Paper Title
Precision Medicine for Non-Smoker’s Lung Cancer: Targeting EGFR Mutations for Effective Treatments and LDCT Screening to Save Lives

Lung cancer is the #1 cancer killer in the world, while about 85% of lung cancer is NSCLC (non-small-cell lung cancer). Many NSCLC adenocarcinoma express mutations on the Epidermal Growth Factor Receptor (EGFR), especially for non-smoking, female, Asian, young patients. The small molecules of EGFR tyrosine kinase inhibitors (TKI) can diffuse across the cell membrane and bind to the ATP binding sites on the EGFR kinase domain, effectively inhibiting cancer cells as a precision medicine. Many EGFR-mutant NSCLC patients have exhibited good responses to the 1st-generation EGFR TKIs (e.g., gefitinib, erlotinib), and/or the 2nd-generation EGFR TKIs (e.g., afatinib), but almost all patients will eventually develop acquired resistance to those TKIs, with ~50% developed T790M mutation. Therefore, the third-generation EGFR TKI osimertinib has been approved by the US FDA in2016 for patients with T790M mutation, and later in 2018 as a standard 1st-line treatment for EGFR-mutant NSCLC. However, acquired resistance to osimertinib will also develop and the mutational landscape can be very complex to overcome: patients who retain T790M (EGFR-dependent) vs. those who lose T790M (mostly EGFR-independent) areon rather different pathways. For EGFR-dependent NSCLC, combining TKI with an EGFR antibody can be effective to inhibit EGFR mutations, as first demonstrated in afatinib + cetuximab, and recently shown in osimertinib + necitumumab, and lazertinib+ amivantamab. As very limited FDA-approved treatment options are currently available for many acquired resistance cases after osimertinib (other than chemotherapies and potential clinical trials), there is an urgent clinical need worldwide to find the best treatment option(s) after acquired resistance to osimertinib, especially for non-smoker’s lung cancer patients. Keywords - EGFR Tyrosine Kinase Inhibitor (TKI), C797S, EGFR (epidermal growth factor receptors), Non-Small-Cell Lung Cancer (NSCLC); Non-Smoker’s Lung Cancer; Osimertinib Resistance