Dr Kasper on the Evaluation of Nirogacestat in Desmoid Tumors in the DeFi Trial

Bernd Kasper, MD, PhD, professor, Mannheim University Medical Center, discusses the effect of nirogacestat on tumor volume and T2 hyperintensity in patients with desmoid tumors.

Patients with desmoid tumors are known to experience substantial disease-related pain symptoms that greatly decrease their quality of life, Kasper begins. The phase 3 DeFi trial (NCT03785964) assessed the ability of the novel gamma secretase inhibitor nirogacestat to improve survival outcomes and reduce aspects of disease-related pain for patients with progressing desmoid tumors when compared with placebo, Kasper states.

Initial findings from the DeFi trial were reported at the 2022 ESMO Annual Congress, and showed that patients with progressing desmoid tumors experienced a statistically significant progression-free survival (PFS) increase with nirogacestat (n = 70) vs placebo (n = 72; HR, 0.29; 95% CI, 0.15–0.55; P < 0.001). Based on these findings, the FDA granted priority review status to a new drug application (NDA) for nirogacestat in this population.

The impact of nirogacestat on MRI tumor volume and T2 hypersensitivity in patients enrolled in the DeFi study was reported at the 2023 ASCO Annual Meeting, Kasper continues. Changes in MRI tumor volume or T2 signal intensity were hypothesized to have prognostic or predictive value for responses in this space. This is the largest dataset to prospectively evaluate these metrics in desmoid tumors, Kasper notes.

Imaging-based results showed that nirogacestat significantly reduced tumor volume and T2 hypersensitivity vs placebo, he reports. Patients in the nirogacestat arm and placebo arm had similar ratios of T2 hyperintensity, which were 95% and 97% respectively. However, this ratio changed from greater than 90% at baseline to less than 90% at any time after baseline in 34% of patients in the nirogacestat arm and 15% of those in the placebo arm.

These exploratory findings are consistent with improvements in overall response rate seen with nirogacestat and indicate that these measures can help guide the evaluation of treatment responses for patients with desmoid tumors.

Dr. Kaspar reports serving as a consultant or in an advisory role for Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehringer Ingelheim, GlaxoSmithKline, and SpringWorks Therapeutics; he received honoraria from Bayer, GlaxoSmithKline, and Pharmamar-zeltia.