ROS1 基因融合是一种已确定的致癌驱动因素，占非小细胞肺癌 (NSCLC) 的 1%-2%。使用口服小分子酪氨酸激酶抑制剂 (TKI) 成功靶向 ROS1 融合癌蛋白，彻底改变了转移性 ROS1 融合阳性 (ROS1) NSCLC 的治疗格局，并改变了患者的治疗结果。美国食品和药物管理局批准的首选一线疗法包括克唑替尼、恩曲替尼和瑞泊替尼，目前，在这些选项中进行选择需要考虑全身和中枢神经系统疗效、耐受性和治疗的可及性。值得注意的是，对 ROS1 TKI 的耐药性总是会产生，限制了这些药物的临床益处并导致疾病复发。在了解耐药分子机制方面取得的进展使得许多下一代 ROS1 TKI 得以开发，这些下一代 ROS1 TKI 比第一代 TKI 实现了更广泛的 ROS1 耐药突变覆盖范围和更好的 CNS 渗透性，以及解决 TKI 耐药性的其他治疗策略。后续治疗方法取决于初始 ROS1 TKI 疾病进展的速度和模式，以及 TKI 耐药机制（如果已知）。在此，我们描述了一种基于这些临床考虑因素选择转移性 ROS1 NSCLC 初始和后续治疗的实用方法。此外，我们探索早期非转移性 ROS1 NSCLC 最佳治疗的不断变化的证据，同时强调未来的研究方向，目标是继续巩固 ROS1 NSCLC 治疗方面的巨大进展，并最终改善患有这种疾病的人的寿命和福祉。© 作者 2024。由牛津大学出版社出版。

ROS1 gene fusions are an established oncogenic driver comprising 1%-2% of non-small cell lung cancer (NSCLC). Successful targeting of ROS1 fusion oncoprotein with oral small-molecule tyrosine kinase inhibitors (TKIs) has revolutionized the treatment landscape of metastatic ROS1 fusion-positive (ROS1+) NSCLC and transformed outcomes for patients. The preferred Food and Drug Administration-approved first-line therapies include crizotinib, entrectinib, and repotrectinib, and currently, selection amongst these options requires consideration of the systemic and CNS efficacy, tolerability, and access to therapy. Of note, resistance to ROS1 TKIs invariably develops, limiting the clinical benefit of these agents and leading to disease relapse. Progress in understanding the molecular mechanisms of resistance has enabled the development of numerous next-generation ROS1 TKIs, which achieve broader coverage of ROS1 resistance mutations and superior CNS penetration than first-generation TKIs, as well as other therapeutic strategies to address TKI resistance. The approach to subsequent therapy depends on the pace and pattern of progressive disease on the initial ROS1 TKI and, if known, the mechanisms of TKI resistance. Herein, we describe a practical approach for the selection of initial and subsequent therapies for metastatic ROS1+ NSCLC based on these clinical considerations. Additionally, we explore the evolving evidence for the optimal treatment of earlier-stage, non-metastatic ROS1+ NSCLC, while, in parallel, highlighting future research directions with the goal of continuing to build on the tremendous progress in the management of ROS1+ NSCLC and ultimately improving the longevity and well-being of people living with this disease.© The Author(s) 2024. Published by Oxford University Press.