FDA OKs Nirogacestat for Treatment of Desmoid Tumors


Patients with desmoid tumors can now receive nirogacestat following the FDA’s approval of the agent.

 “I think the most important thing that comes out of having a second active drug and the first FDA-approved drug for the treatment of desmoid tumors is that patients actually have choices,” according to Brian Van Tine, MD, PhD.

“I think the most important thing that comes out of having a second active drug and the first FDA-approved drug for the treatment of desmoid tumors is that patients actually have choices,” according to Brian Van Tine, MD, PhD.

The News

The FDA has granted approval to nirogacestat as a treatment for patients with progressing desmoid tumors that require systemic therapeutics, according to a press release from the FDA.1

Expert Perspective

“I think the most important thing that comes out of having a second active drug and the first-FDA approved drug for the treatment of desmoid tumors is that patients actually have choices,” Brian Van Tine, MD, PhD, a professor of medicine in the Division of Oncology, Section of Medical Oncology at Washington University School of Medicine’s Siteman Cancer Center, said in an interview with CancerNetwork®.

“Sorafenib is a drug that you have to use carefully because you can get rashes on your hands and feet; you have some tolerance for nausea and some tolerance for fatigue. Nirogacestat has a different adverse effect profile…. There may be a selective advantage for one drug or over the other depending on a patient-centered discussion of which drug they'd like to try.”

Supporting Data

The approval of nirogacestat was supported by findings from the phase 3 DeFi trial (NCT03785964),in which investigators assessed the safety and efficacy of the agent compared with placebo among those with progressing desmoid tumors.2

According to data published in New England Journal of Medicine, the median progression-free survival (PFS) was not estimable (NE; 95% CI, NE-NE) with nirogacestat vs 15.1 months (95% CI, 8.4-NE) with placebo (HR, 0.29; 95% CI, 0.15-0.55; P <.001). Moreover, nirogacestat produced PFS benefits across patient subgroups based on characteristics including sex, tumor location, treatment status, focality, genetic mutation status, and history of familial adenomatous polyposis.

The confirmed objective response rates (ORR) in the nirogacestat and placebo arms, respectively, were 41% vs 8% (P <.001). Additionally, 7% and 0% of patients in each group experienced complete responses. The median time to confirmed first response was 5.6 months vs 11.1 months in each group.

Safety Information

Investigators indicated that nirogacestat elicited statistically significant improvements in patient-reported outcomes after 10 weeks of treatment, which included average worst pain intensity score (P <.001), total symptom score (P <.001), role functioning score (P <.001), physical functioning score (P <.001), and overall HRQOL score (P ≤.01).

The most common adverse effects (AEs) in the DeFi trial were diarrhea (84%), nausea (54%), fatigue (51%), hypophosphatemia (42%), and muscular rash (32%). Additionally, 95% of the observed AEs were grade 1 or 2. Of 36 patients of childbearing potential, 75% experienced AEs consistent with ovarian dysfunction, of whom 74% (n = 20/27) had their toxicities resolve.

DeFi Trial Design

In the international, double-blind phase 3 DeFi trial, patients were randomly assigned 1:1 to receive 150 mg of nirogacestat or matched placebo orally twice a day in continuous 28-day cycles.

The study’s primary end point was PFS. Secondary end points included ORR, changes in patient-reported outcomes, and HRQOL.

Patients 18 years and older with histologically confirmed progressing desmoid tumors and aggressive fibromatosis were able to enroll on the trial. Patients also needed to have an ECOG performance status of 0 to 2, and adequate organ and bone marrow function to enroll.

The FDA granted priority review to nirogacestat for those with desmoid tumors in February 2023.3


  1. FDA approves nirogacestat for desmoid tumors. News release. FDA. November 27, 2023. Accessed November 27, 2023. https://tinyurl.com/3zezwe53
  2. Gounder M, Ratan R, Alcindor T, et al. Nirogacestat, a γ-secretase inhibitor for desmoid tumors. N Engl J Med. 2023;388:898-912. doi:10.1056/NEJMoa2210140
  3. 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 July 6, 2023. bit.ly/3SxA1Qk
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