PURPOSE: Mutations or silencing of the von Hippel-Lindau tumor suppressor gene accumulate hypoxia-inducible factors (HIF). 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. PATIENTS AND 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, are 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, two 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 occurring in 25 patients (63%). Only five patients (13%) experienced treatment-related anemia, and no hypoxia was observed. The only serious treatment-related adverse event, hypertension, was reported in one patient. The maximum tolerated dose was not reached. CONCLUSIONS: Although 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.

Biomedical Research Novartis Pharma AG Basel Switzerland

Biomedical Research Novartis Pharmaceuticals Corporation East Hanover New Jersey

Department of Cancer Medicine Gustave Roussy Paris Saclay University Villejuif France

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Genitourinary Medical Oncology The University of Texas MD Anderson Cancer Center Houston Texas

Department of Haematology Oncology National University Cancer Institute Singapore Singapore

Department of Medical Oncology and Experimental Therapeutics City of Hope Comprehensive Cancer Center Duarte California

Department of Medical Oncology Cancer Institute Hospital Japanese Foundation for Cancer Research Tokyo Japan

Department of Oncology and Hematology IRCCS National Cancer Institute Foundation Milan Italy

Division of Hematology and Oncology Department of Medicine Massachusetts General Hospital Cancer Center Boston Massachusetts

Division of Oncology Siteman Cancer Center Washington University St Louis Missouri

Genitourinary Oncology Service Department of Medicine Memorial Sloan Kettering Cancer Center New York New York

Medical Oncology University of Milan Milan Italy

Medical Oncology Vall d'Hebron Institute of Oncology Vall d'Hebron University Hospital Vall d'Hebron Barcelona Hospital Campus Barcelona Spain

Novartis Pharmaceuticals Corporation East Hanover New Jersey

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