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FDA Grants Breakthrough Designation to Nirogacestat for Desmoid Tumors

Lisa Astor
Published Online:9:47 PM, Tue September 3, 2019
The FDA has granted nirogacestat (PF-03084014), an investigational gamma-secretase inhibitor, with a breakthrough therapy designation for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.1

The breakthrough designation was granted as a result of positive findings seen in phase I and II trials of nirogacestat monotherapy in patients with desmoid tumors. A phase III trial has also been initiated investigating nirogacestat in patients with desmoid tumors or aggressive fibromatosis (NCT03785964).

“We are committed to pursuing the rapid development of nirogacestat given the important need for new therapies for patients with desmoid tumors and are pleased to receive this breakthrough therapy designation,” Saqib Islam, CEO of SpringWorks, the company developing the small molecule inhibitor, said in a statement. “We are currently enrolling adult patients in our phase III DeFi trial and will continue to work closely with the FDA with the goal of bringing nirogacestat to patients as quickly as possible.”

The open-label, single-center phase II trial of nirogacestat enrolled 17 patients with desmoid tumors who were not eligible for surgical resection or definitive radiation therapy and who had experienced disease progression after at least 1 prior treatment regimen. Patients received 150 mg twice per day of continuous, oral nirogacestat in 21-day cycles.2

The median age of patients was 34 years (range, 19-69), 82% of the patients were female, and 53% of patients had a CTNNB1 T41A somatic missense mutation. The median number of prior therapies was 4 (range, 1-9), which included cytotoxic chemotherapy in 71% and a tyrosine kinase inhibitor in 59%.

Sixteen patients were evaluable for response. After a median follow-up of more than 25 months, 5 patients (29%) achieved a partial response and 11 (65%) had stable disease, for a disease control rate of 100%. Ten patients (59%) remained on treatment with nirogacestat for more than 2 years.

Grade 1/2 adverse events were observed in all patients, with diarrhea (76%) and skin disorders (71%) being the most common toxicities. The only treatment-related grade 3 event was reversible hypophosphatemia, which was reported in 8 patients (47%) and was considered to be a class effect of gamma-secretase inhibitors. Four patients met the criteria for dose reduction.

Findings from the phase I study also showed a disease control rate of 100% with nirogacestat. However, the median progression-free survival was not reached in either study due to a lack of patients progressing on treatment. Only 1 patient discontinued treatment due to an adverse event between the 2 studies.1 

The FDA had previously granted nirogacestat with an orphan drug designation in June 2018 for the treatment of desmoid tumors, and with a fast track designation in November 2018 for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.
  1. SpringWorks Therapeutics Receives Breakthrough Therapy Designation for Nirogacestat for the Treatment of Adult Patients with Progressive, Unresectable, Recurrent or Refractory Desmoid Tumors [press release]. Stamford, CT: SpringWorks Therapeutics, Inc; August 29, 2019. https://bit.ly/30IV0Eb. Accessed September 3, 2019.
  2. Kummar S, O’Sullivan Coyne G, Do KT, et al. Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis). J Clin Oncol. 2017;35(14):1561-1569. doi: 10.1200/JCO.2016.71.1994.

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