Current status and perspectives of molecular target therapy for advanced lung cancer

Recent advances of molecular biology have led to the development of agents that target specific molecular pathways. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib, erlotinib and afatinib showed a significant high response and prolonged progression-free survival, compared with conventional cytotoxic chemotherapy in patients with non-small lung cancer (NSCLC) harboring EGFR mutations. In addition, crizotinib, inhibitor of anaplastic lymphoma kinase (ALK), shows marked therapeutic effects against ALK rearranged NSCLC. Molecular targeted therapy selected on the basis of somatic targetable driver genes such as EGFR mutations and ALK rearrangements has been established as standard treatment for NSCLC. On the other hands, bevacizumab, a humanized anti-VEGF monoclonal antibody, in combination with first-line chemotherapy demonstrated significant clinical benefit in non-squamous NSCLC. Recently, new somatic targetable driver gene alterations such as BRAF, ROS1, and RET has been identified, and new drugs targeting for these gene alterations are under clinical evaluation. However, the frequency of these driver gene alterations is rare in lung adenocarcinoma, and the construction of the effective screening system has been required. The nationwide screening system, Lung Cancer Genomic Screening Project for Individualized Medicine in Japan (LC-SCRUM-Japan) is ongoing. Moreover, advances in the understanding of immunology and antitumor immune responses have led to the development of new immunotherapies, including vaccination approaches and monoclonal antibodies that inhibit immune checkpoint pathways. Especially, the immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed death (PD-1) pathway have shown durable and meaningful response. In the near future, molecular targeted therapy will be able to provide more benefits to many lung cancer patients.