Background: Mutations or silencing of the von Hippel Lindau (VHL) tumor suppressor gene accumulates hypoxia-inducible factors (HIFs). HIF-2α is implicated in the oncogenesis of ~50% of patients with clear cell renal cell carcinoma (ccRCC) but, has been considered "undruggable". DFF332, an orally administered novel allosteric inhibitor of HIF-2α showed dose-dependent antitumor efficacy in preclinical models of ccRCC.
Methods: This first-in-human study evaluated the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of DFF332 in patients with heavily pretreated advanced ccRCC. Preliminary data from the dose escalation of DFF332 monotherapy, administered orally at 50 or 100 mg weekly or 25, 50, 100, or 150 mg once daily in 28-day treatment cycles is reported.
Results: As of January 15, 2024, 40 patients (median age, 62.5 years) received DFF332 for a median duration of 12.1 weeks. Overall, 2 patients (5%) achieved a partial response and 19 (48%) achieved stable disease as the best overall response. DFF332 showed a favorable safety profile, with treatment-related adverse events (TRAEs) occurring in 25 patients (63%). Only 5 patients (13%) experienced treatment-related anemia, and no hypoxia was observed. The only serious TRAE, hypertension, was reported in 1 patient. The maximum tolerated dose wasn't reached.
Conclusions: While clinical responses were limited in the doses evaluated, dose exploration halted prematurely, making it difficult to draw definitive conclusions about the efficacy of DFF332. Further investigation is required to establish a recommended dose regimen, assess its efficacy and safety, and evaluate its full potential as a partner in combination studies.
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