Activity of imatinib mesylate in desmoid tumors: Interim analysis of a Sarcoma Alliance for Research thru Collaboration (SARC) phase II trial

Abstract

9013 Background: Desmoid tumors (aggressive fibromatosis) are rare clonal neoplastic proliferations of connective tissues. Although classified as benign, local aggressiveness can lead to significant impairment. Standard treatment involves wide surgical resection and/or radiation therapy. In cases of unresectable or recurrent disease, tamoxifen, chemotherapy, and NSAIDs have been used with varying success. We and others have previously reported desmoid tumors expressing c-kit, PDGFRα, and/or PDGFR. We reported two patients with extraabdominal desmoid tumors treated with the selective tyrosine kinase inhibitor imatinib (Gleevec) with significant shrinkage. SARC, in association with the Connective Tissue Oncology Society, initiated a prospective phase II trial in patients with desmoid tumors, or one of nine sarcoma subtypes. Here, we report specifically on patients with desmoid tumors. Methods: Patients ≥ 10 years old with desmoid tumors that were not curable by surgical management or in whom curative surgery would lead to undesirable functional impairment were eligible. Imatinib was prescribed at 300 mg BID (BSA≥1.5m2), 200 mg BID (BSA=1.0–1.49m2), or 100 mg BID (BSA<1.0m2). Response outcomes at two and four months were collected. Rules for early termination within each disease type were based on a hierarchical Bayesian probability model accounting for correlation of the responses of the 10 disease types. Tissue specimens were analyzed by immunohistochemistry for expression of c-kit, PDGFRα, PDGFRß, AKT, PTEN, FKHR, and beta catenin. Tumor DNA was analyzed for PDGFRα exon 18 and APC mutations by allelic discrimination PCR. Results:26 patients with desmoid tumors have been enrolled with 22 currently evaluable. Two and four month progression-free survival rates of patients are 91% (20/22) and 78% (14/18), respectively. We have found polymorphisms/mutations of PDGFRα exon 18.Conclusions: Imatinib appears to be a promising agent in the management of unresectable or difficult to resect desmoid tumors. We postulate that responsiveness is a function of alteration of that gene or other downstream effectors. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis