Erlotinib, launched as once daily oral treatment for patients with
non-small-cell lung cancer (NSCLC), is an inhibitor of the epidermal growth factor
receptor (EGFR) tyrosine kinase, and it is the second small-molecule drug to
be marketed with this mechanism of action. Both erlotinib and its predecessor,
gefitinib, are members of the anilinoquinazoline class of tyrosine kinase inhibitors.
They compete with the binding of ATP to the intracellular tyrosine kinase domain
of EGFR, thereby inhibiting receptor autophosphorylation and blocking downstream
signal transduction. Erlotinib is prepared by the condensation of 3-ethynylaniline
with 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline, which is a key
intermediate obtained in five synthetic steps starting from ethyl 3,4-
dihydroxybenzoate. In vitro, Erlotinib inhibits purified human EGFR tyrosine
kinase with an IC50 of 2 nM and blocks EGFR autophosphorylation in cellular
assays with an IC50 of 20nM. Treatment of human colon cancer cells with erlotinib
was associated with growth inhibition, G1 cell cycle arrest, and apoptosis.
Oral administration of erlotinib in athymic mice produced potent antitumor effects
with an ED50 of 9.2 mg/kg/day for HN5 head and neck xenografts and 14 mg/
kg/day for A431 epidermoid xenografts. The absorption of Erlotinib following oral
dosing is approximately 60%. Food greatly enhances the absorption allowing for
almost 100% bioavailability of the dose. The time to reach peak plasma levels of the drug is about 4 hours, and the half-life is approximately 36 hours. Steady-state drug
levels are reached in 7 to 8 days. Erlotinib has high protein binding (93%) and has
an apparent volume of distribution of 232 L. It is metabolized primarily by
CYP3A4 and to a lesser extent by CYP1A2 and CYP1A1. The drug is mainly
excreted in the feces with less than 9% of the dose found in the urine. Erlotinib is
labeled for the treatment of patients with locally advanced or metastatic NSCLC
who have failed one or more previous chemotherapy regimens. The recommended
dosage is 150 mg daily until disease progression is detected. In a randomized, double
blind, placebo-controlled trial involving 731 patients, 150 mg/day oral dose of
erlotinib resulted in a median overall survival of 6.7 months compared with 4.7
months in the placebo group (p＜0.001). Progression-free survival was 9.9 weeks
and 7.9 weeks in the erlotinib and placebo groups, respectively (p＜0.001). Survival
at one year was 31.2% in the erlotinib group versus 21.5% in the placebo group.
The use of erlotinib showed greater benefit in patients with EGFR positive tumors
and in those who never smoked. The most common adverse events reported in
clinical trials were rash (9%) and diarrhea (6%). Elevations in liver function
tests were also seen; however, these effects were mainly transient or associated with
liver metastases. As previously noted for gefitinib, erlotinib is also shown to
lack any clinical benefit in concurrent administration with platinum-based chemotherapy.
