FDA Grants Nirogacestat Breakthrough Designation for Desmoid Tumors

The FDA has granted a breakthrough therapy designation to the investigational gamma-secretase inhibitor nirogacestat (PF-03084014) for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.¹

The designation was based on phase I and phase II data of single-agent nirogacestat in patients with desmoid tumors. Based on the early encouraging results, the phase III DeFi trial (NCT03785964) is investigating nirogacestat in patients with desmoid tumors or aggressive fibromatosis.

“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, stated in a press release. “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 ineligible for surgical resection or definitive radiation therapy and who had experienced disease progression after ≥1 prior therapy. 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 (71%) and a TKI (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, leading to a disease control rate (DCR) of 100%. Ten patients (59%) remained on treatment with nirogacestat for >2 years.

Regarding safety, grade 1/2 adverse events were reported in all patients, with diarrhea (76%) and skin disorders (71%) being the most common AEs. The only treatment-related grade 3 AE 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.

Additionally, data from the phase I trial also showed a DCR of 100% with nirogacestat. However, the median progression-free survival was not reached in either study due to a lack of patients progressing on therapy. Only 1 patient discontinued treatment due to an AE between the 2 studies.

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.

References

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.