Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis)

Abstract

Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the γ-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.

Fig 1.

Patient response and mutation status. Best response of partial response is shown with a blue arrow. Mutations in APC and CTNNB1 genes are shown. Ten patients remain on study (gold arrow).

Fig 2.

Antitumor activity of PF-03084014. (A) Objective response measured by RECIST 1.1 criteria. Five patients achieved a partial response to PF-03084014. Dotted lines represent cutoffs for partial response (−30% change from baseline) and for progressive disease (+20% change from baseline). Patient #01 is not shown because of a missing baseline computed tomography measurement, and patient #14 was not evaluable per protocol. Patients who consented to magnetic resonance imaging (MRI) are denoted with an asterisk (*). (B) Representative pre- and post-treatment MRI scans for patient #16 who presented with a left axillary mass that had recurred after surgical resection before enrollment in the current study. Contrast-enhanced axial T1-weighted MRI of the chest shows a 3.4 × 2.02 cm soft-tissue lesion in the left axilla at baseline MRI (red arrow), which decreased in size after cycle 12 (ie, 9 months of treatment [2.17 × 1.36 cm; red arrow]). For this patient, drug-induced tumor regression was accompanied by meaningful improvement in symptoms, such as pain, and increased range of motion. (C) Relative change in tumor volume over time measured by contrast-enhanced MRI and labeled with patient numbers.

Fig 3.

Longitudinal symptom severity and interference by therapeutic response. (A) Individual symptoms demonstrating clinically meaningful improvement in partial responders (PRs) were pain (three of five), numbness/tingling (two of five), fatigue (one of five), sleep disturbance (one of five), and distress (two of five). Thumbnails show longitudinal evolution of mean severity of these symptoms in PRs (solid gold line) and in patients with sustained stable disease (SD, dashed blue line). Patients with a best response of SD also experienced modest improvements in these symptoms. Neither group experienced clinically meaningful worsening in any individual symptom. (B) Thumbnails show longitudinal changes in mean symptom interference with respect to activities of daily living, mood, work, and walking for PRs (solid gold line) and patients with SD (dashed blue line).