EMA Validates Marketing Authorization Application for Nirogacestat in Desmoid Tumors

Bernd Kasper, MD, PhD

The European Medicines Agency (EMA) has validated a marketing authorization application (MAA) seeking the approval of nirogacestat (Ogsiveo) for the treatment of adult patients with desmoid tumors. If approved, nirogacestat would be the first agent for the management of desmoid tumors to receive marketing authorization in the European Union (EU).¹

The application was supported by findings from the phase 3 DeFi trial (NCT03785964), which were presented at the 2022 ESMO Congress and published in March 2023 in The New England Journal of Medicine.^1,2 In DeFi, treatment with the oral γ-secretase inhibitor nirogacestat met the trial’s primary end point of statistically significant progression-free survival (PFS) improvement vs placebo, with an HR of 0.29 (95% CI, 0.15-0.55; P < .001), translating to a 71% reduction in the risk of disease progression or death. The median PFS was not reached vs 15.1 (95% CI, 8.4-not estimable) months in the nirogacestat (n = 70) and placebo (n = 72) arms, respectively.

“Desmoid tumors can have a significant impact on patients’ lives, and there is a pressing need for a new treatment for patients in Europe,” Bernd Kasper, MD, PhD, chair, Sarcoma Unit, Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, University of Heidelberg, Mannheim, Germany and principal investigator of the DeFi trial, said in a press release.¹ “In the DeFi trial, nirogacestat demonstrated significant improvements across PFS, objective response rate [ORR], and patient-reported outcomes [PROs], and had a safety profile that supports long-term dosing. These results support that nirogacestat will be a practice-changing therapy if approved by the EMA.”

In DeFi, between May 2019 and August 2020, 142 patients with progressing desmoid tumors were randomly assigned 1:1 to receive twice-daily dosing with either nirogacestat at 150 mg or placebo.² Patients were eligible for enrollment if they had not received prior treatment for progressing desmoid tumors not amenable to surgery or if they had recurrent or refractory desmoid tumors after 1 or more prior lines of therapy.

PFS served as the primary end point. Prespecified secondary end points included confirmed ORR and change in PROs from baseline at cycle 10.

The confirmed ORRs per BICR and RECIST v1.1 criteria in DeFi were 41% vs 8% with nirogacestat and placebo, respectively (P < .001), including respective complete response rates of 7% and 0%.1 Treatment with nirogacestat also generated early and sustained PRO improvements vs placebo, measured per the cycle 10 assessment. Improvements with nirogacestat were seen regarding desmoid tumor-specific symptoms (P < .001), pain (P < .001), physical/role functioning (P < .001), and overall health-related quality of life (P ≤ .01).

Nirogacestat displayed a manageable and tolerable safety profile. The most common adverse effects occurring in over 15% of patients in the nirogacestat arm included ovarian toxicity, diarrhea, nausea, rash, fatigue, headache, stomatitis, abdominal pain, alopecia, cough, dyspnea, and upper respiratory tract infection.

Previously, nirogacestat was granted orphan drug designation from the European Commission for the treatment of patients with soft tissue sarcoma. Moreover, in November 2023, the FDA approved the agent for the treatment of adults with progressing desmoid tumors necessitating systemic treatment. The United States nirogacestat prescribing information includes warnings and precautions for ovarian toxicity, diarrhea, hepatotoxicity, electrolyte abnormalities, non-melanoma skin cancers, and embryo-fetal toxicity.

“The validation of our MAA is an important step toward bringing nirogacestat to patients with desmoid tumors in the EU who currently do not have an approved therapy,” Saqib Islam, chief executive officer of SpringWorks Therapeutics, added in the press release. “We look forward to working with the EMA on this important submission.”

References

1. SpringWorks Therapeutics announces European Medicines Agency validation for Marketing Authorization Application of nirogacestat for the treatment of adults with desmoid tumors. News Release. SpringWorks Therapeutics, Inc. February 29, 2024. Accessed February 29, 2024. https://ir.springworkstx.com/news-releases/news-release-details/springworks-therapeutics-announces-european-medicines-agency
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