Nirogacestat Provides Long-Term Benefits in Desmoid Tumors

Nirogacestat in Desmoid Tumors |

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Long-term treatment with nirogacestat (Ogsiveo) was linked with an improved objective response rate (ORR), further reduction in tumor size, and sustained quality-of-life benefits in patients with desmoid tumors, according to updated from the phase 3 DeFi (NCT03785964) presented at the 2025 ESMO Sarcoma and Rare Cancers Congress.1

Patients in the intention-to-treat population (n = 70) had a median duration of nirogacestat exposure of 33.6 months (range, 0.3-61.8). An increased ORR was observed in those who received the agent for up to 4 years vs those who continued treatment for up to 1 year, at 45.7% (complete response [CR], 11.4%; partial response [PR], 34.3%) and 34.3% (CR, 4.3%; PR, 30.0%), respectively. Across years 3 and 4, additional CRs and PRs were reported in 3 patients each.

“These results show the long-term efficacy and safety of continuous use of nirogacestat with a median exposure of [33.6] months, extended from 20.6 months at the primary analysis,” lead study author Bernd Kasper, MD, PhD, of the Sarcoma Unit at the University of Heidelberg and Mannheim University Medical Center, Mannheim Cancer Center, in Germany, said during a presentation of the data.

Delving Into DeFi: Background and Design

In November 2023, the FDA approved nirogacestat for the treatment of adult patients with progressing desmoid tumors who require systemic treatment.2 This regulatory decision was based on previously reported data from DeFi.

The global, multicenter, randomized, placebo-controlled trial enrolled adult patients with desmoid tumors progressing by at least 20% per RECIST 1.1 who were randomly assigned 1:1 between the nirogacestat and placebo arms.2 In double-blind portion of the study, patients received 150 mg of nirogacestat twice per day (n = 70) or placebo. During the open-label extension portion of the study, patients in the experimental arm continued twice-daily dosing with nirogacestat (n = 39), and eligible patients in the placebo arm were allowed to begin receiving nirogacestat at 150 mg twice per day.

The primary objective of DeFi was to evaluate the efficacy and safety of nirogacestat at years 1 to 4. In the landmark ORR analysis, investigators looked at patients randomly assigned to the nirogacestat arm in the double-blind portion of the study prior to the data cutoff date of December 19, 2024.

The primary end points of the landmark analysis were tumor response and durability per RECIST 1.1; patient-reported outcomes (PROs); and safety.

Looking at Long-Term Efficacy and Safety

Additional findings demonstrated that among evaluable patients in the nirogacestat arm (n = 66), the median best change in target tumor size was –32.3% (range, –100% to 6%) with at least 1 year of treatment (n = 46), –42.5% (range, –100% to 2%) with at least 2 years of treatment (n = 40), –51.3% (range, –100% to 2%) with at least 3 years (n = 33), and –75.8% (range, –100% to 2%) with at least 4 years (n = 15).

Notably, PRO gains were sustained in patients who received nirogacestat. The least squares (LS) mean change from baseline ranged from –1.26 to –1.86 for BPI-SF average worst pain intensity score; –0.84 to –1.26 for DTSS total symptom score; and –0.41 to –0.69 for DTIS physical functioning. LS mean change from baseline ranged from –0.60 to 7.96 for EORTC QLQ-C30 GHS/QoL score; 0.88 to 7.83 for EORTC QLQ-C30 physical functioning score; and 8.45 to 14.18 for EORTC QLQ-C30 role functioning score.

Regarding safety (n = 69), most treatment-emergent adverse effects (TEAEs) were grade 1 or 2, and the incidence and severity of common TEAEs decreased after year 1. The most frequently reported TEAEs consisted of diarrhea, nausea, ovarian toxicity, fatigue, hypophosphatemia, and headache.

Data regarding ovarian toxicity were consistent with findings from the study’s primary analysis. Three patients experienced an additional instance of ovarian toxicity following a previously reported TEAE, and 1 patient experienced first-time ovarian toxicity.

Between years 2 and 3, TEAEs led to dose reductions in 5 patients; no patients required dose reductions after year 3.

References

1. Kasper B, Ratan R, Alcindo T, et al. Long-term nirogacestat treatment in adult patients with desmoid tumors: Updated efficacy and safety from the phase III DeFi trial. ESMO Open. 2025;10(suppl 3):104381. doi:10.1016/j.esmoop.2025.104381
2. FDA approves nirogacestat for desmoid tumors. FDA. November 27, 2023. Accessed March 26, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nirogacestat-desmoid-tumors