The FDA has requested additional time to assess the analyses of previously submitted data from the phase 3 DeFi trial of nirogacestat in desmoid tumors, leading to an extension of the Prescription Drug User Fee Act decision date.
The FDA has extended the Prescription Drug User Fee Act decision date by 3 months for the new drug application (NDA) seeking the approval of nirogacestat in the treatment of adult patients with desmoid tumors, according to SpringWorks Therapeutics, Inc.1
Previously in February 2023, the FDA granted priority review to the NDAand set an action date of August 27, 2023, based on findings from the phase 3 DeFi trial (NCT03785964).2 In the study, treatment with nirogacestat reduced the risk of disease progression or death by 71% vs placebo in this patient population (HR, 0.29; 95% CI, 0.15-0.55; P < .001).3
The FDA has since notified the drug developer that they needed more time to assess the additional analyses of the previously submitted data in response to initial information requests. The additional information provided was determined to represent a major amendment to the application. Therefore, the decision date was extended.1 Additionally, the FDA has not requested new or additional findings or studies, with their request.
“We are confident that the comprehensive data from our phase 3 DeFi trial demonstrate the transformative benefits that nirogacestat can bring to people with desmoid tumors, who currently do not have an approved therapy,” said Saqib Islam, chief executive officer of SpringWorks, in a press release. “We remain committed to bringing this much needed therapy to patients and believe that our operational and manufacturing readiness positions us well to rapidly serve the desmoid tumor community following an approval.”
In the international, double-blind, randomized, phase 3 trial, patients were enrolled if they had a histologically confirmed diagnosis of progressing desmoid tumors, were 18 years of age or older, had not received prior treatment for progressing disease, was not amenable to surgery, or had refractory or recurrent disease after receiving at least 1 prior line of therapy.3
Once enrolled, patients were randomized in a 1:1 fashion to receive either oral nirogacestat at 150 mg twice a day or placebo twice daily, given continuously as part of 28-day treatment cycles. Patients continued to receive treatment until completion of the trial, clinical progression, intolerable toxicity, withdrawal per patient or investigator decision, or another reason preventing the patient from adhering to protocol.
The primary end point of the study was PFS with secondary end points of confirmed objective response rate (ORR) and change from baseline at cycle 10 in several patient-reported outcome measures. Additional end points of the study assessed safety.
According to additional data from the trial that were published in The New England Journal of Medicine, the PFS data were overall consistent across subsets such as sex, tumor location, focality, treatment status, prior treatment, genetic mutational status, and history of familial adenomatous polyposis.
Among patients treated with nirogacestat (n = 70), the Kaplan-Meier-estimated median progression-free survival (PFS) could not be estimated as there were a low number of events. However, those given placebo (n = 72) had a median PFS of 15.1 months (95% CI, 8.4-not estimable), and the likelihood of being event-free at 1 year was higher for those given nirogacestat vs placebo, at 85% (95% CI, 73%-92%) and 53% (95% CI, 40%-64%), respectively. Moreover, the rates for being event free at 2 years were 76% (95% CI, 61%-87%) and 44% (95% CI, 32%-56%).
Treatment with nirogacestat also led to a confirmed ORR of 41% vs 8% with placebo (P < .001). The complete response rates were 7% with nirogacestat and 0% with placebo, respectively. In the investigative vs control arms, the median time to confirmed first response was 5.6 months and 11.1, respectively, and the median best percent change in target tumor size was -27.1% (range, -100 to 37) vs 2.3% (range, -100 to 47).
Looking at safety, any-grade adverse events (AEs) were observed in 100% of patients given nirogacestat vs 96% of patients given placebo. Grade 3 or higher AEs were seen in 55% of patients in the nirogacestat arm and 17% of patients in the placebo arm, respectively.
“We look forward to continuing to work closely with the FDA as they complete their review of the nirogacestat NDA,” added Islam, in the press release.1