Desilets Antoine, Repetto Matteo, Yang Soo-Ryum, Drilon Alexander
Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Cancer. 2025 Mar 15;131 Suppl 1:e35784. doi: 10.1002/cncr.35784.
ROS1 rearrangements define a molecular subset of non-small cell lung cancer (NSCLC) by accounting for 1%-2% of cases. Targeted therapy with ROS1 tyrosine kinase inhibitors (TKIs) has significantly improved the outcomes for these patients. First-generation inhibitors, such as crizotinib and entrectinib, have demonstrated impressive efficacy, with objective response rates exceeding 60%-70%. However, the emergence of resistance mechanisms, including solvent-front mutations such as ROS1 G2032R, and limited blood-brain barrier penetration have limited the long-term efficacy of early-generation agents. Next-generation TKIs, including lorlatinib, taletrectinib, and repotrectinib, have been developed to overcome these challenges. These agents show enhanced central nervous system (CNS) penetration and activity against on-target ROS1 resistance mutations. Repotrectinib, a potent, CNS-penetrant ROS1 inhibitor, has demonstrated superior activity in both TKI-naive and -resistant tumors, including those harboring the G2032R mutation. Zidesamtinib, a highly selective next-generation ROS1 inhibitor, further addresses TRK-mediated off-target neurological toxicities seen with prior agents, and is poised to offer improved tolerability. Ongoing research is focused on optimizing sequencing strategies for ROS1 inhibitors and exploring combination approaches to prevent or overcome resistance. In addition, the development of novel diagnostic tools, including RNA-based next-generation sequencing, has enhanced the detection of functional ROS1 fusions by ensuring that patients with actionable mutations receive appropriate targeted therapies. These advances highlight the evolving landscape of treatment for ROS1-positive NSCLC, with the aim of maximizing long-term survival and quality of life.
ROS1重排定义了非小细胞肺癌（NSCLC）的一个分子亚群，约占病例的1%-2%。使用ROS1酪氨酸激酶抑制剂（TKIs）进行靶向治疗显著改善了这些患者的治疗结果。第一代抑制剂，如克唑替尼和恩曲替尼，已显示出令人印象深刻的疗效，客观缓解率超过60%-70%。然而，耐药机制的出现，包括溶剂前沿突变如ROS1 G2032R，以及血脑屏障穿透有限，限制了早期药物的长期疗效。已开发出下一代TKIs，包括洛拉替尼、他雷替尼和瑞波替尼，以克服这些挑战。这些药物显示出增强的中枢神经系统（CNS）穿透能力和对ROS1靶向耐药突变的活性。瑞波替尼是一种强效的、可穿透CNS的ROS1抑制剂，在初治和耐药肿瘤中均显示出卓越的活性，包括那些携带G2032R突变的肿瘤。齐德沙替尼是一种高度选择性的下一代ROS1抑制剂，进一步解决了先前药物所见的TRK介导的脱靶神经毒性问题，并有望提供更好的耐受性。正在进行的研究集中在优化ROS1抑制剂的序贯策略以及探索联合治疗方法以预防或克服耐药性。此外，新型诊断工具的开发，包括基于RNA的下一代测序，通过确保具有可操作突变的患者接受适当的靶向治疗，提高了功能性ROS1融合的检测率。这些进展凸显了ROS1阳性NSCLC治疗格局的不断演变，旨在最大限度地提高长期生存率和生活质量。
