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

Isabelle Ray-Coquard, Philippe Cassier, Intidhar Labidi Galy, Pierre Heudel, Louis Tassy, Maria Chelghoum, Amandine Burghas, Pierre Meeus,Jean Yves Blay

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 analysis reveals that acquired resistance is frequently caused by secondary missense mutations in KIT exons 13, 14 or 17 (corresponding to the kinase 1 domain and kinase activation loop). Primary resistance is associated with primary activating mutations that are not sensitive to imatinib or have reduced sensitivity to the drug. Considering the molecular heterogeneity of tumors at relapse, the activation of the antiapoptotic pathway and the potential relevance to treating tumor cells and stromal cells, combination treatment targeting different pathways could be relevant in GIST resistant to imatinib. In this article, we will review the trials of combination treatment in advanced GIST after failure of imatinib and sunitinib. These trials are based on the understanding of the biological mechanisms of secondary resistance to imatinib in GIST, in particular the emergence of clones with secondary mutations. The trials exploring combinations of tyrosine kinase inhibitors (TKIs), TKIs with mTOR inhibitors and TKIs with cytotoxic agents will be reviewed and their results presented.