Findings from the phase 3 DeFi trial support the new drug application for nirogacestat as a treatment for adults with desmoid tumors.
The FDA has accepted and granted priority review to an investigational new drug application for nirogacestat as a treatment for adult patients with desmoid tumors, according to a press release from SpringWorks Therapeutics.1
The FDA has set a Prescription Drug User Fee Act date for August 27, 2023.
The investigational new drug application was supported by data from the phase 3 DeFi trial (NCT03785964), which read out at the 2022 European Society for Medical Oncology Congress (ESMO).
In the DeFi trial, the median progression-free survival (PFS) was not reached with nirogacestat compared with 15.1 months in the placebo arm; the former demonstrated a 71% reduction in the risk of disease progression (HR, 0.29; 95% CI, 0.15-0.55; P <.001).2 Additionally, nirogacestat yielded a PFS benefit across all prespecified subgroups based on factors such as gender, tumor location, prior treatment or surgery, and mutational status.
“The acceptance of our [new drug application] for nirogacestat with priority review represents a significant milestone in our ambition to provide the first approved therapy for patients with desmoid tumors,” Saqib Islam, chief executive officer at SpringWorks, said in the press release.
Investigators of the global, randomized, double-blind, placebo-controlled phase 3 DeFi trial compared the efficacy and safety of nirogacestat with placebo in adult patients with progressing desmoid tumors. A total of 142 patients were randomly assigned 1:1 to either receive 150 mg of nirogacestat (n =70) or placebo (n = 72) twice a day.
The primary end point of the trial was PFS as assessed by blinded independent central review. Secondary and exploratory end points included safety, objective response rate (ORR), duration of response, changes in tumor volume, and patient-reported outcomes.
Patients 18 years and older with histologically confirmed desmoid tumors that have progressed by at least 20% per RECIST v1.1 guidelines within 12 months of screening were eligible for enrollment. Additional inclusion criteria included having provided archival or new tumor tissue for reconfirmation of disease, an ECOG performance status of 2 or lower, and adequate organ and bone marrow function.
Confirmed ORR in the DeFi trial was 41% with nirogacestat vs 8% with placebo (P <.001), with complete response rates of 7% vs 0%. Additionally, nirogacestat produced statistically significant and clinically meaningful improvements in patient-reported outcomes including pain reduction (P <.001), other desmoid tumor-specific symptoms (P <.001), improved physical role functioning (P <.001), and overall health-related quality of life (P = .007).
Overall, 95% of treatment-emergent adverse effects (TEAEs) following nirogacestat therapy were grade 1 or 2. The most frequent TEAEs in the nirogacestat and placebo arms, respectively, included diarrhea (84% vs 35%), nausea (54% vs 39%), and fatigue (51% vs 36%). In each respective arm, dose reductions due to TEAEs occurred in 42% vs 0%, and treatment discontinuation due to TEAEs was necessary in 20% vs 1%, respectively.
Investigators observed ovarian dysfunction in 75% (n = 27/36) of patients of childbearing potential who received nirogacestat. Of these patients, 74% had their AEs resolve, including 64% who remained on nirogacestat treatment.