In this trial, 61 patients with Von Hippel-Lindau (VHL) disease and at least 1 solid renal tumor were recruited. These patients were required to have no tumors >3cm (since this would prompt surgical intervention) and no prior exposure to systemic anticancer therapy. These patients received 120mg once-daily oral MK-6482 and were monitored with CT every 12 weeks. The primary endpoint was overall response rate in the renal tumors per RECIST v1.1 criteria. A key secondary endpoint was response of non-renal tumors, which were highly prevalent in this population: 100% had pancreatic lesions, 70% had central nervous system hemangioblastomas, and 26% had retinal lesions.
The ORR for the renal masses (assumed to be ccRCC) was 36% with no complete responses. PFS was 98.3% at 52 weeks. ORR for pancreatic lesions was 64% with 4 complete responses, 30% in the CNS hemangioblastomas with 5 complete responses, and 69% in the retinal lesions. Notably, there was no progression in any of these, except for one patient who had progression in a brain hemangioblastoma. Although follow-up was relatively short and RECIST criteria are relatively stringent for progression for these purposes, the lack of progression is encouraging in this patient population for whom prevention of progression is a particularly pertinent outcome.
Tolerability is also particularly important for these patients for whom there is no apparent short-term endpoint for therapy. Fortunately, MK-6482 was notably well tolerated, with 92% of patients remaining on treatment with a minimum of 60 weeks of follow up. 13% of patients had grade >= 3 treatment-related adverse events, and 98% of patients had at least one adverse event of any kind. The most common adverse event (AE) was, as might be expected from MK-6482’s mechanism of action, anemia, which was noted in 90% of patients overall with 6% of patients experiencing grade 3 anemia.
Dr. Srinivasan concluded his talk and the Q&A with some personal comments in the text chat about his experience with the drug: “Having treated VHL patients over a number of years and with several systemic treatment strategies, I feel the HIF2 inhibitors are by far the most satisfying- 1) unequivocal activity in both renal and non renal tumors (we don't see much activity in non renal tumors with VEGFR TKIS, etc in the VHL population) and 2) very manageable AE profile, unlike VEGFR TKIs”. He also highlighted two trials of MK-6482 in metastatic clear cell RCC, a phase II trial in which it showed similar efficacy and tolerability, and an ongoing phase III trial comparing it to everolimus. In all of these trials, results are very promising, and further data is anxiously anticipated.
Presented By: Ramaprasad Srinavasan, MD, PhD, Head, Molecular Cancer Therapeutics Section, National Cancer Institute
Written by: Marshall Strother, MD, Society for Urologic Oncology Fellow, Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia PA @mcstroth at the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC