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Certain cancerous cells have been associated with overexpressed or mutated tyrosine kinases.1 Ovarian, head and neck, breast, bladder, lung, and squamous cell carcinomas have been linked with overexpression of the tyrosine kinase epidermal growth factor receptor (EGFR), which also has been linked with chemoresistance and poor prognosis.2 Therefore, targeting (or inhibiting) overexpressed EGFR may significantly improve response to antineoplastic chemotherapy. Filling this role is OSI Pharmaceuticals'recently released Tarceva (erlotinib), which is approved for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have failed at least one other chemotherapy regimen.3
Erlotinib is a tyrosine kinase inhibitor. NSCLC often exhibits a high frequency of EGFR overexpression, which erlotinib targets to inhibit intracellular phosphorylation.1,4
Erlotinib was studied in a randomized, double-blind, placebo-controlled study of 731 NSCLC patients who had previously failed at least one chemotherapy regimen. Overall, the erlotinib group had a survival rate of about 6.7 months, while the placebo group survival rate was 4.7 months. After 12 months, the erlotinib group's survival rate of 31.2% significantly exceeded the placebo group's rate of 21.5%.3
The incidence of EGFR overexpression may affect the efficacy of erlotinib. In the previous study, the EGFR overexpression status was known for only 238 patients. In those patients known to be EGFR-positive, however, erlotinib increased survival. Minimal data are currently available, but the correlation between EGFR status and efficacy is worthy of additional investigation.4
Erlotinib typically is dosed at 150 mg orally once a day, 1 hour before or 2 hours after a meal. Erlotinib is metabolized by CYP3A4. Concurrent use of strong CYP3A4 inhibitors, such as ketoconazole, may require a dose reduction, whereas the use of CYP3A4 inducers?such as carbamazepine, rifampin, or phenytoin?may require a dose increase.4
Frequently reported adverse reactions include skin rash and diarrhea.4 Skin rash appears to be dose-related and may be positively associated with efficacy.5 Although potentially bothersome, diarrhea usually can be managed by treatment with loperamide. Patients unable to tolerate loperamide may require a lower dose of erlotinib or a temporary discontinuation of therapy. In some patients, erlotinib was associated with liver function test elevation of 2.5 to 5 times normal values. These changes were usually transient and may have been due to liver metastases. Other adverse reactions include anorexia, fatigue, dyspnea, cough, nausea, infection, vomiting, stomatitis, pruritus, dry skin, conjunctivitis, keratoconjunctivitis sicca, and abdominal pain.4
Warnings and Precautions
Erlotinib has been associated infrequently with cases of interstitial lung disease (ILD). Patients developing dyspnea, cough, and fever should be evaluated immediately, and treatment should be discontinued if ILD is diagnosed.4
Erlotinib is in Pregnancy Category D. Both breast-feeding and pregnancy should be avoided in patients receiving erlotinib.4
Increased bleeding time and increased international normalized ratio (INR) have been noted in some patients receiving erlotinib, especially those also receiving warfarin. INR monitoring is recommended during concurrent administration of erlotinib and anticoagulant medications.4
Erlotinib is metabolized hepatically. Caution should be used in patients with hepatic insufficiency.
Dr. Holmberg is a pharmacist with Phoenix Children's Hospital, Phoenix, Ariz.
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