(P 33) DESCRIPTIVE EVALUATION OF PATIENTS WITH DESMOID TUMOR AND CO-OCCURRING SOMATIC MUTATIONS OF CTNNB1 AND APC IN THE PHASE 3 DEFI TRIAL

Objective: Desmoid tumors (DT) are rare, soft-tissue tumors driven by Wnt/β-catenin signaling pathway alterations. Most DT are sporadic tumors characterized by somatic mutations in the CTNNB1 gene that encodes for β-catenin. Approximately 10%–20% of DT are associated with mutations in the APC gene, which encodes for the adenomatous polyposis coli tumor suppressor protein that regulates cellular β-catenin levels.

Little is known about patients with DT and co-occurring somatic CTNNB1 and APC aberrations. The objective of this analysis was to describe the characteristics and outcomes of patients with this mutational profile who were enrolled in the DeFi trial.

Nirogacestat is an oral targeted gamma secretase inhibitor that is the only FDA-approved treatment for adults with progressing DT who require systemic treatment. In the phase 3 DeFi trial, nirogacestat demonstrated significant improvement vs placebo 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). In prespecified subgroup analyses of PFS and ORR, improvements with nirogacestat compared to placebo were observed in patients with somatic CTNNB1 mutations and in those with somatic APC mutations.

Methods: DeFi (NCT03785964) was a global, multicenter, double-blind, pivotal, phase 3 trial that evaluated the efficacy, safety, and tolerability of nirogacestat in adults (aged ≥18 years) with progressing DT. Patients were randomized (1:1) to receive oral nirogacestat (150 mg) or placebo twice daily in continuous 28-day cycles. This descriptive analysis represents data from patients identified with co-occurring somatic mutations in CTNNB1 and APC from DeFi. Tumor response was determined according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 through blinded independent central review and was confirmed.

Results: Of 142 patients randomized in the DeFi trial, 3 patients (n=2, nirogacestat; n=1, placebo) with evaluable tumor samples had co-occurring somatic mutations of CTNNB1 (nirogacestat: 1 patient each with S45F and S45P mutation; placebo: 1 patient with S45F mutation) and APC. All 3 patients had DT in the upper extremity or abdominal wall and had no family history of familial adenomatous polyposis. The 2 patients on nirogacestat had received prior therapy (systemic therapy and/or surgery), whereas the 1 patient on placebo had no prior therapy. Of the 2 patients randomized to nirogacestat, both achieved a best overall response of partial response (with time to response of 6.0 and 13.8 months). The 1 patient randomized to placebo experienced disease progression in 2.6 months. Adverse events reported in patients with co-occurring somatic mutations of CTNNB1 and APC were consistent with those reported in the overall DeFi population.

Conclusion: In the DeFi trial, 3 patients were identified with co-occurring somatic mutations of CTNNB1 and APC. The small number of patients limited a formal analysis. However, descriptive results suggest that patients with this mutational profile benefit from nirogacestat treatment in a manner that is generally consistent with the overall DeFi population.