Desmoid Tumors: Phase 3 Clinical Trial Data With Nirogacestat Shows Promise

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07/04/23

Bernd Kasper, MD, PhD, University of Heidelberg, Mannheim Cancer Center, Mannheim, Germany and Principal Investigator of the phase 3 DeFi clinical trial, discusses the impressive results of the trial, which evaluated nirogacestat in the treatment of desmoid tumors.

Desmoid tumors can grow anywhere on the body into surrounding healthy tissues, including joints, muscle, and viscera. These rare tumors can cause significant pain, internal bleeding, and reduced mobility. These benign tumors are notoriously recurrent, especially with surgical removal, and each recurrence tends to be more aggressive than the previous tumor.

As Dr. Kasper explains, nirogacestat is an oral, selective, small molecule, gamma-secretase inhibitor. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which may contribute to desmoid tumor growth.

Data from the DeFi trial were recently presented as a late-breaking oral presentation during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2022. As Dr. Kasper states, the DeFi trial is a global, randomized (1:1), double-blind, placebo-controlled phase 3 trial evaluating the efficacy, safety and tolerability of nirogacestat in adult patients with progressing desmoid tumors.

The 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. The median Kaplan-Meier estimate of PFS was not reached in the nirogacestat arm and was 15.1 months in the placebo arm. Confirmed objective response rate (complete response + partial response) based on RECIST v1.1 was 41% with nirogacestat versus 8% with placebo. 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 as well, which were key secondary endpoints of the study. Specifically, nirogacestat significantly reduced pain and other DT-specific symptoms, and also significantly improved physical/role functioning and overall health-related quality of life..

SpringWorks Therapeutics plans to submit a New Drug Application (NDA) to the FDA in the second half of 2022, which will be submitted for review under the FDA’s Real-Time Oncology Review (RTOR) program.