Combinatorial Chemistry & High Throughput Screening, 2012, 15, 641-655 641 Targeted Therapies for Advanced Non-Small Cell Lung Cancer Ioannis Starakis *,1 , Achilleas Nikolakopoulos 2 and Elias E. Mazokopakis 3 1 Patras University Hospital, 26504 Rion-Patras, Greece 2 Division of Oncology, Department of Medicine, Patras University Hopsital, 26504 Rion-Patras, Greece 3 Department of Internal Medicine, Naval Hospital of Crete, Greece Abstract: The incorporation of targeted agents has considerably improved the management of patients with advanced non-small cell lung cancer (NSCLC) over the last years. The main targets include the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). Currently available agents with established role in NSCLC include the anti-EGFR tyrosine-kinase inhibitors (TKIs) erlotinib/gefitinib and the anti-VEGF monoclonal antibody bevacizumab. Moreover, several other agents targeting critical pathways in lung carcinogenesis are currently under preclinical or clinical evaluation. This review presents an update on the role of targeted agents in advanced NSCLC. In addition, we present the main clinical studies investigating the activity of these agents in NSCLC and we provide recent data with respect to future therapeutic strategies. Keywords: Non-small cell lung carcinoma, targeted treatments. INTRODUCTION Non-small cell lung cancer comprises almost 85% of all lung cancer incidents and represents the most common cause of death in males and the second most common in females. Treatment modalities implemented in patients with NSCLC depend upon the stage of the disease and the overall assessment of the individual patient’s medical status. Surgical intervention is indicated for early-stage localized disease and the combination of surgery, chemotherapy and radiation treatment is the preferable approach for those with locally advanced disease. Palliative systemic chemotherapy is suitable for those with disseminated metastatic disease, a malignant pleural or pericardial effusion and those with advanced disease who have relapsed after previous curative interventions. Almost forty percent of NSCLC patients have an advanced stage disease when they first seek medical attention, a fact that underlines the necessity for effective therapeutic options [1]. The better understanding of the molecular pathogenetic mechanisms of NSCLC has led to the development of targeted treatment regimens and a number of aberrant cell-signaling and cell-survival pathways have been recognized as potential therapeutic targets. Moreover, immunotherapy (i.e., vaccines and monoclonal antibodies directed against tumor- specific antigens) and antiangiogenic agents have also been used as targeted therapies [2]. Targeted treatment regimens with small molecules targeting the EGFR-TK (erlotinib, gefitinib), a monoclonal antibody targeting the EGFR (cetuximab), and a monoclonal antibody targeting angiogenesis by binding VEGF (bevacizumab), have all demonstrated valuable clinical activity in patients with advanced NSCLC. *Address correspondence to this author at the Patras University Hospital, 26500 Rion-Patras, Greece; Tel: +30 2610 999979; Fax: +30 2610 999740; E-mail: istarakis@yahoo.com Additionaly, other patient groups with different molecular pathways’ aberrations, such as the EML4-ALK fusion gene, might be profited from targeted treatment regimens. THE RATIONALE OF TARGETED AGENTS USE IN THE INITIAL MANAGEMENT OF ADVANCED NON- SMALL CELL LUNG CANCER (NSCLC) Pemetrexed Pemetrexed (Fig. 1) is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes, essential for cell replication. Pemetrexed was studied in a phase III, multicenter trial that enrolled 1725 chemotherapy-naive patients with advanced NSCLC who were randomized to receive either cisplatin plus pemetrexed or cisplatin and gemcitabine. The trial was based on a non-inferiority study design with overall survival (OS) as primary endpoint. Preplanned subset analyses have been carried out in order to evaluate differential efficacy according to histology. Patients with adenocarcinoma (847 patients) and with large cell carcinoma (LCC) (153 patients) had a longer OS (12.6 vs 10.9 months and 10.4 vs 6.7 months, respectively) when treated with cisplatin and pemetrexed. On the other hand, the 473 patients with squamous cell carcinoma (SCC) had a survival advantage when they received cisplatin and gemcitabine (10.8 vs 9.4 months). A significant treatment-by-histology interaction was observed for both progession-free survival (PFS) and OS. Therefore, pemetrexed was widely endorsed for use in combination with cisplatin for first-line treatment in non- squamous NSCLC patients with locally advanced or metastatic disease [3]. Epidermal Growth Factor Receptor (EGFR) Tyrosine- Kinase Inhibitors (TKIs) The receptor tyrosine-kinases is one of the cell surface membrane receptors’ families that regulate adhesion, 1 - /12 $58.00+.00 © 2012 Bentham Science Publishers