Strategies Beyond 3rd EGFR-TKI Acquired Resistance: Opportunities and Challenges

The seminal identification of epidermal growth factor receptor (EGFR) mutations as pivotal oncogenic drivers in non-small cell lung cancer (NSCLC) has catalyzed the evolution of biomarker-guided therapeutic paradigms for advanced disease. Currently, third-generation EGFR tyrosine kinase inhibitors (EGFR-TKI) have revolutionized first-line treatment for advanced EGFR-mutated NSCLC, yet acquired resistance remains an inevitable and formidable clinical challenge. This review systematically summarizes molecular mechanisms underlying treatment resistance, with a focus on clinical challenges associated with central nervous system (CNS) metastases. Therapeutic resistance mechanisms are categorized into EGFR-dependent (on-target) pathways, typified by acquired kinase domain mutations (e.g., C797S), and EGFR-independent (off-target) pathways, involving compensatory activation of parallel signaling effectors (e.g., MET amplification, HER2 activation) or phenotypic transformation. We further evaluated contemporary diagnostic modalities for identifying resistance drivers and appraised emerging therapeutic strategies, including fourth-generation EGFR-TKI, various combination therapies, and antibody-drug conjugates (ADCs), and so forth, with emphasis on ongoing clinical trials that may transform the existing treatment paradigm. By synthesizing preclinical and clinical insights, this review aims to advance mechanistic understanding and propose therapeutic strategies to overcome acquired resistance to third-generation EGFR-TKI in first-line treatment.