Nirogacestat Yields Positive Findings in Progressing Desmoid Tumors

Findings from the phase 3 DeFi study indicated that treatment with nirogacestat met the trial’s end points in patients with progressing desmoid tumors.

Investigators reported positive topline findings from the double-blind placebo controlled phase 3 DeFi trial (NCT03785964), assessing the use of nirogacestat as a treatment for adult patients with progressing desmoid tumors, according to a press release from developer SpringWorks Therapeutics.

The study met its primary end point of progression-free survival (PFS) after nirogacestat demonstrated a statistically significant improvement compared with the placebo. Nirogacestat yielded a 71% reduction in risk of disease progression vs placebo (HR, 0.29; 95% CI, 0.15-0.55; P <.001). The investigational oral gamma-secretase inhibitor also yielded a statistically significant improvement in objective response rate and patient-reported outcomes (PROs) vs placebo, meeting the trial’s secondary end points.

A new drug application for nirogacestat is expected to be submitted to the FDA in the second half of 2022.

“Desmoid tumors are aggressive soft-tissue tumors that can lead to severe negative outcomes for patients, including long-lasting pain, disfigurement, and amputation. In rare cases, when vital organs are impacted, desmoid tumors can also be life-threatening,” Saqib Islam, chief executive officer at SpringWorks, said in a press release. “Today’s announcement represents a significant milestone towards our goal of bringing the first approved therapy to the desmoid tumor community. 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.”

In terms of safety, nirogacestat had a manageable safety profile and was well tolerated. Notably, most individuals capable of bearing children experienced an adverse effect that was consistent with ovarian dysfunction, although most toxicities were consistent with previously reported findings.

The trial enrolled a total of 142 patients who were randomized to receive either 150 mg of nirogacestat or the placebo twice daily. To enroll on the trial, patients were required to have tumor progression of 20% or more within 12 months of the first dose of study treatment. Moreover, patients needed to have an ECOG performance status of 0 to 2 at screening and adequate organ and bone marrow function. Those with malabsorption syndrome or preexisting gastrointestinal conditions hindering absorption, abnormal QT interval at screening, or who are using concomitant agents known to prolong QT or QTcF interval were excluded from the study.

The trial’s primary end point was PFS by blinded independent central review, with key secondary and exploratory end points including safety, overall response rate, duration of response, changes in tumor volume, and PROs.

Both the FDA and the European Commission have given nirogacestat an orphan drug designation for patients with soft tissue sarcomas. The agent has also received a breakthrough therapy designation for the treatment of progressive, unresectable, recurrent, or refractory desmoid tumors or deep fibromatosis.


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 Therapeutics. May 24, 2022. Accessed May 25, 2022.