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Notch pathway inhibitor nirogacestat improves outcomes in patients with desmoid tumours

Desmoid tumours are rare, locally aggressive and invasive soft-tissue tumours for which there is no approved systemic therapy. By targeting the Notch pathway with the novel gamma secretase inhibitor nirogacestat, the DeFi trial obtained positive results for patients with these types of tumours. In fact, in this study, nirogacestat improved the progression-free survival (PFS) and reduced the symptom burden of patients with desmoid tumours.

Desmoid tumours (DT) are rare, locally aggressive and invasive soft-tissue tumours that are challenging to manage due to their heterogenous presentation, their unpredictable disease course and a lack of approved therapies. Treatment should be individualised to optimise tumour control and improve symptom burden, including pain, physical function and overall quality of life. There is a mechanistic rationale for the use of gamma secretase inhibitors (GSI) in DT as these tumours highly express Notch, which can be blocked by GSI. Nirogacestat is an investigational, oral, selective, small-molecule GSI that has shown evidence of antitumour activity in DT in phase I and II trials with a manageable adverse event profile.

Study design

DeFi is a global, phase III, randomised, double-blind, placebo-controlled trial comparing the efficacy, safety and tolerability of nirogacestat (niro) vs. placebo in adults with progressing DT per RECIST v1.1 (NCT03785964). In order to be eligible, patients had to be treatment-naïve with DT not amenable to surgery or have refractory or recurrent disease (after ≥1 line of therapy). In total, 142 participants across 37 sites in North-America and Europe were stratified by target tumour location (intra-/extra-abdominal) and randomised 1:1 to niro (N= 70) 150 mg or placebo (N= 72) BID. The primary endpoint was PFS per blinded independent central review, with safety, objective response rate (ORR), and patient-reported outcomes (PROs) as pre-specified secondary endpoints.


Baseline demographics and characteristics were generally well-balanced between the two treatment arms and patients had a median age of 34 years. Two third of patients were female. Results showed a statistically significant improvement in PFS in patients randomised to nirogacestat compared to the placebo group, with a 71% lower risk of disease progression (HR[95%CI]: 0.29[0.15-0.55], p< 0.001). Median PFS was not reached for niro and was 15.1 months for placebo. The PFS advantage of niro was consistent across all subgroups, including gender, mutation status, target tumour location, focality, and prior treatments. In addition, the response rate was also much higher – 41% in the nirogacestat arm and only 8% in the placebo arm (p< 0.001). Five patients (7%) showed a complete response with the agent. Median time to objective response was 5.6 months with niro, as compared to 11.1 months with placebo. Niro resulted in substantial reductions in tumour size. There was a statistically significant benefit in reduction of pain and total symptom burden and improvement in physical and role functioning and in health-related quality of life at cycle 10 compared with placebo.

Nearly all adverse events (95%) with niro were of grade 1/2, the most frequently reported being diarrhoea (84%), nausea (54%), fatigue (51%), hypophosphatemia (42%), and maculopapular rash (32%). Ovarian dysfunction occurred in 75% (27/36) of women of childbearing potential treated with niro and resolved in 20 (74%), including all eleven women who discontinued niro for any reason. No treatment-emergent adverse events leading to death were reported for niro.


DeFi represents the largest and most rigorous randomised controlled trial conducted to date in DT. Nirogacestat demonstrated rapid, sustained, and statistically significant improvements in all primary and secondary efficacy endpoints. Nirogacestat exhibited a manageable safety profile, with 95% of all treatment-emergent adverse events being grade 1 or 2. In conclusion, nirogacestat has the potential to become the standard of care for patients with DT requiring systemic treatment.


Kasper B, et al. DeFi: A phase 3, randomized controlled trial of nirogacestat versus placebo for progressing desmoid tumors (DT). Presented at ESMO 2022; Abstract LBA2.

Speaker Bernd Kasper

Bernd Kasper

Bernd Kasper, MD, PhD, Mannheim Cancer Center (MCC), Mannheim, Germany


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