Nirogacestat Improves Progression-Free Survival in Adults With Progressing Desmoid Tumors


Treatment with nirogacestat resulted in a 71% reduction in the risk of disease progression among adults with progressing desmoid tumors.

The phase 3 DeFi trial of nirogacestat, an investigational oral gamma secretase inhibitor, found statistically significant improvements in progression-free survival (PFS) among adult patients with progressing desmoid tumors.

DeFi is an ongoing, global, randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy, safety, and tolerability of nirogacestat in adults with progressing desmoid tumors. The trial randomized 142 patients to receive 150 mg of nirogacestat or placebo twice daily and the primary endpoint is PFS. Secondary and exploratory endpoints include safety and tolerability measures, objective response rate (ORR), duration of response, changes in tumor volume, and changes in patient-reported outcomes.

“Desmoid tumors are aggressive soft-tissue tumors that can lead to severe negative outcomes for patients, including long-lasting pain, disfigurement, and amputation,” said Saqib Islam, JD, CEO of SpringWorks Therapeutics, in a press release. “In rare cases, when vital organs are impacted, desmoid tumors can be life-threatening.”

Although desmoid tumors do not metastasize, they are associated with a high rate of recurrence. They are most commonly diagnosed in patients between the ages of 20 and 44 years, with a 2-to-3 times higher prevalence in women. Historically, desmoid tumors were treated with surgical resection, although this approach has become less favored due to the high recurrence rate after surgery. There are currently no FDA-approved therapies for the treatment of desmoid tumors.

Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to desmoid tumor growth. In addition, gamma secretase has been shown to directly cleave membrane-bound B cell maturation antigen (BCMA), resulting in the release of the BCMA extracellular domain from the cell surface.

According to study results, the DeFi trial met its primary endpoint of improving PFS, demonstrating a statistically significant improvement for nirogacestat over placebo, with a 71% reduction in the risk of disease progression. The trial also met all key secondary endpoints, with statistically significant improvements compared to placebo in ORR and patient-reported outcomes.

Nirogacestat was generally well tolerated with a manageable safety profile. The majority of women with childbearing potential had adverse events (AEs) consistent with ovarian dysfunction and other AEs were generally consistent with previously reported data. Additional data are expected to be presented at an upcoming medical conference in the second half of 2022 and the company plans to submit a new drug application to the FDA this year.

Nirogacestat has received Orphan Drug Designation for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma. The FDA also granted Fast Track and Breakthrough Therapy Designations for the treatment of adults with progressive, unresectable, recurrent, or refractory desmoid tumors or deep fibromatosis.

“Today’s announcement represents a significant milestone toward our goal of bringing the first approved therapy to the desmoid tumor community,” Islam said in the press release. “We look forward to sharing the DeFi trial data with the FDA and to presenting detailed study results at a medical meeting later this year.”


SpringWorks Therapeutics Announces Nirogacestat Achieved Primary and All Key Secondary Endpoints in Phase 3 DeFi Trial in Adult Patients with Progressing Desmoid Tumors. News release. SpringWorks; May 24, 2022. Accessed May 24, 2022.

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