Nirogacestat Yields Clinical Improvement in Patients With Desmoid Tumors

Results from the phase 3 placebo-controlled DeFi trial (NCT03785964) show that nirogacestat (PF-03084014) yielded significant improvement vs placebo in progression-free survival (PFS), objective response rate (ORR), and patient-reported outcomes (PRO) in patients with progressing desmoid tumors (DT).¹

What were the safety and efficacy results?

The median exposure was 20.6 months (range, 0.3-33.6 months). The median duration of exposure was 33.6 months (range, 0.3-61.8 months) (n = 69; safety population). Median PFS was not achieved in the nirogacestat arm and was about 15 months in the placebo arm (HR, 0.29; 95% CI, 0.15-0.55; P <.001]). ORR with up to 4 years of nirogacestat treatment was 45.7% (n = 32/70), with 3 additional partial responses (PR) and 3 additional complete responses (CR) since the primary analysis.

Progression or death did not occur with additional exposure after year 2. ORR improved with long-term treatment of nirogacestat (n = 70). The ORR was 34.3%, 41.4%, 44.3%, and 45.7% in patients who received nirogacestat for up to 1, 2, 3, and 4 years, respectively. Between years 3 and 4 of treatment, 34.3% of patients experienced PRs, and 11.4% of patients experienced CRs.

Target tumor size continued to reduce through long-term nirogacestat treatment, inclusive of patients with stable disease (SD).

Most treatment-emergent adverse events (TEAEs) were grade 1 or 2 and reported during the first year of treatment. TEAEs decreased in severity and frequency through the years of treatment in patients who continued after the first year. Since the primary analysis, 5 additional patients experienced a dose reduction due to TEAEs, and no patients had a dose reduction after year 3. Between years 2 and 4, 4 patients discontinued treatment due to TEAEs. The most common TEAEs among patients were diarrhea, nausea, and fatigue.

What was the methodology of the study?

The DeFi trial had a total of 142 patients randomly assigned to a double-blind (DB) placebo-controlled phase. If eligible, patients continued in an optional open-label extension (OLE) phase that evaluated efficacy and safety.

Patients who were initially randomly assigned to receive oral nirogacestat 150 mg twice daily in continuous 28-day cycles were included in the long-term analysis. Patients who received nirogacestat in the DB phase of the trial were eligible to continue receiving treatment in the OLE phase after the primary analysis was completed, or after experiencing imaging-based disease progression per ICR. The final data cutoff date of the trial was December 19, 2024.

What were the patient inclusion and exclusion criteria?

Patient eligibility for the DB phase of the trial included, but was not limited to, having histologically confirmed DT that has progressed by ≥ 20% as measured by RECIST v1.1 within 12 months of the screening visit scan, having treatment naive, measurably progressing DT that is not amenable to surgery, recurring, measurably progressing DT following at least 1 line of therapy, and having a DT tumor where continued progressive disease will not result in immediate significant risk to the participant.

Patient exclusion criteria for the DB phase of the trial included, but were not limited to, having a known malabsorption syndrome or preexisting gastrointestinal conditions, having an abnormal QT interval at screening, and having a congenital long QT syndrome.

In the OLE phase of the trial, to be eligible, patients had to be enrolled in the DB phase when the estimated number of PFS events had been observed and the primary PFS analysis had been completed, or the patient was randomized to receive placebo in the DB phase and central imaging review determined that the patient had radiographic progressive disease.

Exclusion criteria of the OLE phase included, but were not limited to, the patient needing surgery to prevent organ dysfunction, prematurely discontinuing from the DB phase for any reason other than radiographic progressive disease, and developing a concurrent illness or condition that would represent a risk to overall health.

What are the next steps in research?

A phase 4 study (NCT07176689)² is currently recruiting premenopausal women with progressing DT/aggressive fibromatosis (AF) to evaluate the efficacy of nirogacestat on ovarian function. Additionally, a phase 2 study (NCT05879146)³ is being conducted to evaluate the safety and efficacy of nirogacestat in patients with DT/AF.

“These data characterize the long-term efficacy and safety of continuous nirogacestat use in adult patients with DT,” concluded the authors of the study, Ratan et al.¹ “Ongoing nirogacestat treatment was associated with a manageable safety profile, sustained PRO benefit, improved ORR, and further reduction in tumor size. These results provide a better understanding of the long-term benefit of nirogacestat in patients with progressing DT and may help inform treatment decisions to improve patient care.”

REFERENCES:

1. Ratan R, Kasper B, Alcindor T, et al. Efficacy and Safety of Long-Term Continuous Nirogacestat Treatment in Adults With Desmoid Tumors: Results From the DeFi Trial. J Clin Oncol 0, JCO-25-00582 doi:10.1200/JCO-25-00582.

2. Nirogacestat in Premenopausal Females With Desmoid Tumor/Aggressive Fibromatosis (DTAF). ClincialTrials.gov. Updated September 16, 2025. Accessed October 27, 2025. https://www.clinicaltrials.gov/study/NCT07176689

3. Evaluation of the Response and Non-response of Nirogacestat in Demoid Tumors-Clinical Study. ClinicalTrials.gov. Updated August 14, 2025. Accessed October 27, 2025. https://www.clinicaltrials.gov/study/NCT05879146