Nirogacestat Improves Outcomes Across Prognostic Subgroups of Patients With Desmoid Tumors
Clinical Summary:
- Design/Population: This post hoc analysis of the phase 3 DeFi trial evaluated nirogacestat in 142 patients with desmoid tumors across subgroups defined by prognostic risk factors.
- Key Outcomes: Nirogacestat improved progression-free survival, response rates, and patient-reported outcomes across both high-risk and lower-risk subgroups.
- Clinical Relevance: Treatment benefit with nirogacestat appears independent of traditional prognostic factors, supporting its use across a broad population of patients with desmoid tumors.
Results from a post hoc analysis of the phase 3 DeFi trial demonstrate that nirogacestat provides consistent clinical benefit across prognostic subgroups of patients with desmoid tumors.
“Nirogacestat, a targeted gamma secretase inhibitor, is the only FDA-approved treatment for adults with progressing [desmoid tumors] who require systemic treatment,” stated Charlotte Benson, The Royal Marsden Hospital, London, United Kingdom, and coauthors. “This study assessed the efficacy of [nirogacestat] vs [placebo] in patient subgroups with or without a poor prognostic factor.”
In this study, 142 patients with desmoid tumors were randomized 1:1 to receive either 150 mg of twice daily nirogacestat (n = 70) or placebo (n = 72). Primary end points included progression-free survival (PFS), objective response rate (ORR), and patient-reported outcomes. This post hoc analysis evaluated outcomes in subgroups defined by prognostic factors, including tumor size, age, CTNNB1 mutation status, and baseline pain. Poor prognostic factors were defined as tumor size >10 cm, age ≤30 years, presence of somatic S45F or T41A CTNNB1 mutations, or baseline pain.
Across patients with poor prognostic features, nirogacestat consistently improved PFS, with hazard ratios ranging from 0.18 to 0.39. Similar benefits were observed in patients without poor prognostic factors, with hazard ratios ranging from 0.27 to 0.45. Differences in ORR between nirogacestat and placebo ranged from 18.1% to 56.0% in high-risk subgroups and from 31.1% to 45.8% in lower-risk groups, favoring nirogacestat in all comparisons.
Patient-reported outcomes, including pain, disease-specific symptom burden, physical functioning, role functioning, and overall quality of life improved with nirogacestat compared with placebo regardless of subgroup. These improvements were observed early and were sustained throughout treatment.
“[Nirogacestat] was associated with consistent improvement in PFS, ORR, and [patient-reported outcomes] vs [placebo] regardless of the presence or absence of [desmoid tumor] poor prognostic factors,” concluded Dr Benson et al.
Source:
Benson C, Chugh R, Bui NQ, et al. Efficacy of nirogacestat in patients with desmoid tumors and presence or absence of poor prognostic factors: Post hoc analyses of the phase III DeFi trial. Ann Oncol. Published online: September 2025. doi:10.1016/j.annonc.2025.08.3340
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