Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors
Mrinal Gounder1, Ravin Ratan1, Thierry Alcindor1
1From Sarcoma Medical Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, New York (M.G.), and Northwell Health Cancer Institute, New Hyde Park (T.P.) - all in New York; the Department of Sarcoma Medical Oncology, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (R.R.); the Department of Oncology, McGill University, Montreal (T.A.); the Department of General Medical Oncology, University Hospitals Leuven, KU Leuven, Leuven (P.S.), the Department of Medical Oncology, Ghent University Hospital, Ghent University, Ghent (L.L.), and King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Catholic University of Louvain, Brussels (F.M.) - all in Belgium; the Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam (W.T.G.), and the Department of Medical Oncology, Leiden University Medical Center, Leiden (H.G.) - both in the Netherlands; the Department of Medicine, University of Colorado Cancer Center, Aurora (B.A.W.); Duke Cancer Institute, Duke University Medical Center (R.F.R.), and PharPoint Research (S.M.) - both in Durham, NC; SpringWorks Therapeutics, Stamford (A.L., L.M.S.), and Smilow Cancer Hospital, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven (H.D.) - both in Connecticut; the Department of Hematology and Oncology, Mayo Clinic, Jacksonville (S.A.), and Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami (G.D.) - both in Florida; the Sarcoma Oncology Center, Santa Monica (S.C.), the David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (N.F.), and the Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford (N.Q.B.) - all in California; the Sarcoma and Bone Cancer Treatment Center, Dana-Farber Cancer Institute and Harvard Medical School (P.M.), and the Henri and Belinda Termeer Center for Targeted Therapies, Massachusetts General Hospital Cancer Center (G.M.C.) - both in Boston; Washington University in St. Louis, St. Louis (B.A.V.T.); the Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, and Fondazione Policlinico Universitario Campus Bio-Medico - both in Rome (B.V.), the Osteoncology, Bone and Soft Tissue Sarcoma, and Innovative Therapy Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna (E.P.), the Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (S.S.), and Medical Oncology, Candiolo Cancer Institute FPO-IRCCS, Candiolo (G.G.) - all in Italy; the Royal Marsden NHS Foundation Trust (C.B.) and the Department of Medical Oncology, University College London Hospital Foundation Trust (P.D.) - both in London; the University of Michigan Rogel Cancer Center, Ann Arbor (R.C.); the Ohio State University Comprehensive Cancer Center, Columbus (G.T.), and the Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati (J.G.P.); the Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee (J.C.), and the University of Wisconsin Carbone Cancer Center, Madison (H.H.B.); the Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, Philadelphia (L.H.), and the University of Pittsburgh Medical Center, Pittsburgh (M.A.B.); the Sarcoma Center Berlin-Brandenburg, Helios Klinikum Berlin-Buch, Berlin (P.R.), and the University of Heidelberg, Mannheim University Medical Center, Mannheim Cancer Center, Sarcoma Unit, Mannheim (B.K.) - both in Germany; the Knight Cancer Institute, Oregon Health and Science University, Portland (L.E.D., S.K.); and the Division of Medical Oncology, University of Washington, the Clinical Research Division, Fred Hutchinson Cancer Research Center, and Seattle Cancer Care Alliance, Seattle (E.L.).
Nirogacestat significantly improved progression-free survival and response rates in patients with desmoid tumors. The treatment showed benefits in pain and quality of life, with manageable side effects.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Desmoid tumors are rare, aggressive soft-tissue neoplasms with high recurrence rates.
- Currently, no treatments are specifically approved for desmoid tumors.
- These tumors present a significant challenge due to their local invasiveness and lack of targeted therapies.
Purpose of the Study:
- To evaluate the efficacy and safety of nirogacestat in adults with progressing desmoid tumors.
- To assess the impact of nirogacestat on progression-free survival and objective response rates.
- To investigate the effects of nirogacestat on patient-reported outcomes, including pain and quality of life.
Main Methods:
- A Phase 3, international, double-blind, randomized, placebo-controlled trial was conducted.
- Adults with progressing desmoid tumors were assigned to receive either oral nirogacestat (150 mg twice daily) or a placebo.
- Progression-free survival served as the primary endpoint, with objective response and patient-reported outcomes as secondary endpoints.
Main Results:
- Nirogacestat demonstrated a significant improvement in progression-free survival compared to placebo (HR 0.29, P<0.001).
- The objective response rate was significantly higher in the nirogacestat group (41%) versus placebo (8%), with a 7% complete response rate.
- Patients receiving nirogacestat reported significant improvements in pain, symptom burden, functioning, and quality of life.
Conclusions:
- Nirogacestat offers significant clinical benefits for patients with progressing desmoid tumors, including improved survival and quality of life.
- The adverse events associated with nirogacestat were predominantly low-grade and manageable.
- Nirogacestat represents a promising therapeutic option for desmoid tumors, addressing an unmet medical need.
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