The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic drivers in non-small-cell lung cancer (NSCLC) has propelled a biomarker-directed treatment paradigm for patients with advanced-stage disease. Numerous EGFR and ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients with EGFR-mutant and ALK-rearranged NSCLCs have been developed, culminating in the availability of the highly effective third-generation TKIs osimertinib and lorlatinib, respectively. Despite their marked efficacy, resistance to these agents remains an unsolved fundamental challenge. Both ‘on-target’ mechanisms (largely mediated by acquired resistance mutations in the kinase domains of EGFR or ALK) and ‘off-target’ mechanisms of resistance (mediated by non-target kinase alterations such as bypass signalling activation or phenotypic transformation) have been identified in patients with disease progression on osimertinib or lorlatinib. A growing understanding of the biology and spectrum of these mechanisms of resistance has already begun to inform the development of more effective therapeutic strategies. In this Review, we discuss the development of third-generation EGFR and ALK inhibitors, predominant mechanisms of resistance, and approaches to tackling resistance in the clinic, ranging from novel fourth-generation TKIs to combination regimens and other investigational therapies.

EGFR突变和ALK重排作为非小细胞肺癌 (NSCLC) 中可行的致癌驱动因素的发现推动了针对晚期疾病患者的生物标志物导向治疗模式。许多 EGFR 和 ALK 酪氨酸激酶抑制剂 (TKI) 已被开发出来，并在EGFR突变和ALK重排 NSCLC 患者中显示出疗效，最终分别推出了高效的第三代 TKI 奥希替尼 (osimertinib) 和劳拉替尼 (lorlatinib)。尽管它们具有显着的功效，但对这些药物的耐药性仍然是一个尚未解决的根本挑战。 “靶向”机制（主要由 EGFR 或 ALK 激酶结构域中的获得性耐药突变介导）和“脱靶”耐药机制（由非靶标激酶改变介导，例如旁路信号激活或表型转化）已在接受奥西替尼或劳拉替尼治疗后出现疾病进展的患者中发现。对这些耐药机制的生物学和谱系的日益了解已经开始为更有效的治疗策略的开发提供信息。在这篇综述中，我们讨论了第三代 EGFR 和 ALK 抑制剂的开发、主要耐药机制以及临床中应对耐药性的方法，从新型第四代 TKI 到联合治疗方案和其他研究疗法。