Clinical experience with erlotinib in non-small-cell lung cancer.
Lung cancer is the leading cause of cancer death worldwide. Despite the introduction of more- effective chemotherapeutic agents, it appears that a survival plateau has been reached, so new treatment strategies are clearly needed. One innovative therapeutic cancer strategy is the introduction of biological agents that target specific intracellular pathways related to the distinctive properties of cancer cells. Among these agents, epidermal growth factor receptor (EGFR)-targeting agents have received particular attention in lung cancer. Numerous EGFR blockers have been evaluated, including monoclonal antibodies to the receptor and small-molecule tyrosine kinase inhibitors. The present review focuses on the tyrosine kinase inhibitor erlotinib. Preclinical studies have shown that erlotinib blocks the growth of human non-small-cell lung cancer (NSCLC) cell lines in vitro by inhibiting the receptor and the downstream protein phosphorylation. In a randomized study conducted by the National Cancer Institute of Canada (BR.21) in second- and third-line NSCLC treatment, erlotinib significantly prolonged overall survival and decreased symptoms compared with placebo. A crucial aspect of the clinical development of molecular-targeted therapies is to understand which patients will obtain clinical benefit from their use. Sensitivity to erlotinib has been associated with EGFR mutations, most commonly deletions of four to six amino acids in exon 19 or a point mutation (L858R) in exon 21. Increased EGFR gene copy number has also been pointed out as a good predictive marker for erlotinib response. Intense research activity is ongoing to validate known predictive markers and to discover new tools which maximize clinical benefit using erlotinib. However, there is no conclusive evidence, as yet, linking response to survival.
Felip
Enriqueta
E
Vall d'Hebron University Hospital, Barcelona, Spain.
Rosell
Rafael
R
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000493:pharmacokinetics / Q000627:therapeutic use*
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases