EGFR inhibitors for wild-type EGFR NSCLC: to use or not to use?

Gefitinib and erlotinib—EGFR tyrosine kinase inhibitors—were the first molecularly targeted drugs used to treat advanced non-small-cell lung cancer (NSCLC). The positive results of BR.21—a phase 3 study comparing erlotinib with placebo in patients with NSCLC in whom first-line or second-line chemotherapy had failed—paved the way for the widespread use of these drugs. 1 Shepherd FA Rodrigues Pereira J Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005; 353: 123-132 Crossref PubMed Scopus (5068) Google Scholar When BR.21 was started, EGFR mutations in NSCLC had not yet been identified, therefore the study included molecularly unselected patients. The discovery and characterisation of EGFR mutations in 2004 was a key example of oncogene addiction, associated with high efficacy of biomarker-driven treatment. 2 Lynch TJ Bell DW Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004; 350: 2129-2139 Crossref PubMed Scopus (9922) Google Scholar , 3 Paez JG Jänne PA Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304: 1497-1500 Crossref PubMed Scopus (8405) Google Scholar As a result, EGFR tyrosine kinase inhibitors are now the treatment of choice for patients with EGFR-mutated tumours (about 10% of all NSCLCs in white populations). Although EGFR tyrosine kinase inhibitors are generally more efficacious than chemotherapy for these patients, 4 Rosell R Carcereny E Gervais R et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13: 239-246 Summary Full Text Full Text PDF PubMed Scopus (4356) Google Scholar , 5 Mitsudomi T Morita S Yatabe Y et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010; 11: 121-128 Summary Full Text Full Text PDF PubMed Scopus (3514) Google Scholar , 6 Zhou C Wu YL Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12: 735-742 Summary Full Text Full Text PDF PubMed Scopus (3354) Google Scholar the value of these compounds in second-line and third-line treatment of patients with wild-type or unknown EGFR mutation status is still controversial. Almost all of the data about efficacy for use in these populations are based on retrospective subset analyses of clinical studies comparing EGFR tyrosine kinase inhibitors with chemotherapy or placebo. These studies included genotypically heterogeneous populations of patients, most of whom had unknown EGFR mutation status. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trialOur results show that chemotherapy is more effective than erlotinib for second-line treatment for previously treated patients with NSCLC who have wild-type EGFR tumours. Full-Text PDF