Emerging Molecular Targets, Resistance Mechanisms, and Multimodal Therapeutic Paradigms in Non-Small Cell Lung Cancer: A Systematic Synthesis

Targeted kinase inhibitors and immune checkpoint inhibitors have transformed non-small cell lung cancer (NSCLC) management from empiric chemotherapy to biomarker-guided treatment. Despite improved progression-free survival across actionable subsets (EGFR, ALK, ROS1, RET, KRAS), acquired resistance inevitably emerges through secondary kinase mutations, bypass signaling cascades, and small-cell histologic transformation. Concurrently, spatial immune exclusion and defective antigen presentation limit durable responses to PD-1/PD-L1 monotherapy. This review synthesizes findings from 14 recent studies evaluating next-generation macrocyclic TKIs, bi-functional constructs (bispecific antibodies and antibody-drug conjugates), and perioperative multimodal integration. Evidence demonstrates that dual-targeting strategies—such as EGFR/MET bispecifics and HER2/HER3 ADCs—effectively bypass single-target kinase resistance, while neoadjuvant chemo-immunotherapy significantly improves complete pathologic response rates in resectable disease. However, high-grade adverse events, lack of head-to-head sequencing trials, and low ctDNA sensitivity in minimal shedding states remain critical barriers. Addressing these gaps requires rational combinatorial sequencing and dynamic, multi-analyte liquid biopsies.