Targeted Therapies in Non-Small Cell Lung Cancer: A Contemporary Review

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung carcinoma (NSCLC) comprising over 85% of cases. Advances in molecular diagnostics and precision oncology have shifted treatment toward mutation-driven strategies, resulting in significantly improved patient outcomes. This review synthesizes current evidence on the most clinically relevant genetic alterations in NSCLC and their corresponding targeted therapies, including epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, ROS1 fusions, BRAF V600E mutations, MET exon 14 skipping mutations, RET and NTRK fusions, HER2 alterations, and KRAS G12C mutations. We outline mechanisms of action, clinical efficacy, and limitations of FDA-approved tyrosine kinase inhibitors (TKIs) and emerging agents, with emphasis on resistance pathways, both on-target and bypass-mediated, observed during treatment with drugs such as osimertinib, crizotinib, sotorasib, and entrectinib. The role of next-generation sequencing (NGS), liquid biopsy, and comprehensive biomarker profiling in guiding personalized therapy selection is also discussed, along with strategies for sequential therapy and rational combination approaches.