TY - JOUR
T1 - Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.
AU - Gounder, Mrinal
AU - Ratan, Ravin
AU - Alcindor, Thierry
AU - Schöffski, Patrick
AU - Van Der Graaf, Winette T.
AU - Wilky, Breelyn A.
AU - Riedel, Richard F.
AU - Lim, Allison
AU - Smith, L. Mary
AU - Moody, Stephanie
AU - Attia, Steven
AU - Chawla, Sant
AU - D'Amato, Gina
AU - Federman, Noah
AU - Merriam, Priscilla
AU - Van Tine, Brian A.
AU - Vincenzi, Bruno
AU - Benson, Charlotte
AU - Bui, Nam Quoc
AU - Chugh, Rashmi
AU - Tinoco, Gabriel
AU - Charlson, John
AU - Dileo, Palma
AU - Hartner, Lee
AU - Lapeire, Lore
AU - Mazzeo, Filomena
AU - Palmerini, Emanuela
AU - Reichardt, Peter
AU - Stacchiotti, Silvia
AU - Bailey, Howard H.
AU - Burgess, Melissa A.
AU - Cote, Gregory M.
AU - Davis, Lara E.
AU - Deshpande, Hari
AU - Gelderblom, Hans
AU - Grignani, Giovanni
AU - Loggers, Elizabeth
AU - Philip, Tony
AU - Pressey, Joseph G.
AU - Kummar, Shivaani
AU - Kasper, Bernd
N1 - Publisher Copyright:
© 2023 Massachusetts Medical Society.
PY - 2023
Y1 - 2023
N2 - Background Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. Methods 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. Results 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%). Conclusions 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.)
AB - Background Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. Methods 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. Results 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%). Conclusions 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.)
KW - Genetics
KW - Genetics General
KW - Hematology/Oncology
KW - Hematology/Oncology General
KW - Treatments in Oncology
UR - http://www.scopus.com/inward/record.url?scp=85149934876&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa2210140
DO - 10.1056/NEJMoa2210140
M3 - Article
C2 - 36884323
AN - SCOPUS:85149934876
SN - 0028-4793
VL - 388
SP - 898
EP - 912
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 10
ER -