Nirogacestat Wins EU Approval for Progressing Desmoid Tumors

The European Commission (EC) has approved nirogacestat (Ogsiveo) for the treatment of adult patients with progressing desmoid tumors who require systemic treatment.1

The regulatory decision was supported by data from the phase 3 DeFi trial (NCT03785964), which showed that patients treated with nirogacestat experienced a statistically significant improvement in progression-free survival (PFS) compared with those given placebo (HR, 0.29; 95% CI, 0.15-0.55; P < .001).

Additionally, those in the nirogacestat arm achieved an objective response rate (ORR) of 41% compared with 8% for those treated with placebo (P < .001). The complete response rates were 7% and 0%, respectively, and the respective median times to first response were 5.6 months vs 11.1 months.

Nirogacestat was also associated with improvements in patient-reported outcomes regarding pain (P < .001), desmoid tumor-specific symptoms (P < .001), physical/role functioning (P < .001), and overall health-related quality of life (P ≤ .01).

Regarding safety, pooled data from 88 patients treated with nirogacestat during DeFi (n = 69) and other early-phase studies (n = 19) showed that the most common adverse effects comprised diarrhea (85%), rash (65%), ovarian toxicity in women of childbearing potential (60%), nausea (59%), fatigue (50%), hypophosphatemia (50%), headache (40%) and stomatitis (40%).

“Desmoid tumors can have a profound impact on people’s lives and are difficult to manage due to their invasive nature and high rates of recurrence. Until now, there have been no approved medicines in Europe,” Bernd Kasper, MD, PhD, professor at the University of Heidelberg, Mannheim Cancer Center, in Germany, and principal investigator of the DeFi trial, stated in a news release. “[Nirogacestat] is a highly innovative therapy with efficacy data demonstrating both meaningful antitumor activity and a significant improvement in desmoid tumor symptoms, including a significant reduction in pain, which is the most debilitating symptom reported by patients.”

In November 2023, the FDA approved nirogacestat for adult patients with progressing desmoid tumors who require systemic treatment, based on data from DeFi.2

DeFi Deep Dive

The randomized, double-blind, placebo-controlled trial enrolled patients 18 years and older with histologically confirmed desmoid tumor or aggressive fibromatosis per local pathologist assessment that had progressed by at least 20% per RECIST 1.1 criteria within 12 months of screening.3 Patients needed to have treatment-naive disease that was measurably progressing and not amenable to surgery without the risk of significant morbidity, recurrent disease that was measurably progressing following at least 1 line of therapy, or refractory disease that was measurably progressing following at least 1 line of therapy.

Other key inclusion criteria consisted of an ECOG performance status of 2 or lower, as well as adequate organ and bone marrow function.

During the double-blind portion of the study, patients were randomly assigned to receive oral nirogacestat at 150 mg twice per day or matching placebo. The study also featured an open-label phase, where all patients could receive nirogacestat once eligible.

PFS served as the trial’s primary end point. Secondary end points included ORR and quality of life outcomes.

“We would like to extend our gratitude to the patients, families, investigators, and advocacy organizations who helped make this EC approval possible,” Danny Bar-Zohar, MD, CEO of healthcare and executive board member at Merck KGaA, added in a news release.1 “[Nirogacestat] is already established as the standard of care systemic therapy for desmoid tumors in the US, and our goal is to bring the same treatment benefits to patients in Europe. Following last month’s EC approval of our therapy [mirdametinib (Ezmekly)] for patients with neurofibromatosis type 1 [associated] plexiform neurofibromas, we are in the unique position of launching 2 innovative treatments, underscoring our commitment to the rare tumor patient community.”

References

1. European Commission grants approval of Ogsiveo (nirogacestat) for the treatment of adults with desmoid tumors. News release. August 18, 2025. Accessed August 18, 2025. https://ir.springworkstx.com/news-releases/news-release-details/european-commission-grants-approval-ogsiveor-nirogacestat
2. FDA approves nirogacestat for desmoid tumors. FDA. Updated November 28, 2023. Accessed August 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nirogacestat-desmoid-tumors
3. Nirogacestat for adults with desmoid tumor/​aggressive fibromatosis (DT/​AF) (DeFi). ClinicalTrials.gov. Updated January 31, 2025. Accessed August 18, 2025. https://clinicaltrials.gov/study/NCT03785964