Systemic treatment is the basic treatment approach to advanced-stage non-small-cell lung cancer (NSCLC), and chemotherapy and targeted treatments are commonly employed in these patients. Recently, positive results achieved with immunotherapy have led to a growing number of treatment options and prolonged survival time. Today, specific tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and the TKI crizotinib, which targets anaplastic lymphoma kinase gene rearrangement, have become the standard treatment among targeted therapies for patients with sensitive molecular anomalies. However, resistance develops against all these agents after a while. Numerous genetic mutations, T790M+ in particular, have been identified as resistance mechanisms against EGFR-TKIs, and researchers are developing specific inhibitors against them. Among those inhibitors, third-generation EGFR-TKIs such as osimertinib and rociletinib have gained prominence due to their high level of effectiveness and low toxicity profile. Besides, systemic chemotherapy and immunotherapy are proper alternatives. A second biopsy during the progression stage and better clarification of the mechanisms causing secondary resistance will enable more successful treatments in the future.
KEYWORDS:Epidermal growth factor receptor, tyrosine kinase inhibitors, resistance, non-small-cell lung cancer
INTRODUCTIONLung cancer is still the primary cause of cancer-related death for both sexes worldwide, causing approximately 1.4 million deaths every year [1]. Non-small-cell lung cancer (NSCLC) cases comprise approximately 80%-85% of all lung cancers. More than half of the NSCLC cases are advanced-stage at the time of diagnosis, and those patients are characterized by poor prognosis. Systemic chemotherapy has long been employed as the primary treatment approach for advanced-stage NSCLC. Despite a series of advances in chemotherapy and the application of histology-based approaches in the course of time, median survival time does not exceed 1 year [2]. On the other hand, recent discoveries of somatic mutations in NSCLC and the employment of specific inhibitors against them have led to significant changes in the treatment of advanced-stage NSCLC. Currently, there are two key oncogenic molecular anomalies reflected in routine practice: epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase gene rearrangement.Epidermal growth factor receptor mutations are observed in approximately 10% of the whole patient group, whereas this rate may go up to 40% among Asians, non-smokers, and in patients who have adenocarcinoma histology. Deletion at exon 19 and point mutation at exon 21 (L858R) are the most common EGFR mutations [3]. The presence of these mutations indicates sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. The use of erlotinib and gefitinib (first-generation TKIs) and afatinib (second-generation TKIs) in first-, second-, a...