Abstract

11556 Background: Desmoid tumors (DT) are rare, locally aggressive, soft-tissue tumors with a highly unpredictable natural course and substantial patient burden, including pain and functional limitations. Prognosis of DT is potentially dependent on multiple factors, including tumor location, size, patient’s age, mutational status, and presence of pain. Nirogacestat (niro), a targeted gamma secretase inhibitor, is the only treatment approved in the US for adults with progressing DT. In the phase 3 DeFi study, niro demonstrated significant and clinically meaningful improvement vs placebo (pbo) in the primary and key secondary endpoints of 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 (pain, DT-specific symptom burden, physical and role functioning, and overall quality of life; P≤0.01, all). The objective of this analysis was to determine the effect of niro in patient subgroups that have been associated with poor prognosis (larger tumor size, younger age, CTNNB1 mutation types, and pain). Methods: DeFi (NCT03785964) was a global, multicenter, double-blind study to determine the efficacy, safety, and tolerability of niro in adults with progressing DT. Patients were randomized 1:1 to niro 150 mg (n=70) or pbo (n=72), taken twice-daily in 28-day cycles. Post hoc analyses of PFS and ORR were conducted in individuals stratified by patient- and tumor-related prognostic factors. Results: PFS and ORR improvement favored niro vs pbo regardless of the patient subgroup, including: baseline tumor size (≤10 cm, >10 cm); age (≤30 y, >30 y); CTNNB1 mutation type (S45F, T41A); and baseline pain (uncontrolled, controlled) (Table). Across the subgroups analyzed, PFS hazard ratio ranged from 0.18 to 0.39, with values <1 favoring niro over pbo. ORR risk difference (niro – pbo) ranged from 18.1% to 56.0%, with values >0 favoring niro. Conclusions: Niro demonstrated consistent improvement in PFS and ORR vs pbo in patients with characteristics implicated as poor prognostic factors for DT—including larger tumor size, younger age, CTNNB1 mutation types, and pain. These results indicate that niro can provide substantial benefit across the subgroups analyzed. Clinical trial information: NCT03785964 . [Table: see text]