Nirogacestat Awaits Review Following Positive CHMP Opinion for Desmoid Tumors

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Nirogacestat (Ogsiveo) has received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) in favor of approval for the treatment of patients with progressing desmoid tumors who require systemic therapy.1

The agency’s recommendation was based on the marketing authorization application for nirogacestat, which was supported by findings from the phase 3 DeFi trial (NCT03785964) published in The New England Journal of Medicine.2 The study showed that treatment with the oral gamma secretase inhibitor improved progression-free survival (PFS) vs placebo in patients with progressing desmoid tumors (HR, 0.29; 95% CI, 0.15-0.55; P < .001).

The Kaplan–Meier estimated median PFS was not estimable (NE) with nirogacestat vs 15.1 months (95% CI, 8.4-NE) with placebo. The 1-year event-free rate was 85% (95% CI, 73%-92%) with nirogacestat vs 53% (95% CI, 40%-64%) with placebo. The 2-year event-free rate was 76% (95% CI, 61%-87%) with nirogacestat vs 44% (95% CI, 32%-56%) with placebo.

A final decision regarding the approval is expected from the European Commission in the third quarter of 2025.1 If approved, nirogacestat will be the sole therapy with marketing authorization in the European Union for desmoid tumor treatment.

“The positive opinion from the CHMP reflects the meaningful benefits nirogacestat can offer patients in Europe, where currently there are no approved treatment options,” Saqib Islam, chief executive officer of SpringWorks, stated in a news release. “We look forward to the European Commission’s decision as we strive to bring nirogacestat to [patients with] desmoid tumor globally.”

In the United States, nirogacestat received approval from the FDA in November 2023 for the treatment of patients with progressing desmoid tumors who require systemic therapy.3

Approval was based on data from the global, randomized, multicenter, double-blind, placebo-controlled pivotal phase 3 DeFi trial, which was designed to assess the efficacy, safety, and tolerability of nirogacestat in patients with progressing desmoid tumors.1 During the double-blind portion of the study, 142 patients were randomly assigned to 150 mg of nirogacestat (n = 70) or placebo (n = 72) twice daily in continuous 28-day cycles.1,2

To be eligible for enrollment, patients needed to be at least 18 years of age with a histologically confirmed diagnosis of relapsed or refractory desmoid tumors following at least 1 line of therapy.2 Progressing desmoid tumor was defined as tumor progression measuring at least 20% according to RECIST 1.1 criteria within 12 months of screening. Patients could not have received prior treatment for progressing desmoid tumors that were not amenable to surgery.

The primary end point was PFS according to blinded independent central review, or death by any cause. Secondary and exploratory end points included safety and tolerability measures, objective response rate (ORR), duration of response, changes in tumor volume according to magnetic resonance imaging, and changes in patient-reported outcomes (PROs).

Additional findings from the trial illustrated a significant improvement in ORR and PROs, including pain, physical functioning, and overall quality of life with nirogacestat. The confirmed ORR was 41% with nirogacestat vs 8% with placebo (P < .001). Complete responses occurred in 7% of patients on nirogacestat vs no patients on placebo. The median time to a confirmed first response was 5.6 months with nirogacestat vs 11.1 months with placebo. The median best percent change in target-tumor size was −27.1% (range, −100%-37%) with nirogacestat vs 2.3% (range, −100%-47%) with placebo. At the time of the analysis, 97% (n = 28/29) of patients who previously responded to nirogacestat and 83% (n = 5/6) of patients who had responded to placebo had an ongoing response.

With respect to safety, the most common adverse effects that occurred in patients who received nirogacestat were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection, and dyspnea.1

“Desmoid tumors can have a profound impact on patients as well as their loved ones, and the positive CHMP opinion underscores the potential benefit of nirogacestat for these patients,” Bernd Kasper, MD, PhD, a professor at the University of Heidelberg’s Mannheim University Medical Center in Germany, and principal investigator of the DeFi trial, added in the news release. “It is very encouraging that a significant number of people taking nirogacestat experienced reductions in their tumor size and also rapid and sustained relief of their desmoid tumor symptoms, including pain.”

References

1. SpringWorks Therapeutics receives positive CHMP opinion for nirogacestat for the treatment of adults with desmoid tumors. News release. SpringWorks Therapeutics. June 20, 2025. Accessed June 20, 2025. https://ir.springworkstx.com/news-releases/news-release-details/springworks-therapeutics-receives-positive-chmp-opinion-0
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
3. FDA approves nirogacestat for desmoid tumors. FDA. November 28, 2023. Accessed June 20, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nirogacestat-desmoid-tumors