Nirogacestat in patients with desmoid tumors and mutations of adenomatous polyposis coli ( <i>APC</i> ): Findings from the DeFi trial.
Authors: Noah Federman, Bernd Kasper, Peter Reichardt, Richard F. Riedel, Ana Belen Oton, Yucheng Chu, Brian Andrew Van Tine
Journal: Journal of Clinical Oncology (2025)

134 Background: Nirogacestat (niro) is an oral, targeted gamma secretase inhibitor FDA-approved for adults with progressing desmoid tumors (DT) who require systemic treatment. In the phase 3 DeFi trial (NCT03785964), niro demonstrated significant improvement vs placebo (pbo) in progression-free survival (PFS; HR 0.29 [95% CI: 0.15–0.55], P &lt;.001) and objective response rate (ORR; 41% vs 8%, P &lt;.001). Most DT are sporadic tumors characterized by somatic mutations in the CTNNB1 gene. About 10%–20% of DT are associated with APC mutations, the majority being germline that may cause familial adenomatous polyposis (FAP), an inheritable trait linked to an increased risk of colorectal cancer and may also confer more aggressive DT behavior. Methods: In DeFi, adult patients (pts) were randomized to oral niro (150 mg) or pbo twice daily. In pts with evaluable blood and tumor samples, descriptive post hoc analyses assessed effects of niro in pts with germline and/or somatic APC mutations, including pts with co-occurring somatic mutations of APC and CTNNB1 . Results: Of the 142 pts in DeFi, 29 pts had APC mutations (niro=13, pbo=16; 22 somatic, 21 germline, and 14 somatic and germline), including 3 pts (niro=2, pbo=1) with co-occurring somatic mutations of APC and CTNNB1 . Of these 29 pts, 19 (66%) were female, 16 (55%) were aged ≤30 y, 22 (76%) had a family history of FAP, and 22 (76%) were refractory to prior therapy (median of 3 prior lines of therapy). 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; median time to response with niro was 8.31 months. All 3 pts with co-occurring somatic mutations of APC and CTNNB1 were female, aged 18–56 y, had DT in the upper extremity or abdominal wall, and had no family history of FAP. The 2 pts on niro had received prior systemic therapy and/or surgery and the 1 pt on pbo had no prior therapy. Of the 2 pts on niro, both achieved a partial response (median time to response: 9.9 months). The 1 pt randomized to pbo experienced disease progression in 2.6 months. In pts with APC mutations, diarrhea was the most frequently reported adverse event. In niro-treated pts, increased rates of skin events (maculopapular rash, 62%; dermatitis acneiform, 38%) and stomatitis (46%) were reported in pts with APC mutations compared with those in the overall DeFi population (32%, 22%, and 29%, respectively). Conclusions: Improvement in PFS and ORR was observed with niro vs pbo in pts with DT harboring APC mutations. Efficacy and safety of niro in pts with APC mutations were generally consistent with findings for the overall DeFi population. Although analyses were limited due to small sample size, these results suggest that niro can provide clinically meaningful benefit to pts with progressing DT and APC mutations, including those with co-occurring somatic mutations of APC and CTNNB1 . Clinical trial information: NCT03785964 .