Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.

Abstract

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.).

• Authors: 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, Bernd Kasper
• Journal: The New England journal of medicine (N Engl J Med) Vol. 388 Issue 10 Pg. 898-912 (Mar 09 2023) ISSN: 1533-4406 [Electronic] United States
• PMID: 36884323 (Publication Type: Randomized Controlled Trial, Clinical Trial, Phase III, Journal Article)
• Copyright: Copyright © 2023 Massachusetts Medical Society.

Chemical References

• Amyloid Precursor Protein Secretases
• Antineoplastic Agents
• Gamma Secretase Inhibitors and Modulators
• nirogacestat
• Tetrahydronaphthalenes
• Valine

Topics

• Adult
• Female
• Humans
• Amyloid Precursor Protein Secretases (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Double-Blind Method
• Fibromatosis, Aggressive (drug therapy)
• Gamma Secretase Inhibitors and Modulators (therapeutic use)
• Progression-Free Survival
• Quality of Life
• Tetrahydronaphthalenes (therapeutic use)
• Valine (analogs & derivatives)