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


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
APC mutant desmoid tumor predicted - sensitive Nirogacestat Phase III Actionable In a Phase III trial (DeFi), Ogsiveo (nirogacestat) treatment resulted in improved progression-free survival (HR=0.21, p=0.016) and improved objective response rate (38% (5/13) vs. 13% (2/16)) compared to treatment with placebo in patients with desmoid tumors harboring mutations in APC (J Clin Oncol 42, 2024 (suppl 16; abstr 11558); NCT03785964). detail...