The data from the Phase 3 DeFi trial of nirogacestat, an investigational oral gamma-secretase inhibitor, in adult patients with progressing desmoid tumours, was published in the New England Journal of Medicine (NEJM). Results from this study were previously presented at the European Society for Medical Oncology (ESMO) Congress in September 2022.
“Desmoid tumours are aggressive soft tissue tumours that can lead to substantial negative impacts on patients’ lives,” said Mrinal M. Gounder, M.D., sarcoma medical oncologist at Memorial Sloan Kettering Cancer Center (MSK) in New York City, an investigator in the DeFi trial and first author of the NEJM publication. “In the Phase 3 DeFi trial, nirogacestat demonstrated significant clinical efficacy and substantially improved pain, symptom burden, physical and role functioning, and health-related quality of life in desmoid tumour patients. Importantly, nirogacestat exhibited a manageable safety profile. These results represent a noteworthy therapeutic advance for patients.”
As reported in the NEJM publication and previously presented at ESMO, the DeFi trial met its primary endpoint of improving progression-free survival (PFS), 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). Median PFS was not reached in the nirogacestat arm and was 15.1 months in the placebo arm. Nirogacestat improved PFS across pre-specified subgroups, including sex, tumour location, focality, prior treatment status (including treatment-naïve or previous treatment with chemotherapy or tyrosine kinase inhibitors), prior surgery, mutation status, and history of familial adenomatous polyposis.
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 also demonstrated statistically significant and clinically meaningful improvements in patient-reported outcomes (PROs), which were key secondary endpoints of the study. Specifically, at Cycle 10 nirogacestat significantly reduced pain (p<0.001) and other desmoid tumour-specific symptoms (p<0.001) and also significantly improved physical/role functioning (p<0.001) and overall health-related quality ofi life (p≤0.01).1 Improvements in most PROs occurred early (at Cycle 2, the first post-treatment timepoint evaluated) and were sustained throughout the trial.
At the time of primary analysis data cutoff on April 7, 2022, the median follow-up for PFS was 15.9 months. 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 that occurred in participants receiving nirogacestat were diarrhoea (84%), nausea (54%), fatigue (51%), hypophosphatemia (42%), and maculopapular rash (32%). Ovarian dysfunction, which was defined by events of amenorrhea, premature menopause, menopause, and ovarian failure, was observed in 75% (27/36) of women of childbearing potential receiving nirogacestat. As of the extended follow-up date of July 20, 2022, these events resolved in 74% (20/27) of the affected participants, including 64% (9/14) of participants who remained on nirogacestat treatment and 100% (11/11) of participants who were off of treatment for any reason.
“There is a great unmet need for patients with desmoid tumours as there are no approved therapies. We are very pleased that nirogacestat provided benefit across all prespecified subgroups in the study, which underscores the potential to broadly serve desmoid tumour patients regardless of tumour location, prior treatments or surgery, or genetic mutation,” said Saqib Islam, Chief Executive Officer of SpringWorks. “We look forward to working with the FDA as they review our NDA, and we are excited by the opportunity to make a profound impact on this underserved patient population.”
Watch Dr Bernd Kasper's video on the phase 3 DeFi trial here.
Watch Dr Bishal Gyawali's comment here.