The advance of the third‑generation EGFR‑TKI in the treatment of non‑small cell lung cancer (Review)

Abstract

Lung cancer is currently the second most common type of cancer with the second incidence rate and the first mortality rate worldwide. Non-small cell lung cancer (NSCLC) accounts for ~85% of the total number of cases of lung cancers. Concerning the treatment of NSCLC, targeted therapy has become a research hotspot in recent years because of its favorable efficacy, high selectivity and minimal adverse reactions. Among the drugs used in targeted therapy, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the most common and are categorized into four generations. The use of first and second-generation drugs leads to drug resistance within 8-14 months. This resistance is primarily caused by the T790M mutation, which is the most observed mechanism. A third-generation drug has been developed to address this issue and a fourth-generation drug is expected to overcome multiple resistance mechanisms, including third-generation drug resistance. However, the fourth-generation drug has not been launched yet. At present, multiple third-generation targeted drugs have been launched globally, with three being launched in China and several being at research and clinical trial stages. The present article provides a review of the development process, mechanism of action and clinical trials of the third-generation EGFR-TKIs, aiming to provide some reference and suggestions for the clinical treatment of NSCLC and scientific research on third-generation targeted drugs. Contents 1. Introduction 2. History of the EGFR-targeted drugs 3. Mechanism 4. Third-generation EGFR-TKIs 5. Comparison of drug efficacy and clinical plan recommendations 6. Advantages and disadvantages of the third-generation EGFR TKIs 7. Prospects

Chemical Scaffolds for the Clinical Development of Mutant-Selective and Reversible Fourth-Generation EGFR-TKIs in NSCLC

“…During the last years, a third generation of new TKIs were lunched, and their clinical development is extensively reviewed by recent publications. 42,43 Among them, the most promising active inhibitors include Almonertinib, developed by Jiangsu Hansoh Pharmaceutical Co., Ltd., 44 and Lazertinib (Leclaza) which is under investigation by Johnson & Johnson and currently in phase III for nonsmall cell lung cancer 45 (Figure 4). Unfortunately, like other targeted therapies, new EGFR mutations have emerged.…”

“…One of the most recent third-generation TKIs, Osimertinib, developed by AstraZeneca in the United States, dominated the global landscape of treatment of EGFR-positive NSCLC for several years, and it is currently the standard of care for the first-line treatment of advanced EGFR-mutated NSCLC and EGFR T790M-positive NSCLC after first- or second-generation EGFR-TKIs. During the last years, a third generation of new TKIs were lunched, and their clinical development is extensively reviewed by recent publications. , Among them, the most promising active inhibitors include Almonertinib, developed by Jiangsu Hansoh Pharmaceutical Co., Ltd., and Lazertinib (Leclaza) which is under investigation by Johnson & Johnson and currently in phase III for nonsmall cell lung cancer (Figure ). Unfortunately, like other targeted therapies, new EGFR mutations have emerged.…”

The Importance of Screening for EGFR Mutation in Lung Cancer

“…The EGFR protein, which is essential for cell division and proliferation, is the target of these inhibitors. First-generation and third-generation EGFR inhibitors differ primarily in their mechanism of action, resistance profiles, and therapeutic uses [12].…”

“…However, the emergence of resistance to them can restrict their efficacy and frequently cause the condition to worsen. When first-generation EGFR inhibitors are no longer effective for treating NSCLC patients because of the T790M mutation, third-generation EGFR inhibitors are typically utilized as a second-line treatment [12].…”

Dark under the Lamp: Neglected Biological Pollutants in the Environment Are Closely Linked to Lung Cancer

“…Although lung cancer is currently not the most common type of cancer, it is still the leading cause of cancer mortality worldwide [ 11 ]. Lung cancer is frequently utilized to investigate the carcinogenic effects of environmental pollution on humans, since the lung is an important organ exposed to environmental substances and has an essential gas exchange capability for survival.…”