Drug targeting HIF-2α ‘well-tolerated’ in advanced clear-cell RCC
medwireNews: MK-6482, a first-in-class hypoxia-inducible factor (HIF)-2α inhibitor, has a favorable safety profile and demonstrates clinical activity in patients with advanced clear-cell renal cell carcinoma (RCC), phase 1/2 trial data suggest.
Toni Choueiri (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) told delegates of the 2020 Genitourinary Cancers Symposium in San Francisco, California, USA that the defective tumor suppressor VHL protein present in 90% of patients with sporadic clear-cell RCC is linked to an accumulation of HIF-2α, which dimerizes with HIF-1β and subsequently activates an area of hypoxia-inducible genes. He said that MK-6482 selectively inhibits HIF-2α, preventing the heterodimerization of HIF-2α with HIF-1β.
The study involved a 21-day dose-escalation phase, after which MK-6482 at a dose of 120 mg/day was selected for further clinical development. It was given orally to 55 patients with advanced clear-cell RCC, who were stratified into poor (9%), intermediate (18%), and favorable (73%) risk groups according to the IMDC criteria.
Choueiri described the participants as “heavily pretreated,” with patients receiving a median of three prior anticancer therapies, most commonly anti-VEGF agents and immune checkpoint inhibitors.
During the median 13 months of follow-up, grade 3–5 adverse events (AEs) and treatment-related (TR)AEs were reported in a respective 65% and 36% of patients, with 9% successfully managing their TRAES with a dose reduction.
Notably, two patients experienced a total of four grade 4 AEs: hypercalcemia, sepsis, cardiac arrest, and respiratory failure.
The most common grade 3 AEs of any cause were the on-target toxicities anemia and hypoxia, occurring in 26% and 15% of patients, respectively.
Regarding the high rate of anemia, Choueiri alluded to an “on-target effect due to lowering [erythropoietin] when you target HIF-2,” and described the high rate of hypoxia as “interesting,” while emphasizing that it was generally triggered by an acute event such as pneumonia and seemed to respond to supplemental oxygen treatment.
In total, 71% of patients discontinued treatment, 9% because of AEs and 4% because of TRAEs.
Choueiri reported an overall response rate (ORR) of 24%, where all responses were partial. An additional 56% of participants had stable disease, giving a disease control rate of 80%. The ORRs in the poor, intermediate, and favorable IMDC risk groups were 10%, 25%, and 40%, respectively.
In further support of this “promising clinical activity,” he described responses lasting longer than 6 months in 81% of patients and said that 29% of patients continued treatment beyond 12 months.
The median length of progression-free survival was 11.0 months, although Choueiri emphasized that this ranged from 6.9 months in the poor IMDC risk group to 16.5 months in the favorable IMDC risk group.
In light of their finding that “MK-6482 is well-tolerated and has a favorable safety profile,” Choueiri concluded that “an MK-6482 monotherapy pivotal Phase III trial just opened in previously treated patients with advanced clear cell RCC.”
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