The FDA has granted a priority review to the new drug application for nirogacestat for the treatment of adult patients with desmoid tumors.
The FDA has granted a priority review to the new drug application (NDA) for nirogacestat for the treatment of adult patients with desmoid tumors.1
The agency relied on data from the phase 3 DeFi trial (NCT03785964), which showed that nirogacestat generated a 71% reduction in the risk of disease progression vs placebo (HR, 0.29; 95% CI, 0.15-0.55; P <.001).2 The median progression-free survival (PFS) was not yet reached in the nirogacestat arm compared with 15.1 months for the placebo arm. Notably, investigators observed a PFS benefit across all prespecified subgroups, including gender, tumor location, prior treatment or surgery, and mutational status.
The NDA has been given a Prescription Drug User Fee Act (PDUFA) 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,” Saqib Islam, Chief Executive Officer of SpringWorks Therapeutics, stated in a news 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.”
Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor under development for the treatment of desmoid tumors and ovarian granulosa cell tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which could play a role in activating pathways that contribute to growth of desmoid tumors and ovarian granulosa cell tumors.
The global, randomized, double-blind, placebo controlled DeFi trial enrolled patients with desmoid tumors who experienced tumor progression of at least 20% per RECIST v1.1 criteria within 12 months prior to screening. Investigators enrolled 142 patients who were randomly assigned to receive 150 mg of nirogacestat (n = 70) or placebo (n = 72) twice daily.
Along with the primary end point of PFS per blinded independent central review, secondary and exploratory end points included objective response rate (ORR), duration of response, changes in tumor volume assessed by MRI, changes in patient-reported outcomes (PROs), and safety and tolerability.
Additional data showed that the confirmed ORR was 41% for patients treated with nirogacestat, compared with 8% for those given placebo (P < .001). Additionally, 7% of patients in the nirogacestat arm achieved a complete response vs no patients in the placebo arm.2
Nirogacestat produced statistically significant and clinically meaningful improvements in PROs, and these benefits were observed as early as cycle 2 and sustained over the duration of the study. The agent was associated with 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).
As of the April 7, 2022, data cutoff for the primary analysis of the study, the median duration of treatment was 20.6 months and 11.4 months for nirogacestat and placebo, respectively.
Regarding safety, 95% of all treatment-emergent adverse effects (TEAEs) for patients treated with nirogacestat were grade 1 or 2. The most common TEAEs in the nirogacestat and placebo arm were diarrhea (84% and 35%, respectively), nausea (54% and 39%), and fatigue (51% and 36%).
Dose reductions due to TEAEs occurred in 42% of patients in the nirogacestat arm vs 0% in the placebo arm. Additionally, treatment discontinuation due to TEAEs occurred in 20% of patients in the nirogacestat arm vs 1% in the placebo arm.
Seventy-five percent of women (n = 27 of 36) treated with nirogacestat experienced ovarian dysfunction, which was defined by investigator-reported events of amenorrhea, premature menopause, menopause, and ovarian failure. These events resolved in 74% (n = 20 of 27) of patients, including 64% (n = 9 of 14) of patients who continued to receive nirogacestat and 100% (n = 11 of 11) of those who discontinued treatment for any reason.