FDA Grants Priority Review to NDA of Nirogacestat for Desmoid Tumors


Data from the phase 3 DeFi trial showed that nirogacestat led to a 71% reduction in the risk of disease progression compared with placebo for adult patients with desmoid tumors. Now, the FDA has granted a priority review to the new drug application for nirogacestat.

The FDA has granted a priority review to the new drug application (NDA) of nirogacestat for adult patients with desmoid tumors.1

Data from the phase 3 DeFi trial (NCT03785964) serves as the basis of this decision as findings from the study showed nirogacestat to lead to a 71% reduction in the risk of disease progression compared with placebo in this patient population (HR, 0.29; 95% CI, 0.15-0.55; P <.001).2

In the nirogacestat arm, the median progression-free survival (PFS) was not yet reached vs 15.1 months for the placebo arm. Moreover, there a PFS benefit was observed across all prespecified subgroups, including gender, tumor location, prior treatment or surgery, and mutational status.

Now, the NDA has a Prescription Drug User Fee Act action date of August 27, 2023.1

“People with desmoid tumors can experience severe pain and other debilitating morbidities, and we are excited by the opportunity to potentially transform the standard of care for these patients,” said Saqib Islam, chief executive officer of SpringWorks Therapeutics, in a press release. “The acceptance of our NDA for nirogacestat with priority review represents a significant milestone in our ambition to provide the first approved therapy for patients with desmoid tumors. We look forward to working closely with the FDA during the review process and remain focused on ensuring that we are well-positioned to expeditiously serve the desmoid tumor patient and the physician communities following approval.”

In the global, randomized, double-blind, placebo-controlled DeFi trial, investigators are assessing nirogacestat, an oral, selective, small molecule gamma secretase inhibitor which is currently under development for the treatment of desmoid tumors and ovarian granulosa cell tumors. The trial enrolled patients with desmoid tumors who had tumor progression of at least 20% per RECIST v1.1 criteria within 12 months before the time of screening. A total of 142 patients were randomly assigned to receive 150 mg of nirogacestat (n = 70) or placebo (n = 72) twice daily.

The primary end point of the study is PFS with secondary and exploratory end points of objective response rate (ORR), duration of response, changes in tumor volume assessed by MRI, changes in patient-reported outcomes (PROs), and safety and tolerability.

According to additional data from the study, the confirmed ORR was 41% among patients given nirogacestat vs 8% for patients administered placebo (P < .001). A total of 7% of patients given nirogacestat arm achieved a complete response compared with no patients in the placebo arm.2 Additionally, treatment with nirogacestat led to a statistically significant and clinically meaningful improvement in PROs. Benefits in PROs were seen as early as cycle 2 and sustained over the duration of the study.

Nirogacestat also led to significantly reduced pain (P < .001), other desmoid tumor–specific symptoms (P < .001), improved physical/role functioning (P < .001), and overall health-related quality of life (P = .007) in patients. At the data cutoff for the primary analysis of the study of April 7, 2022, the median duration of treatment was 20.6 months for nirogacestat and 11.4 months for placebo, respectively.

Looking at safety, 95% of all treatment-emergent adverse effects (TEAEs) were grade 1 or 2 among patients given nirogacestat with the most common TEAEs being diarrhea (84% with nirogacestat and 35% with placebo, respectively), nausea (54% and 39%), and fatigue (51% and 36%). Dose reductions that resulted from TEAEs were reported in 42% of patients in the nirogacestat arm vs 0% in the placebo arm. Treatment discontinuation from TEAEs were observed in 20% of patients given nirogacestat vs 1% given placebo.

Further, 75% of women, or 27 of 36, treated with nirogacestat had ovarian dysfunction defined by investigator-reported events of amenorrhea, premature menopause, menopause, and ovarian failure. However, these events were resolved in 74% (n = 20 of 27) of patients, including 64% who continued to receive nirogacestat and 100% of patients who discontinued treatment for any reason.

  1. SpringWorks Therapeutics announces FDA acceptance and priority review of new drug application for nirogacestat for the treatment of adults with desmoid tumors. News release. SpringWorks Therapeutics. February 27, 2023. Accessed March 9, 2023. https://bit.ly/3IWsQN6
  2. SpringWorks Therapeutics announces data from phase 3 DeFi trial evaluating nirogacestat in adult patients with progressing desmoid tumors at the European Society for Medical Oncology (ESMO) Congress 2022. News release. SpringWorks Therapeutics. September 10, 2022. Accessed March 9, 2023. https://bit.ly/3La5YfO
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