![]() ![]() Resistance mechanismsįigures 1 and 2 below summarize mechanism of acquired resistance to 1 st/2 nd generation TKI and osimertinib respectively. Osimertinib is now the standard of care for untreated EGFR mutant (ex19del or L858R) advanced NSCLC due to its superior efficacy and tolerability. FDA-approved EGFR TKIs in the first-line metastatic NSCLC setting are included in Tables 1 and 2. ![]() Table 2 highlights select FDA approved targeted agents with corresponding clinical trials, efficacy, and common adverse effects.ĮGFR mutations such as exon 19 deletions (EX19del) and exon 21 (L858R) point mutations are oncogenic drivers in around 20% of patients with lung adenocarcinoma. Table 1 includes the relative frequencies and most common types of these mutations in different population subgroups along with drugs of interest. Predictive biomarkers in NSCLC include anaplastic lymphoma kinase (ALK) fusion oncogene, ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) gene fusions, sensitizing endothelial growth factor receptor (EGFR) gene mutations, BRAF V600E point mutations, neurotrophin tyrosine kinase (NTRK) gene fusions, c-mesenchymal-epithelial transition factor (c-MET) exon 14 (METex14) skipping mutations and RET rearrangements. Finally, we present summary of ongoing clinical trials in a tabulated fashion at the end of each section. Each study was individually reviewed, and data points have been summarized. Literature was searched for first-in-human, phase I and phase II clinical trials in NSCLC using PubMed, Google Scholar, and the American Society of Clinical Oncology (ASCO) meeting abstracts. We then discuss the recently published data on the first-in-human clinical trials and some of the most promising drugs in the pipeline for this disease. In this review after highlighting the different driver genomic alterations and their relative frequencies in advanced NSCLC we summarize the clinical efficacy and safety of FDA approved targeted therapies. It helps in the rapid identification of actionable mutations and resistance mechanisms. Next-generation sequencing, which can be performed on the tumor tissue and circulating tumor DNA (ctDNA) in the blood, is now the standard of care for all patients with advanced NSCLC. This has led to research in identifying drugs that can overcome these resistance pathways. ![]() Despite these new therapeutic options for patients with advanced NSCLC, there continues to be significant challenges as resistance development and disease progression occurs in most of these patients. Similar patterns have been found among women with NSCLC. The approval and adoption of agents targeting these alterations has contributed to the decline in incidence-based mortality from 35% among men with NSCLC diagnosed in 2001 to 26% among those diagnosed in 2014. Identification of targetable alteration (i.e., EGFR, ALK, PI3K/AKT/mTOR, RAS-MAPK, RET, MET, BRAF, and NTRK/ROS1) in patients with advanced NSCLC has evolved its treatment paradigm. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for more than two-thirds of the cases, with most patients (84%) having advance disease at the time of diagnosis. In 2021, an estimated 235,760 new lung cancer cases will be diagnosed in the US, and 131,880 people will die from this disease. Overall, lung cancer causes more deaths than breast, prostate, colorectal, and brain cancers combined. Lung cancer remains the number one cause of cancer-related death worldwide. We will also summarize the currently available phase I/II clinical trial for NSCLC patients at the end of each section. ![]() This article is aimed to be the most current review of available and upcoming targeted NSCLC treatment options. We have divided our discussion into different topics based on these agents' mechanisms of action. This review summarizes the recent advances in advanced NSCLC targeted therapy, focusing on first-in-human and early phase I/II clinical trials in patients with advanced disease. Advances in molecular and immunohistochemical techniques have made it possible to usher lung cancer into the era of personalized medicine, with the patient getting individualized treatment based on these markers. For a subset of patients with actionable mutations, targeted therapy continues to provide durable responses. Non-small cell lung cancer is the most common variety accounting for 84% of the cases. Lung cancer remains the leading cause of cancer-related mortality in both men and women in the US and worldwide. ![]()
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