Targeted Therapy for NSCLC--A Double-edged Sword?

Advanced or metastatic non-small cell lung cancer (NSCLC) is characterised by a poor prognosis and few second- or third-line treatments. First-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibition has paved the way for targeted therapies in lung cancer. Although these drugs result in excellent responses [and significantly improved progression-free survival (PFS)] in patients with activating EGFR mutations, only few studies revealed improved overall survival (OS), and resistance often develops. Bevacizumab, a monoclonal antibody which targets vascular endothelium growth factor (VEGF), has been fully developed in NSCLC, and small-molecule tyrosin kinase inhibitors (TKIs) have been approved as first-line therapy for patients with advanced and metastatic NSCLC harbouring EGFR mutations. In addition, crizotinib, a novel inhibitor of the anaplastic lymphoma kinase, has been approved for second-line treatment of NSCLC. Several new drugs targeting not only the EGFR pathways, but also signal transduction cascades involved in angiogenesis and the mitogene-activated extracellular signal-regulated kinase kinase pathways are currently evaluated in phase III clinical trials. Experimental monoclonal antibodies are also currently undergoing phase III clinical trials and have shown promising activity which might help to improve the therapeutic landscape of NSCLC. However, many other drugs prolonged PFS, but failed to demonstrate a significant improvement of OS. PFS is often used as a predictor for improved OS since it is independent of subsequent treatment, but OS is acknowledged as the key clinical outcome in the treatment of advanced NSCLC. Furthermore, since there are only very few trials that have shown a benefit from the addition of TKIs to chemotherapy, additional studies using this unselected approach are not recommended. Therefore, there is a definite need for an improved understanding of the complex mechanisms that are involved in TKI-mediated pathways, and for the development of validated predictive markers to allow a better treatment decision on the basis of the probability of response. This would certainly help to avoid the unnecessary use of potential toxic drugs in patients with known resistance and would facilitate the discovery of new targets and drugs on the basis of resistance mechanisms.