DeFi Trial Update Shows Nirogacestat's Efficacy in Desmoid Tumors

Bernd Kasper, MD, PhD, professor, Universitätsmedizin Mannheim, Mannheim, discusses key efficacy results from the phase 3 DeFi trial (NCT03785964) of nirogacestat (Ogsiveo) for the treatment of patients with progressing desmoid tumors.

The global, randomized, multicenter, phase 3 trial previously supported the FDA approval of the agent for the treatment of patients with progressing desmoid tumors after nirogacestat reduced the risk of disease progression or death by 71% compared with placebo in patients with desmoid tumors (HR, 0.29; 95% CI, 0.15-0.55; P < .001).^1,2 Of the patients treated with nirogacestat (n = 70), the Kaplan-Meier-estimated median progression-free survival (PFS), the primary end point of the study, was not estimated. For patients treated with placebo (n = 72), the median PFS was 15.1 months (95% CI, 8.4-not estimable). The likelihood of being event-free at 1 year was higher among patients treated with nirogacestat vs placebo, at 85% (95% CI, 73%-92%) and 53% (95% CI, 40%-64%), respectively.

An updated analysis of DeFi examined the long-term efficacy and safety of nirogacestat in patients who continued treatment beyond the double-blind phase into an open-label extension. The study focused on evaluating outcomes at 1, 2, 3, and 4-year milestones.

Key findings showed that the drug demonstrated sustained efficacy over time, with the overall response rate increasing from 34% at 1 year to approximately 46% at 4 years. The analysis revealed a deepening of responses over time, with 3 additional partial responses and 3 additional complete responses observed, resulting in a total of 8 complete responses within the analyzed patient population.

There were also no new safety signals identified during the extended treatment period. Further, patient-reported outcomes remained consistent, supporting the long-term tolerability of the drug.

References

1. FDA approves nirogacestat for desmoid tumors. News release. FDA. November 27, 2023. Accessed March 25, 2025. https://tinyurl.com/mwyyeeeh

2. Gounder M, Ratan R, Alcindor T, et al. Nirogacestat, a γ-secretase inhibitor for desmoid tumors. N Engl J Med. 2023;388(10):898-912. doi:10.1056/NEJMoa2210140