Systemic Therapy
Imatinib - Rationale
KIT and PDGFRs drive oncogenesis in a variety of solid and hematologic tumors, suggesting their role as potential targets for anticancer therapy.1,2 Because constitutive activity of KIT or PDGFRα underlies GIST development, targeting these receptor tyrosine kinases with a potent, specific inhibitor is a rational therapeutic strategy.3
Clinical evidence in chronic myeloid leukemia: IRIS study
The efficacy of Glivec in targeting an intracellular tyrosine kinase, BCR-ABL, had previously been established in chronic myeloid leukemia (CML).4 The International Randomized Interferon versus STI571 (IRIS) study, a phase 3, multicenter, open-label, randomized trial, investigated Glivec efficacy in newly diagnosed patients with chronic-phase CML and no prior therapy. Patients were randomly assigned to treatment with either Glivec 400 mg/d (n = 553) or interferon-alfa plus cytarabine.
Patients have now been followed for 5 years.5 Estimated progression-free survival at 60 months was 83% (95% confidence interval [CI], 80-87); freedom from progression to accelerated phase or blast crisis was 93% (95% CI, 90-96). Progression was defined as disease progression to accelerated phase or blast crisis (6%), loss of complete hematologic response or increase in white blood cells (WBCs) (2.5%), loss of major cytogenetic response (5%), and death unrelated to CML (2%).
Rates of progression for years 1 through 5, including all definitions of progression, were 3.3%, 7.5%, 4.6%, 1.5%, and 0.9%, respectively. Rates of progression to accelerated phase or blast crisis for years 1 through 5 were 1.5%, 2.8%, 1.6%, 0.9%, and 0.6%, respectively. These rates were remarkable and encouraging; the data indicated a slight downward trend in the rate of disease progression over time, suggesting that long-term Glivec® therapy reduces risk of relapse. Another important finding was the association of earlier treatment (in chronic phase) with a low relapse rate: approximately 7% for progression to accelerated phase or blast crisis and approximately 17% for any progression.
Preclinical data
At micromolar concentrations, Glivec inhibits members of the class III family of receptor tyrosine kinases, including KIT (the receptor for stem-cell factor or steel factor), PDGFRα, and PDGFRβ.6 Glivec is a potent inhibitor of ABL and BCR-ABL intracellular tyrosine kinases as well as PDGFR and KIT, the receptor for stem-cell factor. Fusion proteins containing the transcription factor TEL (translocated ETS leukemia) and ABL or PDGFR are also inhibited by Glivec. It has recently been shown that Glivec targets the macrophage colony-stimulating factor receptor c-FMS.7 Glivec does not inhibit other protein kinases, including epidermal growth factor receptor and the receptors for insulin and insulin-like growth factor I.
Glivec has demonstrated antiproliferative effects and increased apoptosis in GIST cell lines.10,11 Recent findings suggest that the mutational status of KIT/PDGFRα oncoproteins may be useful to predict the clinical response of patients to Glivec therapy.8,9
Proof-of-concept case report
Based on the evidence that GIST cells express the KIT growth factor receptor with tyrosine kinase activity, coupled with the preclinical evidence that Glivec inhibits that activity, Joensuu et al initiated the first clinical use of Glivec® in GIST in a single patient.5 Their patient was a 50-year-old woman who had undergone surgery in 1996 for the removal of 2 GISTs as well as metastases to the peritoneum and omentum. Diagnosis of GIST was confirmed with CD117 immunostaining. Two years later, recurrent tumors and metastases to liver, ovary, and upper abdomen were removed in 2 surgeries 6 months apart. After several cycles of chemotherapy, the disease progressed rapidly, requiring further surgery. In March 2000, the patient consented to investigational treatment with 400 mg of oral Glivec once daily. After 2 weeks of Glivec therapy, the tumor had shrunk to about half its original size, and 6 of 28 liver metastases had disappeared.
Within 1 month of therapy, the tumor demonstrated a complete metabolic response, as evaluated by PET scanning (Figure 1).5 As of February 2001, the tumor continued to respond to treatment, and the patient was considered clinically well. Glivec was well tolerated by this patient, who experienced only mild nausea after ingesting the medication, alleviated by taking the drug with food.
Figure 1 - Positron-emission tomography scans before and after administration of Glivec
Click on the image to enlarge
Positron-emission tomography scans before and after administration of Glivec showing clearing of metastases images with 18F-fluorodeoxyglucose (FDG) as the tracer. Before Glivec therapy (A), there were multiple metastases in the liver and upper abdomen. There was also marked retention of FDG in the right renal pelvis and ureter, a finding indicative of hydronephrosis. After 4 weeks of Glivec therapy (B), there was no abnormal uptake of trace in the liver or right kidney. Reprinted with permission from Joenssu H et al. N Engl J Med. 2001;344:1052-1056.5
This case served as a proof of concept for targeted therapy by demonstrating that inhibition of the KIT tyrosine kinase activity suppressed GIST growth. This case report launched subsequent trials of Glivec in GIST, further documenting its efficacy in this cancer.
References:
1. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol. 2002;33:484-495.
2. Fletcher JA. Role of KIT and platelet-derived growth factor receptors as oncoproteins. Semin Oncol. 2004;31(suppl 6):4-11.
3. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353:172-187.
4. O'Brien SG, Meinhardt P, Bond E, et al. Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer. 2003;89:1855-1859.
5. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344:1052-1056.
6. Buchdunger E, Cioffi CL, Law N, et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and plateletderived growth factor receptors. J Pharmacol Exp Ther. 2000;295:139-145.
7. Buchdunger E, O’Reilly T, Wood J. Pharacology of imatinib (TI571). Eur J Cancer. 2002;28(suppl):S28-S36.
8. Debiec-Rychter M, Dumez H, Judson I, et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2004;40:689-695.
9. Blanke CD, Joensuu H, Demetri GD, et al. Outcome of advanced gastrointestinal stromal tumor (GIST) patients treated with imatinib mesylate: four-year follow-up of a phase II randomized trial [abstract]. Presented at: 2006 Gastrointestinal Cancers Symposium; January 26-28, 2006; San Francisco, Calif. Abstract 7.
10. Tuveson DA, Willis NA, Jacks T, et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene. 2001;20:5054-5058.
11. Frost MJ, Ferrao PT, Hughes TP, Ashman LK. Juxtamembrane mutant V560G Kit is more sensitive to imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. Mol Cancer Ther. 2002;1:1115-1124.