{Reference Type}: Randomized Controlled Trial
{Title}: Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.
{Author}: Gounder M;Ratan R;Alcindor T;Schöffski P;van der Graaf WT;Wilky BA;Riedel RF;Lim A;Smith LM;Moody S;Attia S;Chawla S;D'Amato G;Federman N;Merriam P;Van Tine BA;Vincenzi B;Benson C;Bui NQ;Chugh R;Tinoco G;Charlson J;Dileo P;Hartner L;Lapeire L;Mazzeo F;Palmerini E;Reichardt P;Stacchiotti S;Bailey HH;Burgess MA;Cote GM;Davis LE;Deshpande H;Gelderblom H;Grignani G;Loggers E;Philip T;Pressey JG;Kummar S;Kasper B;
{Journal}: N Engl J Med
{Volume}: 388
{Issue}: 10
{Year}: Mar 2023 9
{Factor}: 176.079
{DOI}: 10.1056/NEJMoa2210140
{Abstract}: <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.).