A Phase 2 Trial in Patients with Desmoid Tumors Shows Clinical Promise

Desmoid tumors, also known aggressive fibromatosis, are a rare mesenchymal disease that consists of slow-growing, locally invasive soft tissue tumors. Although desmoid tumors are non-metastatic, they may lead to impaired organ function and decreased quality of life. While surgical resection, radiation, and 'watch and wait' treatment approaches may be successful for some patients, post-surgical disease recurrence and the heterogeneity of tumors complicate effective treatment strategies. The molecular mechanisms underlying the development of desmoid tumors are not well understood, but recent research has identified the Wnt/β-catenin pathway, which exhibits crosstalk with Notch signaling, as a possible clinical target. Preclinical and Phase 1 testing of agents targeting the Notch pathway in desmoid tumors, specifically with γ-secretase inhibitors, had yielded promising outcomes. These studies led to a Phase 2 trial in 17 patients with recurrent, refractory, progressive desmoid tumors who were treated with the γ-secretase inhibitor, PF-03084014, twice per day, in 21-day cycles. The trial was conducted in NCI's Developmental Therapeutics Clinic (DTC), and the results were recently published in the Journal of Clinical Oncology (Kummar, 2017).

Out of 16 evaluable patients in this study, five exhibited a partial response (PR) and continue to be on study for more than two years. Another five patients remain on study with stable disease. Of the 17 accrued patients, 15 had mutations in either APC or CTNNB1, two genes of the β-catenin pathway; however, the small study size could not lead to associations in mutation status and clinical response. Interestingly, three of the patients experiencing a PR did not exhibit responses until approximately 2 years after starting treatment, which suggests that the mechanism of action of the γ-secretase inhibitor on this tumor may be complex and differ from routine models of cell death. The study investigators also evaluated patient-reported outcomes and determined that statistically significant improvements in symptom burden were reported in those patients exhibiting a PR. This treatment warrants further study in patients suffering from desmoid tumors, and highlights the first positive results of γ-secretase inhibitor PF-03084014 in a Phase 2 trial of this rare disease.

Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults with Desmoid Tumors/Aggressive Fibromatosis. Kummar S, O'Sullivan Coyne G, Khanh TD, Tukrbey B, Meltzer PS, Polley E, Choyke PL, Meehan R, Vilimas R, Horneffer Y, Juwara L, Lih A, Choudhary A, Mitchell SA, Helman LJ, Doroshow JH, Chen A. DOI: 10.1200/JCO.2016.71.1994 Journal of Clinical Oncology - published online before print March 28, 2017