This Phase 3 randomized trial enrolls patients with locally advanced or metastatic clear cell RCC. Patients must have received systemic treatment in the advanced setting with a PD-1 or PD-L1 inhibitor and a VEGF targeted therapy, but must not have received more than 3 prior systemic regimens in this setting. Patients with significant cardiac disease are excluded from enrollment. Patients will be randomized to receive either MK-6482 or everolimus, both given once daily as oral therapies, until the time of disease progression or unacceptable toxicity.
While numerous advances have been made in the treatment of mRCC in the past decade, our armament has been limited to three classes of drugs- immunotherapy, vascular endothelial growth factor (VEGF) inhibitors, and inhibitors of the mammalian target of rapamycin (mTOR). While it has long been recognized that hypoxia inducible factor-2 (HIF-2) is a key transcription factor driving clear cell RCC, attempts to develop an inhibitor of this target in the past have been thwarted. Results from a Phase 1/2 study of the oral HIF-2α inhibitor, MK-6482, in patients with refractory mRCC, however, recently objective response rate (ORR) of 24% with a disease control rate of 80%. Of note, 67% of the patients on this study had received both antiangiogenesis agents as well as anti-PD-1 inhibitors. On the basis of these promising results, a Phase 3 study has been initiated.
The co-primary endpoints of this trial are progression-free survival (PFS) and overall survival (OS). Secondary endpoints include ORR, duration of response, safety and impact to quality of life.