Treatment After First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non- Small-Cell Lung Cancer

Abstract

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...

PCC0208027, a novel tyrosine kinase inhibitor, inhibits tumor growth of NSCLC by targeting EGFR and HER2 aberrations

“…Globally, approximately 1.6 million people die of lung cancer each year 1 . NSCLC is the most common lung cancer subtype, accounting for 80–85% of lung cancers and more than 50% of patients have stage IV disease at the time of diagnosis 1–3 . EGFR is the most common genetic driver in NSCLC development.…”

“…Many pathogenic mutations, deletions, insertions, and duplications in EGFR exons 18–21 have been reported 5 . Small molecule EGFR tyrosine kinase inhibitors (TKIs) have become the mainstay targeted therapy for NSCLC patients with EGFR mutations 3,5,6 .…”

“…Erlotinib, gefitinib, and afatinib are first-line treatments for NSCLC patients with EGFR exon 19 deletion or exon 21 L858R mutations. In clinical practice, these treatments are superior to platinum-based chemotherapy, as in NSCLC patients with EGFR mutations, the response rate (RR) is 80% and progression-free survival (PFS) can be extended by 10–14 months 3,7–10 . However, treatment-related adverse events (AEs) such as diarrhea and rashes are often reported 11 .…”

Efficacy of Next-Generation EGFR-TKIs in Patients With Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials

“…Recent advances in genetic discoveries in NSCLC and the employment of specific inhibitors against them have played a key role in patients with disease at these stages. 2 …”

“…Next-generation TKIs, including second-generation TKIs (such as afatinib) and third-generation TKIs (osimertinib), have offered a potential alternative for patients who progressed after first-generation EGFR-TKI treatment. 2 …”