The Desmoid Tumor Research Foundation

October 2025

Efficacy and Safety of Long-Term Continuous Nirogacestat Treatment in Adults With Desmoid Tumors: Results From the DeFi Trial.

Author Information

Ravin Ratan 1, Bernd Kasper 2, Thierry Alcindor 3, Patrick Schöffski 4, Winette T A van der Graaf 5, Noah Federman 6, Nam Q Bui 7, Gina D'Amato 8, Richard F Riedel 9, Steven Attia 10, Sant Chawla 11, Allison Lim 12, Brad Tumminello 12, Ana B Oton 12, Yucheng Chu 13, Shengfan Zhou 12, Mrinal Gounder 14

1University of Texas, MD Anderson Cancer Center, Department of Sarcoma Medical Oncology, Division of Cancer Medicine, Houston, TX. 2University of Heidelberg; Mannheim University Medical Center, Mannheim Cancer Center, Sarcoma Unit, Mannheim, Germany. 3Dana Farber Cancer Institute, Harvard Medical School, Boston, MA. 4Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium. 5Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands. 6Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA. 7Division of Oncology, Department of Medicine, Stanford University, Stanford, CA. 8Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL. 9Duke Cancer Institute, Duke University Medical Center, Durham, NC. 10Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL. 11Sarcoma Oncology Center, Santa Monica, CA. 12SpringWorks Therapeutics, Inc, Stamford, CT. 13Sumptuous Data Sciences, Monmouth Junction, NJ. 14Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY.

Publication

J Clin Oncol

Summary

In the phase III placebo-controlled DeFi trial (ClinicalTrials.gov identifier: NCT03785964) primary analysis, nirogacestat showed significant improvement versus placebo in progression-free survival (PFS), objective response rate (ORR), and patient-reported outcomes (PRO) in adult patients with progressing desmoid tumors (DT; median [range] exposure: 20.6 [0.3-33.6] months). Here, long-term nirogacestat efficacy and safety were evaluated in patients randomly assigned to nirogacestat and followed through the final data cutoff date of December 19, 2024. End points included PFS and ORR per RECIST v1.1, PRO, and safety. The median (range) duration of exposure was 33.6 (0.3-61.8) months. Median PFS was not reached. The ORR with up to 4 years of nirogacestat treatment was 45.7% (32 of 70), with three additional partial and three additional complete responses since the primary analysis. Further target tumor size reduction occurred in most patients. Benefits in PROs were sustained while on treatment. Frequently reported treatment-emergent adverse events (TEAEs) decreased in incidence and severity over time. Since the primary analysis, four patients discontinued nirogacestat because of TEAEs between years 2 and 4. In conclusion, long-term continuous nirogacestat treatment was associated with further tumor size reductions, durable objective responses, sustained PRO benefits, and a manageable safety profile consistent with the primary analysis.

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