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KEY CONCEPTS

  • Non–small cell lung cancer (NSCLC) can be classified based on recurrent genetic alterations in genes encoding proteins essential to cell proliferation and survival. These genetic alterations are transformative, meaning that they play a pivotal role in transforming a noncancerous cell into a cancerous one. NSCLCs that harbor these alterations are called oncogene-addicted. These genetic alterations are typically mutually exclusive and are characterized by impressive sensitivity to small-molecule receptor tyrosine kinase.

  • Identifying patients with targetable alterations has important therapeutic and prognostic implications. Molecular profiling of advanced NSCLC using tumor tissue, cell-free DNA (cfDNA), or both is strongly recommended irrespective of tobacco exposure history.

  • Oncogene-addicted advanced NSCLC should be treated with targeted agents specific to each genetic alteration. This is based on impressive clinical activity and the tolerability of targeted agents. There are Food and Drug Administration–approved targeted agents for NSCLC that harbor alterations in EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), ROS proto-oncogene 1 (ROS1), rearrangements, B-Raf proto-oncogene (BRAF), rearranged during transfection (RET), neurotrophic receptor tyrosinekinase gene (NTRK1-3), and MET (mesenchymal-epithelial transition) as well as promising agents for HER2 (human epidermal growth factor receptor 2) and NRG1 (neuregulin 1).

  • Targeted treatment based on clinical demographic characteristics alone is not recommended.

  • Emergence of resistance targeted therapy is inevitable. Resistance mechanisms can be broadly divided into target dependent or independent. The latter means activation of bypass pathways, leading to clinical resistance. Identifying resistance mechanisms to targeted therapy can determine treatment decisions and; therefore, obtaining a tissue biopsy, cfDNA, or both on progression is generally indicated.

  • Treatment of patients with oncogene-addicted NSCLC upon progression on a targeted agent should be individualized. Treatment options include clinical trial enrollment, continuing the same targeted agent with local ablative therapy of progressing lesions, and cytotoxic chemotherapy with or without immunotherapy.

INTRODUCTION

The wide use of molecular profiling techniques combined with a better understanding of signaling pathways in lung cancer and other tumors has led to the identification of mutually exclusive, activating genetic alterations in specific tyrosine kinases that can be targeted using tyrosine kinase inhibitors (TKIs). Matching a specific targeted TKI to the specific driver mutation identified has produced a paradigm shift in the treatment of non–small cell lung cancer (NSCLC), with targeted therapy considered the preferred initial treatment for patients with NSCLC who have such genetic alterations. We now have approved targeted therapies for NSCLC that harbor activating alterations in EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), ROS proto-oncogene 1 (ROS1), rearrangements, B-Raf proto-oncogene (BRAF), rearranged during transfection (RET), neurotrophic receptor tyrosinekinase gene (NTRK1-3), and MET (mesenchymal-epithelial transition), as well as promising agents for HER2 (human epidermal growth factor receptor 2) and NRG1 (neuregulin 1). Herein, we will discuss each of these genetic alterations.

The National Comprehensive Cancer Network (NCCN) guidelines recommend testing NSCLC for EGRF, ALK, ROS1, BRAF and NTRK (https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf). This is largely consistent with recommendations from the College of American Pathologists, ...

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