In DeFi, a phase III randomised, placebo-controlled study of nirogacestat, an oral γ-secretase inhibitor, conducted in patients with progressing desmoid tumours, nirogacestat showed rapid and sustained improvements with respect to progression-free survival (PFS), objective response, pain, disease-specific symptom burden, physical functioning, role functioning, and health-related quality of life (HRQoL). Treatment with nirogacestat resulted in a 71% lower risk of disease progression or death than placebo according to blinded central review, with 41% of patients having a confirmed objective response and 7% having a complete response. Adverse events were mainly low-grade and transient. The study findings are published by Dr. Mrinal Gounder of the Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues on 9 March 2023 in The New England Journal of Medicine.
Desmoid tumours, or aggressive fibromatosis, are rare, soft-tissue tumours that are diagnosed in approximately 3 to 5 persons per million annually. Although they are not metastatic, desmoid tumorus are locally aggressive and invasive. Compression of vital structures can result in severe pain, functional impairment, nerve damage, and bowel obstruction or perforation. Symptoms can negatively affect school, work, and psychosocial functioning.
Management of desmoid tumours is challenging because of their variable presentation and unpredictable disease course, with spontaneous regression seen in up to 20-30% of patients over time. Treatment approaches can incorporate periods of active surveillance, as well as interventions including surgery, chemotherapy, tyrosine kinase inhibitors, local ablation, or radiotherapy. Surgery, considered to be the mainstay of treatment, has become less frequent owing to high morbidity and postsurgical recurrence rates of up to 50-88%.
Desmoid tumours are typically characterised by genetic mutations in CTNNB (approximately 90% and primarily in sporadic-type desmoid tumours) and APC (approximately 10% and seen in desmoid tumours associated with familial adenomatous polyposis or Gardner’s syndrome). Along with overexpression of β-catenin, desmoid tumours highly express Notch1. Overactivation of the Notch pathway in desmoid tumours may be regulated by γ-secretase inhibitors. In phase I and II studies, nirogacestat showed activity in patients with desmoid tumours; patient-reported pain palliation was also observed.
In DeFi, patients were assigned in a 1:1 ratio to receive nirogacestat 150 mg or placebo twice daily. The primary endpoint was PFS. From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo.
Nirogacestat had a significant PFS benefit over placebo (hazard ratio for disease progression or death 0.29; 95% confidence interval 0.15 to 0.55; p < 0.001). The likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in PFS were consistent across prespecified subgroups.
The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; p < 0.001), with a median time to response of 5.6 months and 11.1 months. The percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and HRQoL, were observed (p ≤ 0.01).
Frequent adverse events with nirogacestat included diarrhoea in 84% of the patients, nausea in 54%, fatigue in 51%, hypophosphatemia in 42%, and maculopapular rash in 32%. However, 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%).
Based on preclinical data, the ovarian dysfunction associated with nirogacestat may be due to the disruption of Notch signalling required for ovarian follicular cycling. Amenorrhoea was a safety signal identified and monitoring of reproductive hormones was added for all the patients, which enabled a more comprehensive characterisation of these events. Further evaluation of ovarian dysfunction in patients who transitioned to the DeFi open-label extension is ongoing.
The authors commented that inhibitors of γ-secretase, initially developed for Alzheimer’s disease and later investigated as anticancer treatment, have yet to be used in clinical practice. Although long-term treatment with nirogacestat was shown to be feasible, the appropriate treatment duration is unknown. Nirogacestat is being further evaluated in children with desmoid tumours, in patients with ovarian granulosa-cell tumours, and across multiple studies in combination with B-cell maturation antigen therapeutic agents in patients with multiple myeloma.
The study was funded by SpringWorks Therapeutics.
Reference
Gounder M, Ratan R, Alcindor T, et al. Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors. N Engl J Med 2023;388:898-912.
