A decade of tyrosine kinase inhibitor therapy: Historical and current perspectives on targeted therapy for GIST.

The introduction of molecularly targeted therapies has ushered in a considerable transformation in the management of gastrointestinal stromal tumors (GIST) that currently defines the paradigm of targeted therapy for solid tumors. Indeed, in the past decade the management of GIST has evolved from a disease only effectively treatable by surgery to the archetype of a tumor treatable with a molecularly targeted therapy. Better understanding of the molecular and genetic characteristics that underlie the aberrant behavior of GIST has increased the accuracy of its diagnosis and allowed for the identification of distinct genetic hallmarks, prognostic groups, and treatment strategies. Collectively, this has resulted in the development of the targeted tyrosine kinase inhibitors (TKIs) imatinib and sunitinib, and continues to prompt studies of novel agents in this disease. Since approval in 2002, imatinib has been shown to provide a high level of clinical efficacy in patients with advanced GIST, including a median progression-free survival (PFS) of 2 years and median overall survival approaching 5 years, with some patients progression-free after 10 years of treatment. Imatinib is now also approved in adult patients following resection of KIT-positive GIST. In 2006, sunitinib was approved for the treatment of advanced GIST after failure of imatinib. Sunitinib provides significant benefit in this setting, with a median PFS close to 6 months after imatinib failure. Following progression on these agents, patients have limited treatment options. This critical unmet need is being addressed by the development of new TKIs and the use of novel regimens with approved agents.