Medication Summary
Imatinib mesylate (Gleevec), a 2-phenylaminopyridine that functions as a tyrosine kinase inhibitor, targets the c-kit domain expressed by some GISTs. [16] It has been shown to improve disease-free intervals in patients after resection of the tumor. A similar compound, sunitinib (Sutent), has been shown to be effective in patients with mutant GIST cells that are resistant to imatinib mesylate. [17]
Clinical trials are currently investigating agents, such as AP13573 and ET743 (trabectedin), in patients with advanced leiomyosarcomas, liposarcomas, or osteosarcomas.
Trabectedin (Yondelis) was approved in November 2015 in the United States for unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a prior anthracycline-containing regimen. [18, 19] It is an alkylating drug that binds guanine residues in the minor groove of DNA. Approval was based on a phase 3 trial (n = 518) that showed a statistically significant improvement in progression-free survival compared with dacarbazine (4.2 mo vs 1.5 mo; P < 0.0001). No improvement in overall survival was observed. [18, 19]
Tyrosine kinase inhibitors
Class Summary
These agents inhibit the signal transduction pathway regulated by receptor tyrosine kinase.
Imatinib mesylate (Gleevec)
Specifically designed to inhibit tyrosine kinase activity of bcr-abl kinase in GISTs. GISTs are characterized by expression of the product of the proto-oncogene c-kit and often harbor gain-of-function kit mutations, leading to ligand-independent kinase activation. Imatinib inhibits abl, kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinase.
Sunitinib (Sutent)
Mulitkinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. Inhibits PDGFRs (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (kit), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET). Indicated for persons with GISTs whose disease has progressed or who are unable to tolerate treatment with imatinib mesylate (Gleevec). Delays median time to tumor progression.
Antineoplastics, Alkylating
Class Summary
Treatment with trabectedin may be considered in patients who have already received an anthracycline.
Trabectedin (Yondelis)
An alkylating drug that binds guanine residues in the minor groove of DNA. It is indicated for unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a prior anthracycline-containing regimen.
-
Colonic mucosa with gastrointestinal stromal tumor (GIST) involving the adjacent submucosa (hematoxylin and eosin [H&E] stain, medium power).
-
Clusters of tumor cells separated by a hyaline and mucin-rich stroma (hematoxylin and eosin [H&E] stain, medium power).
-
Oval- to spindle-shaped cells forming a fascicle (hematoxylin and eosin [H&E] stain, high power).
-
CD-34 stain showing a tumor (medium power). CD-34 is a myeloid progenitor cell antigen.
-
High-power magnification with CD-34 antigen immunohistochemical stain showing membrane positivity of the tumor cells.
