Combination therapy for gastrointestinal stromal tumors: evidence from recent clinical trials

Gastrointestinal stromal tumors (GIST) are neoplasms of mesenchymal origin arising from the GI tract. These tumors are characterized by activating mutations of the receptor tyrosine kinases, either KIT or PDGFRa, which are found in 85% of cases. Despite the use of imatinib in first-line and sunitinib in second-line treatment, patients with metastatic GIST still have a high risk of progression and death. To date, the median overall survival for metastatic disease is close to 5 years. Treatment with imatinib, an inhibitor of KIT and PDGFRa, results in clinical benefit, that is, objective responses or disease stabilization in approximately 85% of patients with unresectable or metastatic GISTs. However, metastatic GIST develop resistance to imatinib at a median time of 24 months, and sometimes more than 8 years after initiation of the treatment. In addition, as many as 15% of patients do not respond initially to imatinib; therefore, novel therapeutic options, new drugs or combination are needed. Genotypic ana...