Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, with epidermal growth factor receptor (EGFR) mutations present in a substantial proportion of patients. Third-generation EGFR tyrosine kinase inhibitors (EGFR TKI), exemplified by osimertinib, have dramatically improved outcomes by effectively targeting the T790M mutation—a primary driver of acquired resistance to earlier-generation EGFR TKI. Despite these successes, resistance to third-generation EGFR TKIs inevitably emerges. Mechanisms include on-target mutations such as C797S, activation of alternative pathways like MET amplification, histologic transformations, and intricate tumor microenvironment (TME) alterations. These resistance pathways are compounded by challenges in tolerability, adverse events, and tumor heterogeneity. In light of these hurdles, this review examines the evolving landscape of combination therapies designed to enhance or prolong the effectiveness of third-generation EGFR TKIs. We explore key strategies that pair osimertinib with radiotherapy, anti-angiogenic agents, immune checkpoint inhibitors, and other molecularly targeted drugs, and we discuss the biological rationale, preclinical evidence, and clinical trial data supporting these approaches. Emphasis is placed on how these combinations may circumvent diverse resistance mechanisms, improve survival, and maintain a favorable safety profile. By integrating the latest findings, this review aims to guide clinicians and researchers toward more individualized and durable treatment options, ultimately enhancing both survival and quality of life for patients with EGFR-mutated NSCLC.
非小细胞肺癌是全球癌症相关死亡的主要原因，其中表皮生长因子受体突变在相当比例的患者中存在。以奥希替尼为代表的第三代EGFR酪氨酸激酶抑制剂通过有效靶向T790M突变——这是导致前代EGFR TKI获得性耐药的主要驱动因素——显著改善了治疗结局。尽管取得这些成功，针对第三代EGFR TKI的耐药性仍不可避免地出现。耐药机制包括C797S等靶点突变、MET扩增等替代通路激活、组织学转化以及复杂的肿瘤微环境改变。这些耐药通路与耐受性挑战、不良事件及肿瘤异质性相互交织。面对这些障碍，本综述探讨了旨在增强或延长第三代EGFR TKI疗效的联合治疗策略的发展态势。我们重点研究了奥希替尼与放疗、抗血管生成药物、免疫检查点抑制剂及其他分子靶向药物联合的关键策略，并讨论了支持这些方法的生物学原理、临床前证据及临床试验数据。特别关注这些联合方案如何规避多种耐药机制、提高生存率并维持良好安全性。通过整合最新研究进展，本综述旨在为临床医生和研究人员提供更具个体化及持久性的治疗选择指导，最终提升EGFR突变非小细胞肺癌患者的生存率与生活质量。
Optimizing Osimertinib for NSCLC: Targeting Resistance and Exploring Combination Therapeutics
肿瘤(癌症)患者之家