Second-line targeted therapy of gastrointestinal stromal tumours

Abstract

The treatment of patients with unresectable or metastatic imatinib-resistant gastrointestinal stromal tumours is a big challenge. Primary resistance and secondary resistance are under investigation. Secondary resistance can develop through various mechanisms, the most common being secondary KIT mutations in clonally expanded cancer cells. Effective standard treatment after failure of imatinib therapy is a small molecule tyrosine kinase inhibitor sunitinib. Its efficacy is associated with the blockade of receptor tyrosine kinase signalling by KIT, PDGFRs, the three forms of the vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2 and VEGFR-3), Fms-like tyrosine kinase-3 receptor (FLT3) and the receptor encoded by the ret proto-oncogene (RET). Sunitinib induced promising activity in a phase III study with imatinib-resistant patients: time to tumour progression 27.3 weeks for the sunitinib arm vs. 6.4 weeks for the placebo arm, median progression-free survival 24.1 vs. 6.0 weeks, objective response rate – 6.8 vs. 0 weeks. Salvage treatments for progressive disease following the therapy with sunitinib show clinical benefit in a minority of patients. ESMO recommends to include these patients in a clinical trial with new targeted compounds and new drug combinations.