Phase II study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC).
Authors: Iliopoulos Othon , Jonasch Eric , Donskov Frede , Narayan Vivek , Maughan Benjamin Louis , Oudard Stephane , Else Tobias , Maranchie Jodi K. , Welsh Sarah J. , Thamake Sanjay , Perini Rodolfo F. , Park Eric Kristopher , Linehan W. Marston , Srinivasan Ramaprasad , Rathmell W. Kimryn 
Published: March 2021

333 Background: Patients (pts) with VHL disease are at risk of developing benign and malignant tumors, including ccRCC, pancreatic lesions tumors, CNS hemangioblastomas, and retinal lesions. Inactivation of VHL leads to stabilization of HIF-2α, which drives tumor growth. In a phase 1/2 study, MK-6482, a potent, selective, oral small molecule HIF-2α inhibitor, demonstrated favorable safety and antitumor activity in advanced ccRCC. We present results of the open-label phase 2 study of MK-6482 for VHL disease–associated ccRCC (NCT03401788). Methods: Adults with germline VHL alterations, measurable, localized/non-metastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS 0/1 received MK-6482 120 mg once daily until progression, intolerable toxicity, or decision to withdraw. Primary end point: ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent review committee (IRC). Secondary end points: DOR, time to response (TTR), PFS, and safety. Results: As of June 1, 2020, 61 pts enrolled. The majority (82%) of pts had ECOG PS 0, and median number of prior surgeries per pt was 5 (range, 1-15). Lesions outside the kidney (non-RCC tumors) evaluable by IRC included pancreatic lesions (100%) and CNS hemangioblastomas (70%). Median duration of treatment was 68 wk (range, 8-105), and 92% of pts remain on therapy. There were 22 confirmed responses (ORR, 36% [95% CI, 24%-49%]) and 7 (11%) unconfirmed (documented at 1 time point, to be confirmed at subsequent time point) responses; all PRs. In pts with confirmed PR, median DOR was not reached (range, 12-62 wk) and median TTR was 31 wk (range, 12-61); 14 (64%) pts had response duration of ≥26 wk. 56 pts (92%) had any decrease in size of target lesions. PFS rate at 52 wk was 98% (95% CI, 89%-100%). Overall, pretreatment median linear growth rate of ccRCC tumors was +3.6 mm/y (range, −3.4 to +33.1), compared with −4.5 mm/y (range, −12.8 to +5.1) while on treatment. For non-RCC tumors, ORR in pancreatic lesions was 64% (39/61, including 4 CRs) and in CNS hemangioblastomas was 30% (13/43, including 5 CRs). Median (range) TTR was 35 wk (11-60) and 12 wk (10-60) for pancreatic lesions and CNS hemangioblastomas, respectively. 11/16 (69%) pts with evaluable retinal lesions at baseline showed improvement. Of those 16 pts, 29 eyes were followed for retinal lesions; 16 eyes (55%) showed improvement, 12 (41%) remained stable, and no follow-up evaluation was available for 1 (3%) eye. Treatment-related AEs (TRAEs) occurred in 98% of pts, none grade 4/5. Most common TRAE was anemia (87%), considered to be an on-target toxicity. One pt discontinued treatment due to a TRAE (grade 1 dizziness). As of data cutoff, 1 pt (2%) required surgery for ccRCC tumors after treatment. Conclusions: MK-6482 is an active and well-tolerated therapy for VHL disease–associated ccRCC, pancreatic lesions, as well as CNS and retinal hemangioblastomas. Clinical trial information: NCT03401788 .