TYKERB: mechanism of action
TYKERB is a small-molecule tyrosine kinase inhibitor, acting on the ErbB receptors, in particular HER2.1 The ErbB receptors are cell surface receptors that play an essential role in normal cell growth and development. When a growth factor binds to the ErbB receptor extracellular domain, it causes each receptor to partner or dimerize with a second receptor by means of a dimerization arm in its extracellular domain.2 Dimerization activates the intracytoplasmic receptor kinase, which phosphorylates tyrosine residues in the receptor tails, activating intracellular signaling pathways important in cell proliferation and survival. Overactivity of these receptors and their ligands due to overexpression or mutation has been implicated in the growth of many cancers and in their resistance to cancer therapy.2
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Inhibition of these receptors may suppress cell proliferation and survival in tumors whose growth is dependent on ErbB receptor signaling pathways. TYKERB acts within the cell to directly inhibit the activity of the tyrosine kinase enzyme, preventing tyrosine phosphorylation and the subsequent activation of signaling pathways.1
For study data, see Clinical trial results.
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Indication
TYKERB® is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.
Dose Modification Guidelines
For dose modification guidelines, please see complete Prescribing Information.
BOXED WARNING and Additional Important Safety Information
Hepatotoxicity
TYKERB has been associated with hepatotoxicity. Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be retreated with TYKERB.
Decreased Left Ventricular Ejection Fraction
TYKERB has been reported to decrease LVEF. Caution should be taken if TYKERB is to be administered to patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. Confirm normal LVEF before starting TYKERB, and continue evaluations during treatment.
Patients with Severe Hepatic Impairment
If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered.
Diarrhea
Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB and was the most common adverse reaction resulting in discontinuation of TYKERB therapy. Proactive management of diarrhea with anti-diarrheal agents is important, and severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of therapy with TYKERB.
Interstitial Lung Disease/Pneumonitis
TYKERB has been associated with interstitial lung disease and pneumonitis. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis and if symptoms are ≥ Grade 3 (NCI CTCAE), TYKERB should be discontinued.
QT Prolongation
TYKERB prolongs the QT interval in some patients. TYKERB should be administered with caution to patients who have or may develop prolongation of QTc. Hypokalemia or hypomagnesemia should be corrected prior to TYKERB administration. Baseline and on-treatment electrocardiograms with QT measurement should be considered.
Pregnancy
Pregnancy D
TYKERB can cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Adverse Reactions
The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (65%, 40%), nausea (44%, 43%), vomiting (26%, 21%), palmar-plantar erythrodysesthesia (53%, 51%), rash (28%, 14%), and fatigue (46%, 47%).
The most common grade 3 and 4 adverse reaction (NCI CTC v3) with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (14%, 10%) and palmar-plantar erythrodysesthesia (12%, 14%).
Please see full US Prescribing Information, including BOXED WARNING for TYKERB.
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References:
- TYKERB [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2008.
- Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002;21:6255-6263.