SpringWorks Therapeutics, Inc. announced that data from the Phase 3 DeFi trial of nirogacestat, an investigational oral gamma secretase inhibitor, in adult patients with progressing desmoid tumors, are being presented as a late-breaking oral presentation during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2022. The DeFi trial met its primary endpoint of improving progression-free survival (PFS), as assessed by blinded independent central review, demonstrating a statistically significant improvement for nirogacestat over placebo, with a 71% reduction in the risk of disease progression (hazard ratio (HR) = 0.29 (95% CI: 0.15, 0.55); p< 0.001). The median Kaplan-Meier estimate of PFS was not reached in the nirogacestat arm and was 15.1 months in the placebo arm.

A PFS benefit was observed across all prespecified subgroups, including gender, tumor location, prior treatment or surgery, and mutational status. Confirmed objective response rate (complete response + partial response) based on RECIST v1.1 was 41% with nirogacestat versus 8% with placebo (p<0.001). The complete response rate was 7% in the nirogacestat arm and 0% in the placebo arm.

Nirogacestat demonstrated statistically significant and clinically meaningful improvements in patient-reported outcomes (PRO), which were key secondary endpoints of the study. Specifically, nirogacestat significantly reduced pain (p<0.001) and other DT-specific symptoms (p<0.001) and also significantly improved physical/role functioning (p<0.001) and overall health-related quality of life (p=0.007). Most PRO benefits were observed as early as Cycle 2, which was the first timepoint for post-treatment evaluation, and were sustained over the duration of the study.

At the time of primary analysis (April 7, 2022), the median duration of treatment was 20.6 months for participants on nirogacestat and 11.4 months for those on placebo, with the majority of nirogacestat patients continuing on treatment. Nirogacestat exhibited a manageable safety profile in the DeFi trial, with 95% of all treatment-emergent adverse events (TEAEs) reported as Grade 1 or 2. The most frequently reported TEAEs in participants receiving nirogacestat as compared to the placebo arm were diarrhea (84% vs 35%), nausea (54% vs 39%), and fatigue (51% vs 36%). Forty-two percent of patients in the nirogacestat arm vs 0% in the placebo arm required dose reductions due to TEAEs and 20% of patients in the nirogacestat arm vs 1% in the placebo arm discontinued treatment due to TEAEs.

Ovarian dysfunction, which was defined by investigator-reported events of amenorrhea, premature menopause, menopause, and ovarian failure, was observed in 75% (27/36) of women of childbearing potential receiving nirogacestat. These events resolved in 74% (20/27) of the affected participants, including 64% (9/14) of such participants who remained on nirogacestat treatment and 100% (11/11) of those participants who discontinued treatment for any reason.