Role of EGFR-TKIs in Nonmetastatic Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer: A Comprehensive Review

The treatment landscape of non-small cell lung cancer (NSCLC) has advanced considerably in the past two decades, driven largely by molecular profiling and the development of targeted therapies. Among oncogenic drivers, mutations in the epidermal growth factor receptor (EGFR) have proven to be particularly significant, with the introduction of tyrosine kinase inhibitors (TKIs) revolutionizing management. While first- and second-generation EGFR TKIs improved disease-free survival (DFS), they failed to confer overall survival (OS) benefit in the adjuvant setting. Osimertinib, a third-generation EGFR TKI with superior potency, CNS penetration, and tolerability, has emerged as the standard of care for nearly all stages of <i>EGFR</i>-mutated NSCLC. The phase III ADAURA trial demonstrated that adjuvant osimertinib significantly prolonged DFS and OS in patients with stage IB-IIIA, resected <i>EGFR</i> exon 19 deletion, or L858R-mutated NSCLC. Similarly, the phase III LAURA trial established osimertinib as consolidation therapy after chemoradiotherapy in unresectable stage III <i>EGFR</i>-mutated NSCLC, yielding a dramatic progression-free survival benefit and reduced CNS relapse rates. As osimertinib use expands, clinicians must remain vigilant regarding toxicity, including rash, diarrhea, cytopenias, and rarer but serious risks such as interstitial lung disease and cardiotoxicity. Optimal treatment duration, the role of adjuvant chemotherapy, and surveillance strategies remain subjects of active investigation. Emerging technologies, such as circulating tumor DNA for minimal residual disease detection and radiomic analyses, may refine patient selection and duration of therapy. Future directions include perioperative use of osimertinib, as explored in the ongoing NeoADAURA trial, and extension of the adjuvant TKI paradigm to other oncogenic drivers such as <i>ALK</i>, <i>ROS1</i>, and <i>RET</i>. Collectively, these advances herald a new era of precision oncology in NSCLC, where targeted therapies are reshaping curative-intent treatment strategies for oncogene-driven disease.