HIF-2α inhibition ‘promising’ for von Hippel–Lindau disease-associated RCC
medwireNews: Findings from an open-label phase 2 study suggest the first-in-class hypoxia-inducible factor (HIF)-2α inhibitor MK-6482 has “promising efficacy and tolerability” in the treatment of renal cell carcinoma (RCC) associated with von Hippel–Lindau disease.
Speaking at the virtual 2020 ASCO Annual Meeting, Eric Jonasch (The University of Texas MD Anderson Cancer Center, Houston, USA) reported a 27.9% objective response rate (ORR) with MK-6482 among 61 patients with von Hippel–Lindau who had at least one measurable RCC tumor.
He explained that “[m]ultifocal bilateral renal cell carcinomas occur in 25% to 60% of individuals [with von Hippel–Lindau], and [are] a key cause of morbidity and mortality.”
Jonasch added that “MK-6482, a potent, selective, small molecule HIF-2α inhibitor, has [previously] shown favorable safety and antitumor activity in advanced RCC.”
The study participants, aged a median of 41 years, received oral MK-6482 120 mg/day for a median of 9.9 months. None of the patients had metastatic disease or received prior systemic anticancer therapy. But 90.2% had undergone prior surgery, most commonly a partial nephrectomy (52.5%).
At data cutoff, after a median follow-up of 36.1 weeks, treatment was still ongoing for 95.1% of patients, but the median duration of response had not yet been reached.
Jonasch reported that the size of the target RCC lesion decreased in 86.9% of participants. Indeed, an independent central review determined that after treatment, the median linear growth rate of the target lesion decreased by 6.40 mm/year versus an increase of 3.63 mm/year before treatment.
Overall, 27.9% of patients achieved a partial response and although no patient had a complete response, 70.5% had stable disease.
Treatment-related adverse events (TRAEs) of any grade occurred in 96.7% of patients, most commonly anemia (86.9%), which Jonasch said was “an anticipated side effect.” In all, 9.8% of patients experienced grade 3 TRAEs, including fatigue (4.9%), anemia (3.3%), and dyspnea (1.6%). Two patients discontinued because of an AE, but this was not considered to be treatment related in either case.
In addition to RCC, most patients had additional von Hippel–Lindau-associated lesions. The majority (80.3%) were central nervous system hemangioblastomas, followed by pancreatic lesions (50.8%) and retinal lesions (27.9%). And Jonasch noted that “responses occurred in non-renal cell carcinoma tumors as well,” with decreases seen in the size of cerebellar and spinal hemangioblastomas.
He concluded that “MK-6482 is an active and well-tolerated therapy for [von Hippel–Lindau] disease-associated renal cell carcinoma.”
And speaking to medwireNews, Jonasch said that “[t]he big question at this point in time is whether these data are sufficient for accelerated approval in light of the relative rarity of the patient population, the strength of the data and the wisdom/ethics of proceeding with a randomized study.”
He added: “Future trials could include expansion cohorts focusing on non-kidney organ manifestations, as well as assessing whether MK-6482 treatment can prevent the development of von Hippel–Lindau -related organ manifestations in adolescents and young adults.”
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