• Mrinal Gounder, Ravin Ratan, Thierry Alcindor, Patrick Schöffski, Winette T van der Graaf, Breelyn A Wilky, Richard F Riedel, Allison Lim, L Mary Smith, Stephanie Moody, Steven Attia, Sant Chawla, Gina D'Amato, Noah Federman, Priscilla Merriam, Brian A Van Tine, Bruno Vincenzi, Charlotte Benson, Nam Quoc Bui, Rashmi Chugh, Gabriel Tinoco, John Charlson, Palma Dileo, Lee Hartner, Lore Lapeire, Filomena Mazzeo, Emanuela Palmerini, Peter Reichardt, Silvia Stacchiotti, Howard H Bailey, Melissa A Burgess, Gregory M Cote, Lara E Davis, Hari Deshpande, Hans Gelderblom, Giovanni Grignani, Elizabeth Loggers, Tony Philip, Joseph G Pressey, Shivaani Kummar, and Bernd Kasper.
• From 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.).
• N. Engl. J. Med. 2023 Mar 9; 388 (10): 898912898-912.

BackgroundDesmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments.MethodsWe conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival.ResultsFrom May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%).ConclusionsNirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).Copyright © 2023 Massachusetts Medical Society.

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