Efficacy and safety of nirogacestat in patients with desmoid tumor and adenomatous polyposis coli (APC) mutation: Phase 3 DeFi analyses.

• DOI: 10.1200/jco.2024.42.16_suppl.11558
• Publication Date: 2024-06-13T13:44:50Z
• Authors: Bernd Kasper; Noah Federman; Peter Reichardt; Steven Attia; Allison Lim; Vincent Amoruccio; Sunny Cho; Richard F. Riedel
• Keywords: Adenomatous polyposis coli

11558 Background: Nirogacestat (niro) is a targeted and selective gamma secretase inhibitor approved in the US for adults with progressing desmoid tumors (DT). In phase 3 DeFi study, niro demonstrated significant improvement vs placebo (pbo) progression-free survival (PFS: HR, 0.29 [95% CI: 0.15-0.55]; P<.001), objective response rate (ORR: 41% 8%; P<.001); patient-reported outcomes (PROs) of pain, DT-specific symptom burden, physical role functioning, overall quality life ( P≤.01, all). DT are driven by Wnt/β-catenin signaling pathway alterations about 10-20% associated mutations APC tumor suppressor gene, which may confer more aggressive behavior. Because patients do worse, regardless specific therapy, post hoc analysis was conducted to assess effects mutations. Methods: global, double-blind study that evaluated efficacy, safety, tolerability DT. Patients were randomized oral (150 mg) or pbo twice-daily continuous 28-day cycles. Descriptive analyses somatic and/or germline Results: Among 29 (niro=13; pbo=16), 19 (66%) female, 16 (55%) aged ≤30 years, 22 (76%) refractory prior treatment (with median lines treatment). mutation, PFS improved (HR, 0.21 0.05-1.00], P=.016). Confirmed ORR 38% (5/13) 13% (2/16) pbo. Niro-treated also had greater reduction best percent change from baseline compared pbo-treated target size (-29.5 +2.2), volumetric MRI (-71.0 +5.4), T2 hyperintensity (-74.1 -21.0). Across all PROs assessed — Brief Pain Inventory, GODDESS Symptom Scale Impact Scale, European Organisation Research Treatment Cancer Quality Life Questionnaire-Core 30 treated numerically at cycle 10 than Analyses limited due small sample size. Adverse events >50% niro-treated mutation diarrhea, nausea, rash maculopapular, fatigue; ovarian toxicity occurred 9 females reproductive potential (6 resolved, 2 lost follow-up, 1 ongoing receiving niro). Conclusions: Improvement PFS, ORR, imaging characteristics observed harboring Efficacy safety generally consistent findings population, suggesting can provide clinically meaningful benefit APCmutations. Clinical trial information: NCT03785964 .