Department of Medicine, Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Clin Transl Med. 2024 Oct;14(10):e70017. doi: 10.1002/ctm2.70017.
The ROS1 proto-oncogene encodes a receptor tyrosine kinase with structural homology to other oncogenic drivers, including ALK and TRKA-B-C. The FDA-approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion-positive NSCLC. However, limitations such as poor blood-brain barrier penetration and acquired resistance, particularly the ROS1 G2032R solvent-front mutation, hinder treatment durability. Repotrectinib, a next-generation macrocyclic TKI, was rationally designed to overcome on-target resistance mutations and improve brain distribution through its low molecular weight. In the TRIDENT-1 clinical trial, repotrectinib demonstrated significant efficacy in both TKI-naïve and TKI-pretreated patients with ROS1-rearranged NSCLC, including those with CNS metastases and G2032R resistance mutations. In the TKI-naïve cohort (n = 71), 79% of patients achieved an objective response, with a median progression-free survival (PFS) of 35.7 months, surpassing all previously approved ROS1 TKIs. In patients who had received one prior ROS1 TKI but were chemotherapy-naïve (n = 56), objective responses were observed in 38%, and median PFS was 9.0 months. The safety profile of repotrectinib was consistent with earlier-generation ROS1 TKIs and common adverse events included anemia, neurotoxicity, increased creatine kinase levels, and weight gain. These findings underscore the potential of repotrectinib to address unmet needs in ROS1-rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next-generation, selective ROS1 inhibitors to reduce Trk-mediated toxicities and improve treatment tolerance.
ROS1 原癌基因编码一种受体酪氨酸激酶，与其他致癌驱动基因（包括 ALK 和 TRKA-B-C）具有结构同源性。美国食品药品监督管理局（FDA）批准的酪氨酸激酶抑制剂（TKI）克唑替尼和恩曲替尼已被证明对治疗 ROS1 融合阳性 NSCLC 有效。然而，限制因素如较差的血脑屏障穿透性和获得性耐药性，特别是 ROS1 G2032R 溶剂前沿突变，阻碍了治疗的持久性。Repotrectinib 是一种下一代大环 TKI，通过其低分子量被合理设计用于克服针对靶点的耐药性突变，并改善脑分布。在 TRIDENT-1 临床试验中，Repotrectinib 在 ROS1 重排 NSCLC 的 TKI 初治和 TKI 预处理患者中均显示出显著疗效，包括伴有中枢神经系统转移和 G2032R 耐药突变的患者。在 TKI 初治队列（n=71）中，79%的患者达到客观缓解，中位无进展生存期（PFS）为 35.7 个月，超过了所有先前批准的 ROS1 TKI。在接受过一种 ROS1 TKI 但未接受过化疗的患者（n=56）中，观察到 38%的患者有客观缓解，中位 PFS 为 9.0 个月。Repotrectinib 的安全性与早期 ROS1 TKI 一致，常见的不良反应包括贫血、神经毒性、肌酸激酶水平升高和体重增加。这些发现突显了 Repotrectinib 在解决 ROS1 重排 NSCLC 未满足的需求方面的潜力，提供了持久的反应和改善的颅内活性。未来的研究应优先开发下一代、选择性的 ROS1 抑制剂，以减少 Trk 介导的毒性并提高治疗耐受性。
