Novel therapies in non-small cell lung cancer

Abstract

The majority of patients with lung tumors present cancers histologically classified as non-small cell lung cancer (NSCLC) in advanced stage disease. Until recently, platinum-based doublet chemotherapy regimens were the standard treatment for patients with a good performance status. However, these regimens have disappointing results, with only about 30% of responding patients, median survival ranging from 8 to 12 months and 1-year survival rates varying from 33 to 46%. Innovative treatment options are urgently needed to overcome this therapeutic plateau. New insights into the molecular biology of cancer and mechanisms of tumorigenesis have identified key biological processes and several potential molecular targets for anti-cancer treatment. Mutations, chromosomal rearrangements, DNA copy number aberrations, abnormal methylation or microRNAs expression have been highlighted among the genetic and epigenetic alterations involved in cancer development and progression and new targeted therapies have been developed. A number of these novel agents have proven clinical efficacy and have led to some progress in the treatment of advanced NSCLC. Combining bevacizumab with chemotherapy as first-line treatment demonstrated a survival prolongation beyond the historical bench mark of 12 months. The epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs) have proven superior efficacy when compared to standard chemotherapy in patients with activating EGFR mutations, and these are now the recommended first-line treatment for such patients. Cetuximab in combination with platinum-based chemotherapy has been approved for the first-line treatment of EGFR-protein expressing NSCLC patients with good performance status and the extraordinary response seen in ALK-positive NSCLC patients accelerated the approval by the Food and Drug Administration of the potent ALK/c-MET inhibitor crizotinib. However, despite the progress made, several important issues in the clinical development of these targeted agents remained unresolved. Therefore, the present Thesis evaluated the problems linked to the identification of when and how these agents should be safely and effectively integrated with conventional therapies so as to maximize clinical benefit and minimize toxicity. The development of novel targeted agents or combinations potentially useful to overcome NSCLC drug resistance are discussed, and innovative strategies to maximize the effect of the currently approved EGFR-TKIs are also analysed. The increasing knowledge on tumorigenesis, resistance mechanisms, development of novel treatment strategies and emerging imaging and biochemical techniques will permit us to move towards personalized treatment approach for advanced NSCLC.