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

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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
<.001) and objective response rate (ORR; 41% vs 8%,
P
<.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
.