Background
Phase III international, double-blind, randomised, placebo-controlled trial (DeFi). N=142 with progressing desmoid tumours (aggressive fibromatosis) requiring systemic treatment, age ≥18 yr; 54 sites, 12 countries, 2019-2021. Desmoid tumours are locally aggressive, non-metastasising neoplasms driven by aberrant Notch signalling after CTNNB1/APC mutation. Nirogacestat is an oral selective gamma-secretase inhibitor blocking Notch ligand processing; previously no approved systemic therapy existed. NCT03785964.
Interventions and follow up
Arm A: Nirogacestat 150 mg PO twice daily continuously
Arm B: Matching placebo PO twice daily; crossover to nirogacestat permitted at progression
Primary endpoint: Progression-free survival by blinded independent central review per RECIST 1.1
mFollow up: Median ~19 mo
Arm B: Matching placebo PO twice daily; crossover to nirogacestat permitted at progression
Primary endpoint: Progression-free survival by blinded independent central review per RECIST 1.1
mFollow up: Median ~19 mo
Results
mPFS: not reached (nirogacestat) vs 15.1 mo (placebo); HR 0.29 (95% CI 0.15-0.55), P<.001
ORR: 41% (nirogacestat) vs 8% (placebo) — significant
Pain improvement: significantly greater with nirogacestat (patient-reported outcomes)
Physical functioning: significantly improved with nirogacestat
ORR: 41% (nirogacestat) vs 8% (placebo) — significant
Pain improvement: significantly greater with nirogacestat (patient-reported outcomes)
Physical functioning: significantly improved with nirogacestat
Adverse events
Severity: most AEs grade 1-2
Grade ≥3: diarrhea 10%, fatigue 8%, hypophosphatemia 7%, rash 6%
Ovarian toxicity (CTCAE grade ≥1): 75% of premenopausal women (amenorrhoea, premature ovarian insufficiency); most reversible after discontinuation
Other: no increase in non-desmoid malignancies; dose reductions in ~40%
Grade ≥3: diarrhea 10%, fatigue 8%, hypophosphatemia 7%, rash 6%
Ovarian toxicity (CTCAE grade ≥1): 75% of premenopausal women (amenorrhoea, premature ovarian insufficiency); most reversible after discontinuation
Other: no increase in non-desmoid malignancies; dose reductions in ~40%
Conclusions
Nirogacestat significantly improved PFS (HR 0.29, P<.001), ORR (41% vs 8%), pain, and quality of life versus placebo in progressing desmoid tumours — the first positive phase III trial in desmoid tumours and the first FDA-approved therapy for the disease.
Key Limitations
PFS primary endpoint with immature/uncrossed OS and crossover at progression confounding survival inference. High ovarian-toxicity rate (75% of premenopausal women) raises fertility concerns. Some desmoids spontaneously stabilize/regress, so durability of benefit beyond ~19 mo follow-up remains to be defined.
Clinical Context
Nirogacestat received FDA approval (Nov 2023) as the first agent specifically for progressing desmoid tumours requiring systemic treatment. ESMO recognizes active surveillance as initial management, with gamma-secretase inhibition, TKIs (sorafenib, pazopanib), or low-dose chemotherapy for progressive/symptomatic disease.