The “Romance of the Three Kingdoms” of EGFR-TKI Combination Therapy: Relationships Among Efficacy, Toxicity, and Resistance Mechanisms

Epidermal growth factor receptor (EGFR) mutations is one of the most significant driver genes in non-small cell lung cancer (NSCLC), particularly exhibiting a higher incidence among East Asian non-smokers with adenocarcinoma. The successful research and development of Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has significantly improved the survival for this patient population. But primary and secondary resistance remain core challenges in clinical practice. To overcome drug resistance, enhance efficacy, and prolong patient survival, targeted combination therapy strategies have emerged and become a research focus. This review provides a systematic review of the latest clinical evidence for EGFR-TKI combination therapy with chemotherapy, anti-angiogenic agents, other signaling pathway inhibitors, immunotherapy, and emerging dual-target therapies (such as bispecific antibodies and antibody-drug conjugates). The results indicate that TKIs combined with chemotherapy or bispecific antibody drugs have become one of the key options for first-line treatment; Precision combinations targeting resistance mechanisms (such as MET) is the developmental direction for subsequent lines of therapy; while the combination of TKIs with immune checkpoint inhibitors requires cautious exploration. In the future, personalized combination strategies guided by dynamic molecular profiling, the development of novel drugs, and the optimization of treatment modalities will be key to further overcoming therapeutic bottlenecks.