%0 Randomized Controlled Trial
%T Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.
%A Gounder M
%A Ratan R
%A Alcindor T
%A Schöffski P
%A van der Graaf WT
%A Wilky BA
%A Riedel RF
%A Lim A
%A Smith LM
%A Moody S
%A Attia S
%A Chawla S
%A D'Amato G
%A Federman N
%A Merriam P
%A Van Tine BA
%A Vincenzi B
%A Benson C
%A Bui NQ
%A Chugh R
%A Tinoco G
%A Charlson J
%A Dileo P
%A Hartner L
%A Lapeire L
%A Mazzeo F
%A Palmerini E
%A Reichardt P
%A Stacchiotti S
%A Bailey HH
%A Burgess MA
%A Cote GM
%A Davis LE
%A Deshpande H
%A Gelderblom H
%A Grignani G
%A Loggers E
%A Philip T
%A Pressey JG
%A Kummar S
%A Kasper B
%J N Engl J Med
%V 388
%N 10
%D Mar 2023 9
%M 36884323
%F 176.079
%R 10.1056/NEJMoa2210140
%X <B>BACKGROUND: </B>Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments.<BR><B>METHODS: </B>We 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.<BR><B>RESULTS: </B>From 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%).<BR><B>CONCLUSIONS: </B>Nirogacestat 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.).