New Target Therapies in Advanced Non-Small Cell Lung Cancer: A Review of the Literature and Future Perspectives

Abstract

Introduction: Lung cancer (LC) is the most common neoplasm worldwide, and 85% of these tumors are classified as non-small cell lung cancer (NSCLC). LC treatment was initially restricted to cytotoxic chemotherapy-platinum compounds associated with 3rd generation cytotoxic agents (paclitaxel, gemcitabine, pemetrexed) and, more recently, with monoclonal antibodies (bevacizumab, ramucirumab). Advancements in treatment are correlated with prolonged overall survival (OS). Current advances are focused on target therapies. Target agents: Anti-epidermal growth factor receptor (EGFR) therapy consists of 1st and 2nd generation tyrosine kinase inhibitors (TKIs such as erlotinib, afatinib). In 60% of cases, resistance to these TKIs occurs due to T790M mutation in EGFR, which is overcome 3rd generation drugs (osimertinib). Anaplastic lymphoma kinase (ALK) is the target for drugs such as crizotinib, alectinib, ceritinib. Programmed death 1 (PD-1) and its ligand serve as targets for immunotherapy agents such as pembrolizumab, nivolumab, atezolizumab.

Discussion: Challenges in NSCLC treatment include resistance to 3rd generation TKIs, the high cost of ALK inhibitors, and the need for further research on new drugs.

Keywords: ALK inhibitors; immunotherapy; non-small-cell lung cancer; target therapy; tyrosine kinase inhibitors.

Figure 1

Evolution of chemotherapy treatment in non-small cell lung cancer, highlighting some landmark drugs and the accompanying increase in median overall survival. NSCLC = non-small cell lung cancer. OS = overall survival.

Figure 2

Steps of some signaling pathways activated by the binding of a ligand to EGFR. EGFR = endothelial growth factor receptor. TK = tyrosine kinase domain. P = phosphate. RAS = rat sarcoma protein. GTP = guanosine triphosphate. RAF = rapidly accelerated fibrosarcoma protein. MEK = mitogen-activated protein kinase. ERK = extracellular signal-regulated kinase. PI3K = phosphatidylinositol 3-kinase. PIP3 = phosphatidylinositol-3,4,5-trisphosphate kinase. Akt = protein kinase B.