Gastrointestinal Stromal Tumors Medication

  • Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC; Chief Editor: Julian Katz, MD   more...
 
Updated: Jun 29, 2010
 

Medication Summary

Imatinib mesylate is the only available drug that has made a significant impact in the treatment of GISTs.

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Selective tyrosine kinase inhibitors

Class Summary

Imatinib mesylate (STI 571) is a selective tyrosine kinase inhibitor with action against mutant c-Kit as occurs in association with GISTs. It represents a breakthrough in antineoplastic drug therapy because it is targeted against a specific molecular derangement.

In 1996, Druker et al were the first to report this effect in laboratory experiments.[28] In 2001, Druker, Talpaz, and coworkers reported the results of clinical trials demonstrating >90% complete clinical response rates.[29]

Following the Hirota et al 1998 landmark report of the role of c-kit proto-oncogene mutations in the pathogenesis of GISTs, involving activation of KIT tyrosine kinase, it was hypothesized that KIT inhibition might be a successful treatment strategy for GISTs. Druker et al in 1996, Buchdunger et al in 1996, and Heinrich et al in 2000 indeed demonstrated such activity in the laboratory in various cell lines.[28, 30, 31] In 2001, Tuveson et al proved in vivo efficacy against human GIST cells, showing that STI-571 produced cell cycle arrest and apoptosis.[32]

Clinical trials with imatinib quickly followed. In 2001, Blanke et al reported preliminary results using imatinib in 145 subjects. No complete responses were observed.[33] The partial clinical response rate was 59%, and 13% of the group had progression of disease while receiving imatinib doses of 400-600 mg/d.

In 2002, van Oosterom et al published their results from 35 patients with GISTs receiving imatinib doses of 400-1000 mg/d.[34] Partial responses were achieved in 54%, and disease remained stable in an additional 37%. The most common adverse effects were periorbital edema (40%), peripheral edema (37%), fatigue (30%), rash (30%), and nausea and vomiting (25%). Late severe myelosuppression was uncommon. The highest well-tolerated dose in this study was 400 mg bid. At doses of 500 mg bid, severe nausea, vomiting, edema, and rashes were common. After a minimum follow-up of 10 mo, 82% of subjects continued to have a partial disease response (51%) or no evidence of disease progression (31%).

The optimal dose for imatinib mesylate remains unknown. However, despite initial efficacy of imatinib mesylate in most, drug resistance is common. Clinical management of GIST may benefit from further molecular characterization of tumors before and after imatinib mesylate treatment.

Rink et al studied gene expression using oligonucleotide microarrays on tumor samples obtained before and after imatinib mesylate therapy.[35] Thirty-eight genes were expressed at significantly lower levels in the pretreatment biopsy samples from tumors that significantly responded to 8-12 weeks of imatinib mesylate, that is, >25% tumor reduction. Eighteen of these genes encoded Krüppel-associated box (KRAB) domain containing zinc finger (ZNF) transcriptional repressors. Ten KRAB-ZNF genes mapped to a single locus on chromosome 19p, and a subset predicted likely response to imatinib mesylate-based therapy in a naïve panel of GIST. This gene signature that includes KRAB-ZNF 91 subfamily members that may be both predictive of and functionally associated with likely response to short-term imatinib mesylate treatment.

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Imatinib (Gleevec R)

 

Also known as STI-571, first received attention as an inhibitor of the BCR-ABL fusion protein, which induces uncontrolled tyrosine kinase activity in CML.

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Multikinase inhibitors

Class Summary

Elicit actions via multiple tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression.

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Sunitinib (Sutent)

 

Multikinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. Inhibits platelet-derived growth factor receptors (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 gastrointestinal stromal tumors (GISTs) whose disease has progressed or who are unable to tolerate treatment with imatinib (Gleevec). Delays median time to tumor progression.

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Contributor Information and Disclosures
Author

Sandeep Mukherjee, MB, BCh, MPH, FRCPC  Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center

Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Coauthor(s)

Michael AJ Sawyer, MD  Consulting Staff, Department of Surgery, Southwestern Medical Center; Consulting Staff, Department of Surgery, Comanche County Memorial Hospital; Consulting Staff, Great Plains Surgical Clinic, Inc

Michael AJ Sawyer, MD is a member of the following medical societies: American College of Surgeons, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, and Society of Laparoendoscopic Surgeons

Disclosure: Nothing to disclose.

Robert A Decker, MD  Clinical Assistant Professor, Department of Medicine, University of Hawaii at Manoa: Chief, Gastroenterology Service, Kaiser Permanente Medical Center of Honolulu

Disclosure: Nothing to disclose.

Specialty Editor Board

Sandeep Mukherjee, MB, BCh, MPH, FRCPC  Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center

Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Noel Williams, MD  Professor Emeritus, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Professor, Department of Internal Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada

Noel Williams, MD is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Alex J Mechaber, MD, FACP  Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD  Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

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