Pharmaceutical Approval Update: Oncology Sunitinib Malate (Sutent)
Manufacturer: Pfizer, New York, NY
Indication: Sunitinib (SU-11248) is a newly targeted anti-cancer therapy for patients with gastrointestinal stromal tumors (GISTs), a rare stomach cancer, who are intolerant of treatment with imatinib mesylate (Gleevec, Novartis). The capsules are also indicated for the treatment of advanced kidney cancer.
Drug Class: Sunitinib malate is described chemically as bu-tanedioic acid, hydroxy-, (2S)-, compound with N-[2-(diethyl-amino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-hydroxy-, (2S), compound with N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3#-indol-3-ylidine)methyl]-2,4-dimethyl-7#-pyrrole-3-carboxamide (1:1). The molecular formula is C22H27FN4O2 • C4H6O5. The molecular weight is 532.6 daltons.
Uniqueness of Drug: Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs). Some of these are implicated in tumor growth, pathological angio-genesis, and metastatic progression of cancer.
Sunitinib was identified as an inhibitor of platelet-derived growth factor receptors (PDGFR-a and PDGFR-p), vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2 and VEGFR-3), stem cell factor receptor (KIT), Fms-like tyro-sine kinase-3 (FLT-3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell line-derived neurotrophic factor receptor (RET). The primary metabolite exhibits potency similar to that of sunitinib in biochemical and cellular assays.
Sunitinib inhibits the phosphorylation of multiple RTKs (PDGFR-|3, VEGFR-2, KIT) in tumor xenografts expressing RTK targets in vivo and blocks tumor growth in experimental models of cancer. Sunitinib has the ability to inhibit the growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFR-|3-dependent and VEGFR-2-dependent tumor angiogenesis in vivo.
Warnings: Sunitinib was evaluated at doses of 0.3, 1.5, 3.0, and 5.0 mg/kg per day in pregnant rats and at doses of 0.5, 1, 5, and 20 mg/kg per day in pregnant rabbits to determine its effect on the embryos. At 5 mg/kg per day, significant increases in the incidence of embryo fatalities and structural abnormalities were observed in the rats; this is about 5.5 times the systemic exposure in patients receiving the recommended daily dose.
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A significantly increased incidence of embryonic deaths was observed in the rabbits at a dose of 5 mg/kg per day, whereas developmental effects were observed at 1 mg/kg per day or more; this is about 0.3 times the area-under-the-curve (AUC) concentration in patients receiving the recommended daily dose of 50 mg/day.
Because angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of sunitinib should be expected to result in an adverse effect on pregnancy; however, no adequate or well-controlled studies of sunitinib in pregnant women have been performed. If the drug is used during pregnancy or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus.
Left Ventricular Dysfunction. In the two studies of metastatic renal cell carcinoma studies, 25 patients (15%) exhibited decreases in left ventricular ejection fraction to below the lower limit of normal. If clinical manifestations of congestive heart failure are present, sunitinib should be discontinued. If patients have no clinical evidence of congestive heart failure but their ejection fraction is below 50% and more than 20% below the baseline measures, the sunitinib dose should be interrupted or reduced. eriacta
Hemorrhage. Sudden tumor-related hemorrhage has been observed after therapy with sunitinib. In the case of pulmonary tumors, severe and life-threatening hemoptysis and pulmonary hemorrhage have occurred.
Hypertension. All grades of hypertension were reported in 48 of 169 patients with renal cell carcinoma (28%), 31 of 202 GIST patients receiving sunitinib (15%), and 11 of 102 GIST patients taking placebo (11%).
Other Stressors. Physicians prescribing sunitinib are advised to monitor patients for adrenal insufficiency in those who experience stresses such as surgery, trauma, and severe infection.
Dosage and Administration: The recommended dose of sunitinib for GISTs and advanced renal cell carcinoma is one 50-mg oral dose, taken with or without food. Dose increases or reductions in 12.5-mg increments are recommended according to safety and tolerability in individuals.
Commentary: Sunitinib represents hope to patients with GISTs that are resistant to imatinib therapy because it can slow cancer growth and extend survival. This is the first time a molecularly targeted therapy has proved effective after another targeted therapy has failed.
Although GISTs are uncommon, the degree to which they are understood at a molecular level has made this disease a proving ground for new therapies that might be useful for other cancers. Sunitinib is generally well tolerated, with mild-to-moderate adverse effects such as fatigue, diarrhea, nausea, mouth sores, and skin discoloration. These events rarely interfered with the ability of patients to continue taking the drug.