HIF-2α Inhibitor Monotherapy Shows Preliminary Activity, Safety in RCC

DFF332, a small molecule inhibitor selectively targeting HIF-2α, demonstrated clinical activity and a tolerable safety profile in patients with advanced clear cell renal cell carcinoma (ccRCC), according to data from a phase 1, first-in-human trial (NCT04895748) presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

This monotherapy was safe for all doses and dosing schedules observed in the study and daily doses showed initial antitumor activity. However, the study was halted before its completion, according to Sumanta Kumar Pal, MD, chair of the Kidney and Bladder Cancer Disease Team, codirector of the Kidney Cancer Program, and professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center in Duarte, California.

Renal cell carcinoma: © peterschreiber.media - stock.adobe.com

“I want to emphasize that the study was halted before an optimal dose could be identified and this, in my mind, prevents realization of the full potential of DFF332,” Pal said. “If we do see favorable safety and efficacy in larger series, I do think that the agent could potentially be conducive to effective combination strategies.”

Investigators were looking at this HIF-2α inhibitor because HIF-2α is an oncogenic driver in ccRCC and promotes tumor growth and progression in this population. In preclinical models of ccRCC, DFF332 exhibited dose-dependent antitumor activity and tolerability.

In this open-label, multicenter trial, 40 adult patients with histologically confirmed unresectable, locally advanced, or metastatic ccRCC were enrolled in a dose-escalation schedule to receive DFF332 weekly then daily. The dose escalation was as follows: 50 mg weekly (n = 3), 100 mg weekly (n = 6), 25 mg daily (n = 9), 50 mg daily (n = 5), 100 mg daily (n = 12), and 150 mg daily (n = 5). Patients had an ECOG performance status of 1 or lower, disease progression with PD-1/PD-L1 checkpoint and VEGF inhibitor therapy, measurable disease, and tumor amenable to biopsy.

The primary end point was safety and tolerability, and secondary end points included antitumor activity and pharmacokinetics. Pharmacodynamic markers HIF-1α and HIF-2α were also looked at as a key exploratory objective to evaluate the amount of expression in patients’ tumors and the erythropoietin (EPO) levels in their blood.

DFF332 had a disease control rate of 52.5%, 2 patients (5.0%) had a partial response as best response, and 19 patients (47.5%) had stable disease. These confirmed partial responses were observed in 1 patient receiving 25 mg daily and 1 patient receiving 100 mg daily. The median duration of exposure was 17.9 weeks (range, 1.0-75.6). Eleven patients (27.5%) were receiving ongoing treatment at the clinical cutoff date of January 15, 2024.

During the trial, 29 patients (72.5%) discontinued treatment; 25 due to progressive disease, 3 due to physician decision, and 1 due to an adverse event (AE). Eighteen patients (45.0%) discontinued from posttreatment follow-up; 15 discontinuations were due to completion of the 90-day safety follow-up period, 1 due to death, 1 due to progressive disease, and 1 due to patient decision.

There was fast oral absorption with DFF332 with a median Tmax of 1 to 2 hours. The effective half-life was approximately 85 days, showing slow elimination of the drug and there was dose proportional exposure with daily or weekly dosing, according to Pal. With 100 mg daily dosing, “the median area under the curve between the range of 0 to 24 hours was 10-fold higher at cycle 2 day 1 as compared with cycle 1 day 1,” Pal explained.

In terms of AEs, most were grade 1 or 2, and no dose-limiting toxicities were reported. AEs were reported in 38 patients (95.0%) regardless of study treatment, and the most common were fatigue in 37.5% and anemia in 32.5%. Twenty-five patients (62.5%) experienced any-grade treatment-related AEs, including grade 1/2 anemia, fatigue, and hypercholesterolemia. Treatment-related dyspnea was reported in 2 patients and grade 3 treatment-related hypertension was reported as a serious AE in 1 patient. There were no grade 4 treatment-related AEs and no reports of hypoxia among the trial population.

The exploratory analysis demonstrated baseline HIF-1α and HIF-2α were not sufficient to predict efficacy in patients, although HIF-2α was detectable at high levels in most samples. After receiving DFF332, there was a trend towards decreased HIF-2α expression and increased HIF-1α expression, but these trends were not statistically significant.

“There was dose-dependent pathway modulation of plasma EPO levels, and you principally see this at higher doses that we explored,” Pal said. “At those levels with 50 mg daily, 100 mg daily, and 150 mg daily, there was a reduction in the range of 27% to 51% in EPO levels noted by day 8.”

The baseline characteristics of the 40 patients included on the trial showed patients were a median age of 62.5 years (range, 38-79), mostly male (77.5%), with ECOG performance status of 0 in 60.0% and 1 in 40.0%. A majority of patients (57.5%) were characterized as intermediate risk, according to the International Metastatic RCC Database Consortium, although 30.0% were favorable risk and 12.5% were poor risk. There were 5 patients (12.5%) who received 1 prior line of therapy, 15 (37.5%) with 2 prior lines, 9 (22.5%) with 3 prior lines, and 11 (27.5%) with 4 or more prior lines of therapy.

“In summary, in this first-in-human phase 1 study of DFF332, the agent was well tolerated and shown to be safe across all dose levels and schedules with no dose-limiting toxicities, or treatment-related AEs of greater than 3 in patients with clear cell renal cell carcinoma,” Pal concluded.

REFERENCE:

Pal SK, Tannir NM, Grell P, et al. Preliminary safety, pharmacokinetics and clinical activity of DFF332, an oral HIF2α inhibitor, as monotherapy in a phase 1 dose escalation study in patients with advanced clear cell renal cell carcinoma. J Clin Oncol. 2024;42(suppl 16):abstr 4513. doi:10.1200/JCO.2024.42.16_suppl.4513