common lesions outside the kidney (non-RCC tumors) were CNS hemangioblastomas (80.3%) and pancreatic lesions (50.8%). Median (range) duration of treatment was 9.9 mo (1.9-18.2) and 95.1% of pts remain on therapy. Three pts discontinued (AE, n = 1; death [fentanyl toxicity], n = 1; pt decision, n = 1). There were 17 confirmed responses (ORR, 27.9% [95% CI, 17.1-40.8%]) and 8 (13.1%) unconfirmed (documented at 1 timepoint and to be confirmed at subsequent timepoint) responses; all responses were PRs. Of 61 pts, 53 (86.9%) had decrease in size of target lesions. In 17 pts with confirmed response, median (range) DOR was not reached (2.1-9.0 mo) and median (range) TTR was 5.5 mo (2.7-14.0). Responses were also observed in CNS, retinal, and pancreatic lesions. Median PFS was not reached; 12-mo PFS rate was 98.3%. Treatment-related AEs (TRAEs) occurred in 96.7% of pts, mostly grade 1 (44.3%) or grade 2 (42.6%) and primarily (≥20%) anemia (83.6%; considered an on-target-toxicity), fatigue (49.2%), and dizziness (21.3%). Grade 3 TRAEs occurred in 9.8% of pts, primarily fatigue (4.9%) and anemia (3.3%). There were no grade 4 or 5 TRAEs. One pt discontinued because of a TRAE (dizziness). Conclusions: MK-6482 showed promising efficacy and tolerability in pts with VHL-associated ccRCC and responses in other VHL-related lesions. These data support further investigation of MK-6482 in VHL disease. Clinical trial information: NCT03401788 .