Following the initial FDA approval for metastatic and advanced GIST, investigations into the use of imatinib for adjuvant therapy were undertaken. A multi-institutional, double blind randomized controlled trial (ACOSOG Z9001) demonstrated 1 year of adjuvant imatinib after complete surgical resection was associated with improved 1-year recurrence-free survival compared to placebo for patients with GIST >3 cm [12]. Based on these findings, the FDA approved imatinib for use in the adjuvant setting in 2012. Current data suggest that 3 years of adjuvant imatinib is associated with improved recurrence-free and overall survival compared with 1 year of imatinib (Fig. 2) [13]. At the present time, there is a phase II, multicenter trial evaluating outcomes following 5 years of imatinib following after surgical resection [14], demonstrating that the duration of adjuvant TKI is yet to be fully elucidated.

Although the outcomes for patients with GIST have changed dramatically with the advent of imatinib, approximately 10 % of patients have primary resistance to imatinib and ~50 % will acquire secondary resistance, resulting in the need for second line therapies. Sunitinib is a TKI that inhibits KIT, PDGFRA, PDGFRB, and other TKs and was the second TKI approved for treatment of metastatic GIST after demonstrating prolonged progression-free survival in patients with imatinib-resistant GIST compared to placebo [15]. Regorafenib is the most recent FDA-approved TKI for patients with advanced/metastatic GIST, based on a phase III trial demonstrating improved median progression-free survival by 3.9 months compared to placebo [16].

The past 20 years has been a remarkable time in our understanding of the pathogenesis and treatment of GIST. Identification of (1) the cell of origin, (2) a targetable mutation, and (3) drug discovery has changed the outcome for thousands of patients with GIST. Future advances require an understanding of the molecular biology of when imatinib is ineffective, which will open opportunities for new treatments. It remains an exciting time in the study of these unique tumors, with endless possibilities.