[The evolution of the treatment of advanced NSCLC.]

The therapeutic scenario of patients with advanced non-small-cell lung cancer (NSCLC) has dramatically changed in recent years, thanks to the improvement in the knowledge of the biology of NSCLC, the discovery of targetable oncogenic drivers, and the availability of new effective drugs also for non oncogenic addicted patients, defined "wild-type" (WT). NSCLC has been the first epithelial neoplasm treated with a targeted first-line therapy in patients harbouring EGFR activating mutations or ALK rearrangements, and new targeted-based agents directed versus other molecular alterations are currently in development. The recognition of the importance of histology for the definition of a first-line therapy of WT tumors has led to the adoption of different regimens for patients with squamous and non-squamous histology. In particular, in case of WT NSCLC with non-squamous histology, the use of platinum-based combinations including pemetrexed or bevacizumab became the standard treatment and the maintenance therapy with pemetrexed a further opportunity for selected patients. Recently, new active drugs with different mechanisms of action, including angiogenesis inhibitors, such as nintedanib or ramucirumab, and immune checkpoint inhibitors, such as nivolumab, pembrolizumab and atezolizumab, have shown relevant overall survival improvement in pretreated patients, modifying the landscape also of the second line treatment that became more rich and complex. The improvement and the application of novel technologies of molecular analysis and the identification of predictive biomarkers for new agents and in particular for immunotherapy will allow a more comprehensive molecular profiling of NSCLC and a better customization of treatments.