As reported in The New England Journal of Medicine by Gounder et al, the phase III DeFi trial has shown significant improvement in progression-free survival with the investigational oral γ-secretase inhibitor nirogacestat vs placebo in patients with desmoid tumors.

As noted by the investigators, there are no currently approved treatments for desmoid tumors. Nirogacestat may work by an effect of γ-secretase inhibition in blocking Notch pathway signaling, which is involved in desmoid tumor growth.

Study Details

In the double-blind trial, 142 patients with progressing tumors from sites in the United States, Canada, and Europe were randomly assigned between May 2019 and August 2020 to receive nirogacestat at 150 mg  (n =70) or placebo (n = 72) twice daily. Overall, 110 patients (77%) had received previous systemic therapies or radiation therapy or had undergone surgery. The primary endpoint was progression-free survival.

Progression-Free Survival

As of data cutoff (April 7, 2022), median follow-up for progression-free survival was 15.9 months. Progression-free survival events occurred in 12 patients in the nirogacestat group vs 37 in the placebo group (hazard ratio = 0.29; 95% confidence interval [CI] =  0.15-0.55, P < .001). Median progression-free survival was not reached (95% CI = not estimable to not estimable) vs 5.1 months (95% CI = 8.4 months to not estimable). The likelihood of being event-free at 1 and 2 years was 85% vs 53% and 76% vs 44%.

Objective response was observed in 29 patients (41%; complete response in 5, 7%) in the nirogacestat group vs 6 (8%; all partial responses) in the placebo group (P < .001). At time of analysis, responses were ongoing in 28 of 29 responders and in 5 of 6 responders, respectively. Median time to response was 5.6 months and 11.1 months, respectively.

Adverse Events

The most common adverse events of any grade in the nirogacestat group were diarrhea (84% vs 35% in placebo group), nausea (54% vs 39%), fatigue (51% vs 36%), hypophosphatemia (42% vs 7%), and maculopapular rash (32% vs 6%). Grade ≥ 3 adverse events occurred in 55% vs 17% of patients.

Adverse events led to discontinuation of treatment in 20% vs 1% of patients. Among 36 women of childbearing potential in the nirogacestat group, 27 (75%) had adverse events consistent with ovarian dysfunction, with events resolving in 20 women (74%).

Significant differences favoring nirogacestat were observed in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life (all P ≤ 01).

The investigators concluded: “Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade.”

Mrinal Gounder, MD, Memorial Sloan Kettering Cancer Center, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by SpringWorks Therapeutics. For full disclosures of the study authors, visit nejm.org.