Long-Term Follow-Up of Desmoid Fibromatosis Treated with PF-03084014, an Oral Gamma Secretase Inhibitor
Desmoid fibromatosis is a fibroblastic neoplasm driven by aberrations within the WNT pathway, exhibiting mutations in β-catenin or APC. We review the long-term follow-up of patients in a phase I study treated with an oral gamma secretase inhibitor, PF-03084014.
PF-03084014 was administered orally at doses ranging from 20 to 330 mg twice daily. Tumor assessments were performed using computed tomography/magnetic resonance imaging (CT/MRI) within 4 weeks of study entry, and every other cycle through cycle 9. After cycle 9, patients were evaluated as clinically indicated.
Seven patients with desmoid fibromatosis were treated between December 2009 and December 2016 at the University of Colorado. Five patients (71.4%, 95% confidence interval [CI] 29.0–96.3%) achieved a partial response (PR), with a mean time to achieving response of 11.9 months (95% CI 2.5–21.4 months). All patients who achieved a PR continue to maintain responses between 47.9 and 73+ months. Four patients stopped treatment yet remain free of progression between 11 and 53+ months. One patient had PFS of 42+ months, with a 17% decrease in the target lesion. A biopsy performed at the end of the study showed decreased tumoral cellularity compared with previous biopsies. Effective treatment doses ranged from 80 to 330 mg administered orally twice daily.
PF-03084014 was effective in treating desmoid tumors, with an objective response rate of 71.4% (95% CI 29.0–96.3%) in this small cohort of patients. PF-03084014 exhibits promising activity, even at relatively low doses (80 mg twice daily), with high tolerability leading to prolonged disease control even after therapy discontinuation.
This clinical study was sponsored by Pfizer Inc.
Victor Manuel Villalobos, Francis Hall, Antonio Jimeno, Lia Gore, Kenneth Kern, Rossano Cesari, Bo Huang, Jeffrey T. Schowinsky, Patrick Judson Blatchford, Brianna Hoffner, Anthony Elias, Wells Messersmith have nothing disclosures to declare.
- 2.Lewis JJ, Boland PJ, Leung DH, Woodruff JM, Brennan MF. The enigma of desmoid tumors. Ann Surg. 1999;229(6):866–72 (discussion 872–3).Google Scholar
- 5.Woltsche N, Gilg MM, Fraissler L, et al. Is wide resection obsolete for desmoid tumors in children and adolescents? Evaluation of histological margins, immunohistochemical markers, and review of literature. Pediatr Hematol Oncol. 2015;32(1):60–9. doi:10.3109/08880018.2014.956905.CrossRefPubMedGoogle Scholar
- 15.Kasper B, Gruenwald V, Reichardt P, et al. Imatinib induces sustained progression arrest in RECIST progressive desmoid tumours: final results of a phase II study of the German Interdisciplinary Sarcoma Group (GISG). Eur J Cancer. 2017;76:60–7. doi:10.1016/j.ejca.2017.02.001.CrossRefPubMedGoogle Scholar
- 28.Stacchiotti S, Collini P, Messina A, et al. High-grade soft-tissue sarcomas: tumor response assessment—pilot study to assess the correlation between radiologic and pathologic response by using RECIST and Choi criteria. Radiology. 2009;251(2):447–56. doi:10.1148/radiol.2512081403.CrossRefPubMedGoogle Scholar