Efficacy and Safety of Long-Term Continuous Nirogacestat Treatment in Adults With Desmoid Tumors: Results From the DeFi Trial
Abstract
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.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (17)
Ravin Ratan
Bernd Kasper
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Thierry Alcindor
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Patrick Schöffski
From the Sandra and Edward Meyer Cancer Center (J.D.W.) and the Department of Medicine (J.D.W., M.A.P.), Weill Cornell Medicine, and Memorial Sloan Kettering Cancer Center (M.A.P.) — both in New York; Istituto Oncologico Veneto, IRCCS, Padua (V.C.-S.), European Institute of Oncology, IRCCS, Milan (P.Q.), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola (M.G.), University of Siena and the Center for Immuno-Oncology, University Hospital of Siena, Siena (M.M.), and Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples (P.A.A.) — all in Italy; Maria Sklodowska-Curie National Institute of Oncology, Warsaw, Poland (P.R.); Texas Oncology–Baylor Charles A. Sammons Cancer Center, Dallas (C.L.C.); University Hospital Essen, the German Cancer Consortium, the National Center for Tumor Diseases–West, the Research Alliance Ruhr, Research Center One Health, and University Duisburg-Essen — all in Essen, Germany (D.S.); the College of Medicine, Swansea University, Swansea (J.W.), Brist...
Winette T.A. Van Der Graaf
Netherlands Cancer Institute, Amsterdam, Netherlands
Noah Federman
Nam Q. Bui
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Gina D'Amato
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Richard F. Riedel
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Steven Attia
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Sant Chawla
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Allison Lim
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Brad Tumminello
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Ana B. Oton
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Yucheng Chu
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Shengfan Zhou
avin Ratan, MD, MEd, Division of Cancer Medicine, Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX; Bernd Kasper, MD, PhD, Sarcoma Unit, Mannheim University Medical Center, Mannheim Cancer Center, University of Heidelberg, Mannheim, Germany; Thierry Alcindor, MD, MS, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Patrick Schöffski, MD, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium; Winette T. van der Graaf, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Noah Federman, MD, Departments of Pediatrics and Orthopedics, UCLA Jonsson Comprehensive Cancer Center, UCLA David Geffen School of Medicine, Los Angeles, CA; Nam Q. Bui, MD, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; Gina D'Amato, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; Richard...
Mrinal Gounder