FDA Extends Review Period for Nirogacestat NDA in Desmoid Tumors

The FDA has extended the Prescription Drug User Fee Act decision date by 3 months to allow more time to complete their review of the new drug application (NDA) seeking the approval of nirogacestat in the treatment of adult patients with desmoid tumors.¹

The regulatory agency granted priority review to the NDA in February 2023 and had set an action date of August 27, 2023.² The application was supported by findings from the phase 3 DeFi trial (NCT03785964), in which the agent reduced the risk of disease progression or death by 71% compared with placebo in this population (HR, 0.29; 95% CI, 0.15-0.55; P < .001).³

The Kaplan-Meier–estimated median progression-free survival (PFS) could not be estimated with nirogacestat (n = 70) because of a low number of events; however, the median PFS with placebo (n = 72) was 15.1 months (95% CI, 8.4-not estimable). The likelihood of being event free at 1 year was higher in the nirogacestat arm vs the placebo arm, at 85% (95% CI, 73%-92%) and 53% (95% CI, 40%-64%), respectively. The rates for being event free at 2 years were 76% (95% CI, 61%-87%) and 44% (95% CI, 32%-56%).

On June 2, 2023, the FDA notified SpringWorks Therapeutics, Inc., the drug developer, that more time was needed to assess the additional analyses of the previously submitted data that had been provided to the agency in response to initial information requests. Because the additional information provided was determined to represent a major amendment to the application, the decision date required extension.¹

The FDA has not requested additional findings or studies, according to SpringWorks.

“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,” Saqib Islam, chief executive officer of SpringWorks, stated 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.”

The international, double-blind, randomized, phase 3 trial enrolled patients with a histologically confirmed diagnosis of progressing desmoid tumors who were at least 18 years of age and who did not receive prior treatment for progressing disease that was not amenable to surgery or who had refractory or recurrent disease following at least 1 previous line of therapy.³

Study participants were randomly assigned 1:1 to receive oral nirogacestat at a twice-daily dose of 150 mg or placebo twice daily, received continuously as part of 28-day treatment cycles. Treatment continued until trial completion, clinical progression, intolerable toxicity, withdrawal per patient or investigator decision, or other circumstances that prevented the participant from adhering to protocol.

PFS served as the study’s primary end point, and secondary end points comprised confirmed objective response rate (ORR) and change from baseline at cycle 10 in several patient-reported outcome measures. Investigators also evaluated safety.

Overall, baseline characteristics were comparable between the arms and representative of the patient population. The median age was 34.0 years (range, 18-76), with 52% of female patients with childbearing potential. Most patients across the arms were White (83%), non-Hispanic or Latino (86%), from the United States or Canada (68.5%), and had an ECOG performance status of 0 (72.5%) with target tumors located in the extra-abdominal area (75.5%) and a focal category of single (59%).

Regarding treatment status, 26% of those in the nirogacestat arm and 19% of those in the placebo arm did not receive prior treatment; 74% and 81% of patients, respectively, had refractory or recurrent disease following prior treatment. The median number of lines of prior therapy received was 2 (range, 0-19). Previous treatment received in the investigative and control arms included surgery (44% vs 61%), radiation (23% vs 22%), and systemic therapy (61%, both), including chemotherapy (34% vs 38%), a TKI (33%, both), and sorafenib (Nexavar; 24% vs 25%).

Additional data from the trial published in The New England Journal of Medicine showed that 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.

Moreover, nirogacestat elicited a confirmed ORR of 41% compared with 8% who placebo (P < .001), and complete response rates were 7% and 0%, respectively. The median time to confirmed first response was 5.6 months and 11.1 months in the investigative and control arms, respectively. Additionally, the median best percent change in target tumor size in these groups was -27.1% (range, -100 to 37) and 2.3% (range, -100 to 47), respectively.

Any-grade adverse effects (AEs) occurred in all patients who received nirogacestat (n = 69) vs 96% of those who were given placebo (n = 72), with grade 3 or higher AEs reported in 55% and 17% of patients, respectively. Toxicity resulted in death in 1 patient in the placebo arm.

The most common AEs experienced by 15% or more of patients in the nirogacestat and placebo arms, respectively, included diarrhea (84% vs 35%), nausea (54% vs 39%), fatigue (51% vs 36%), hypophosphatemia (42% vs 7%), maculopapular rash (32% vs 6%), stomatitis (29% vs 4%), headache (29% vs 15%), dermatitis acneiform (22% vs 0%), vomiting (20% vs 19%), rash (19% vs 7%), hot flush (19% vs 6%), alopecia (19% vs 1%), increased alanine aminotransferase (17% vs 8%), COVID-19 (17% vs 17%), weight gain (16% vs 7%), cough (16% vs 4%), abdominal pain (16% vs 12%), increased aspartate aminotransferase (16% vs 11%), dyspnea (16% vs 6%), reduced appetite (16% vs 11%), dry skin (16% vs 7%), and tumor pain (7% vs 18%).

“We look forward to continuing to work closely with the FDA as they complete their review of the nirogacestat NDA,” Islam added.¹

Previously, in August 2019, the FDA granted a breakthrough therapy designation to nirogacestatfor use in adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.⁴ The regulatory agency also previously granted the agent orphan drug designation.¹ SpringWorks also shared expectations to file a marketing authorization application with the European Medicines Agency for nirogacestat in 2024.

References

1. FDA extending PDUFA date by three months to allow more time to complete their review; new PDUFA date set to November 27, 2023. News release. SpringWorks Therapeutics, Inc. June 5, 2023. Accessed June 7, 2023. https://ir.springworkstx.com/news-releases/news-release-details/springworks-therapeutics-announces-pdufa-date-extension
2. 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 June 7, 2023. https://ir.springworkstx.com/news-releases/news-release-details/springworks-therapeutics-announces-fda-acceptance-and-priority
3. Gounder M, Ratan R, Alcindor T, et al. Nirogacestat, a γ-secretase inhibitor for desmoid tumors. N Engl J Med. 2023;388(10):898-912. doi:10.1056/NEJMoa2210140
4. SpringWorks Therapeutics receives breakthrough therapy designation for nirogacestat for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors. News release. SpringWorks Therapeutics, Inc. August 29, 2019. Accessed June 7, 2023. https://ir.springworkstx.com/news-releases/news-release-details/springworks-therapeutics-receives-breakthrough-therapy