A Phase I Study of FHD-609, a Heterobifunctional Degrader of Bromodomain-Containing Protein 9, in Patients with Advanced Synovial Sarcoma or SMARCB1-Deficient Tumors

  • Clin Cancer Res. 2025 Feb 17;31(4):628-638. doi: 10.1158/1078-0432.CCR-24-2583.
J Andrew Livingston  1 ,  Jean-Yves Blay  2 ,  Jonathan Trent  3 ,  Claudia Valverde  4 ,  Mark Agulnik  5 ,  Mrinal Gounder  6  7 ,  Axel Le Cesne  8 ,  Meredith McKean  9 ,  Michael J Wagner  10 ,  Silvia Stacchiotti  11 ,  Samuel Agresta  12 ,  Alfonso Quintás-Cardama  12 ,  Sarah A Reilly  12 ,  Kathleen Healy  12 ,  Denice Hickman  12 ,  Tina Zhao  12 ,  Alex Ballesteros-Perez  13 ,  Alexis Khalil  12 ,  Michael P Collins  12 ,  Jessica Piel  12 ,  Kim Horrigan  12 ,  Ariel Lefkovith  12 ,  Scott Innis  12 ,  Alexander J Lazar  14 ,  Gregory M Cote  #  15 ,  Andrew J Wagner  #  16
Affiliations
  • 1. The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 2. Centre Léon Bérard, Lyon, France.
  • 3. University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida.
  • 4. Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona, Spain.
  • 5. City of Hope, Duarte, California.
  • 6. Memorial Sloan Kettering Cancer Center, New York, New York.
  • 7. Weill Cornell Medical College, New York, New York.
  • 8. Institut de Cancérologie Gustave-Roussy, Villejuif, France.
  • 9. Sarah Cannon Research Institute, Nashville, Tennessee.
  • 10. Fred Hutchinson Cancer Center, Seattle, Washington.
  • 11. Istituto Nazionale dei Tumori, Milan, Italy.
  • 12. Foghorn Therapeutics Inc., Cambridge, Massachusetts.
  • 13. Certara Integrated Drug Development, Princeton, New Jersey.
  • 14. Department of Pathology & Genomics Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 15. Mass General Cancer Center, Harvard Medical School, Boston, Massachusetts.
  • 16. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • # Contributed equally.
PMID: 39660994 DOI: 10.1158/1078-0432.CCR-24-2583
Abstract

Purpose: FHD-609, a potent, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), was evaluated for treating patients with advanced synovial sarcoma or SMARCB1-deficient tumors.

Patients and methods: In this multinational, open-label, phase I study (NCT04965753), patients received FHD-609 intravenously at escalating doses either twice weekly (5-80 mg; n = 40) or once weekly (40-120 mg; n = 15).

Results: Fifty-five patients received FHD-609 for a median of 43 days. The maximum tolerated doses were 40 mg twice weekly and the equivalent weekly dose, 80 mg once weekly. Dose-limiting toxicities of QTc (heart rate-corrected QT interval) prolongation and syncope were observed at 40 and 60 mg twice weekly. Treatment-related adverse events were predominantly grades 1 to 2 in severity, most commonly dysgeusia (40%), dry mouth (29.1%), fatigue (27.3%), and anemia (25.5%). Eleven (20%) patients had treatment-emergent QTc (Fridericia formula) prolongation preceded by T-wave inversions; 21 (38.2%) patients had T-wave inversions without further cardiac events or ECG abnormalities. FHD-609 showed dose-dependent increases in pharmacokinetic exposure, with no substantial accumulation. Extensive BRD9 degradation in tumor tissue corresponded to the downregulation of Cancer cell proliferation gene sets. One (2%) patient achieved a partial response; eight (15%) patients achieved stable disease, which lasted longer than 6 months in two patients.

Conclusions: FHD-609 showed dose-dependent increases in systemic FHD-609 exposure and pharmacodynamic response profiles. The maximum tolerated doses were identified (40 mg twice weekly/80 mg once weekly) and preliminary clinical activity was observed. Future studies of BRD9 degraders will require strict cardiac monitoring given the QTc prolongation observed in this study.

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