Trials · for clinicians

DEFI Trial: Nirogacestat for Desmoid Tumors

4/4/2025 · 4 min read · updated 27 Oct 2026

Bottom line

Nirogacestat 150 mg BID: PFS HR 0.29, ORR 41% vs 8% vs placebo. First FDA-approved drug for desmoid tumours (Nov 2023). Ovarian dysfunction and diarrhoea are the key toxicities. Active surveillance is still first for asymptomatic, stable disease.

Background

Desmoid tumours (aggressive fibromatosis): locally aggressive, non-metastasising; driven by Wnt/β-catenin (CTNNB1 or APC/FAP).
Global consensus: active surveillance first; treat only progressive or symptomatic disease. Surgery is no longer default.
Pre-DeFi systemic options: sorafenib (phase 3, Gounder NEJM 2018), low-dose methotrexate–vinblastine, NSAIDs/tamoxifen (weak evidence), doxorubicin-based chemotherapy.

Trial design

Phase 3, double-blind; n=142 (70 nirogacestat, 72 placebo; enrolled May 2019–Aug 2020) with progressing desmoids not amenable to surgery (progression within 12 months of screening). Nirogacestat 150 mg twice daily vs placebo. Primary endpoint: PFS (blinded central RECIST 1.1 or adjudicated clinical progression).

Results

PFS: HR 0.29 (95% CI 0.15–0.55; p<0.001); median PFS not reached vs 15.1 mo (FDA); radiographic-only PFS HR 0.31 (0.16–0.62). [NEJM 2023]
2-year event-free probability: 76% vs 44%.
ORR 41% vs 8%; complete response 7% vs 0%; median time to response 5.6 vs 11.1 mo.
Improvements in pain, desmoid-specific symptoms, physical/role functioning and quality of life (all p≤0.01).

DeFi: key outcomes, nirogacestat vs placebo

2-yr event-free: nirogacestat76%

2-yr event-free: placebo44%

ORR: nirogacestat41%

ORR: placebo8%

Source: Gounder et al., NEJM 2023.

Safety

Diarrhoea 84%, nausea 54%, fatigue 51%, hypophosphataemia 42%, maculopapular rash 32%; 95% of AEs grade 1–2. Ovarian dysfunction in 27/36 (75%) women of childbearing potential, resolved in 20/27 (74%) — counsel on fertility and contraception. [NEJM 2023] Label warnings also include hepatotoxicity, non-melanoma skin cancers, electrolyte abnormalities, hypersensitivity reactions and embryo-fetal toxicity. [Label]

Place in therapy

NCCN lists nirogacestat as a preferred systemic option for progressive/symptomatic desmoids. Longer follow-up and the optimal duration of therapy remain open questions.

How nirogacestat works

γ-Secretase cleaves the Notch receptor; blocking it reduces Notch signalling, which interacts with the Wnt/β-catenin pathway that drives desmoid growth. The same mechanism explains several class effects (diarrhoea, skin changes, ovarian effects).

Endpoints and who was enrolled

Eligible patients had radiographic progression of ≥20% within 12 months before entry — the trial did not test treatment of stable, asymptomatic tumours.
Many had already received surgery, radiotherapy or systemic therapy; both treatment-naïve and pre-treated patients were included.
Progression was assessed by blinded central review (RECIST 1.1), with clinical progression also counted as an event.
Patient-reported outcomes (pain, desmoid symptoms, physical functioning) favoured nirogacestat. [NEJM 2023]

Practical prescribing

Dose: 150 mg (3 × 50 mg tablets) orally twice daily, with or without food, until progression/toxicity; after withholding for severe or intolerable toxicity, restart at 100 mg twice daily (FDA label). [Label]
Check phosphate and potassium; replace as needed.
Counsel women about menstrual changes and fertility; ovarian dysfunction resolved in most women in the trial after stopping or on continued therapy, but long-term effects are unknown.
Avoid strong or moderate CYP3A inhibitors/inducers (including grapefruit, Seville oranges, starfruit) and acid-reducing agents (PPIs, H2 blockers; stagger antacids if needed). [Label]
Adults only: safety/efficacy not established in children; growth-plate widening reported in paediatric patients with open physes.
Responses are slow: tumour shrinkage often takes months, and MRI changes (T2 signal reduction) can precede size change.

How other options compare

Sorafenib (phase 3 vs placebo, n=87): 2-year PFS 81% vs 36%; HR 0.13 (0.05–0.31); ORR 33% vs 20% before crossover; cheaper and available as a generic in India. [NEJM 2018]
Methotrexate + vinblastine/vinorelbine: low-dose, well tolerated, long experience — useful in children. Methotrexate is teratogenic, so it is not an option during pregnancy or for those planning conception without effective contraception.
Surgery: reserved for selected cases; recurrence is common and morbidity can exceed that of the tumour.
Pregnancy-associated desmoids often stabilise or regress after delivery — another reason to observe first.

The original oncosphere.in article was image-based and could not be recovered; this is a rewritten, referenced version under the same title.

Sources

Educational summary, not medical advice. Opinions are labelled as such and are the author's own. Approvals and availability in India (CDSCO) may differ from the US/EU.

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