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.

Sumanta Kumar Pal Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA info_outline Sumanta Kumar Pal, Nizar M. Tannir, Peter Grell, Xin Gao, Ritesh R Kotecha, Joel Picus, Filippo G. De Braud, Shunji Takahashi, Alvin Wong, Cristina Suárez, Javier A Otero, Nicole Kundamal, Xin Yang, Sherif Sharaby, Mike Roy, Patrizia Barzaghi-Rinaudo, Laurence Albiges

Authors Sumanta Kumar Pal Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA info_outline Sumanta Kumar Pal, Nizar M. Tannir, Peter Grell, Xin Gao, Ritesh R Kotecha, Joel Picus, Filippo G. De Braud, Shunji Takahashi, Alvin Wong, Cristina Suárez, Javier A Otero, Nicole Kundamal, Xin Yang, Sherif Sharaby, Mike Roy, Patrizia Barzaghi-Rinaudo, Laurence Albiges Organizations Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic, Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, Division of Oncology, Siteman Cancer Center, Washington University, St. Louis, MO, Department of Oncology and Hematology, IRCCS National Cancer Institute Foundation and Full professor of Medical Oncology, University of Milan, Milan, Italy, Department of Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan, Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore, Medical Oncology, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain, Biomedical Research, Novartis Pharmaceutical Corporation, East Hanover, NJ, Biomedical Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ, Biomedical Research, Novartis Pharma AG, Basel, Switzerland, Department of Cancer Medicine, Gustave Roussy Cancer Campus, Paris Saclay University, Villejuif, France Abstract Disclosures Research Funding Novartis Pharmaceuticals Corporation Background: Targeting HIF2α inhibition has been proven to be an effective therapeutic option in patients (pts) with advanced clear cell renal cell carcinoma (ccRCC). DFF332, a small molecule inhibitor that selectively targets HIF2α transcriptional activity, has shown dose-dependent antitumor efficacy in preclinical models of ccRCC. Methods: This is the first in human, Phase I/Ib, open-label, multicenter, study (CDFF332A12101, NCT04895748) of DFF332 in adult pts with advanced ccRCC. The study evaluated the safety, tolerability, antitumor activity, pharmacokinetics (PK) and pharmacodynamics of DFF332. Here we report the preliminary data of the dose escalation of DFF332 monotherapy, administered orally at 50 mg or 100 mg weekly (QW) or at 25 mg, 50 mg, 100 mg or 150 mg once daily (QD) in 28-day treatment cycles. Results: Between Nov 30, 2021 to Nov 15, 2023, 40 pts (male, 78%) with a median age of 62.5 (38-79) years received treatment with DFF332. All pts received ≥1 prior line of therapy. At data cutoff, 18 pts were continuing treatment, while the treatment was discontinued in 19 pts (48%) due to progressive disease, and in 3 pts (8%) based on the physician's decision. The median (range) duration of exposure was 12.1 (1.0-75.6) weeks. Overall, 37 pts (93%) reported ≥1 adverse event (AE) regardless of relationship to study drug. Most common AEs were fatigue (33%), anemia (30%), increased blood cholesterol, and constipation (each 15%). Treatment-related AEs (TRAEs) were reported in 24 pts (60%): anemia, increased blood cholesterol, fatigue (each 13%), and hypertriglyceridemia (10%) being the most common TRAEs. Grade 3 TRAEs were increased weight and hypertension (1 pt [2.5%] each). Hypertension was the only treatment-related serious AE reported in 1 pt. No grade 4 TRAEs and dose-limiting toxicities have been observed so far. None of the patients reported hypoxia. At cut-off, 18 pts (45%) had stable disease (SD) and two pts (5%) achieved partial response [PR] accounting to a disease control rate (complete response + PR + SD) of 50%. Preliminary PK results demonstrated fast oral absorption, slow elimination, and dose-proportional exposure. Conclusions: During this phase I study, the monotherapy of DFF332 has shown a promising safety profile across all doses and schedules. Additionally, there have been indications of clinical activity and a dose-proportional modulation of erythropoietin. Currently, we are conducting an ongoing analysis of the PK and biomarker data, which will be included in the presentation. Clinical trial information: NCT04895748.

Clinical