NTRKfusions are oncogenic drivers for multiple tumor types. Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases. Given their promising activity in pan-cancer cohorts, larotrectinib and entrectinib received U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for tissue-agnostic indications in patients with advanced solid tumors harboringNTRKfusions. The safety profiles for both drugs are quite manageable, although neurotoxicity driven by the on-target inhibition of normalNTRKcan be a concern. Also, on- and off-target resistance mechanisms can arise during therapy with TRK inhibitors, but they can be addressed with the use of combination therapy and next-generation TRK inhibitors. More recently, the FDA approved the use of repotrectinib, a second-generation TRK inhibitor, in patients with NTRK fusions, based on data suggesting clinical efficacy and safety, which could offer another tool for the treatment ofNTRK-altered cancers. In this review, we summarize the current evidence related to the use of TRK inhibitors in the tissue-agnostic setting. We also elaborate on the safety profiles and resistance mechanisms from a practical perspective.
NTRK融合是多种肿瘤类型的致癌驱动因素。因此，选择性原肌球蛋白受体激酶（TRK）抑制剂（包括拉罗替尼和恩曲替尼）的开发在临床管理领域具有变革性意义，因为这些药物具有较高的应答率，包括对脑转移患者的颅内应答。鉴于其在泛癌种队列中展现出的良好活性，拉罗替尼和恩曲替尼已获得美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）批准，用于治疗携带NTRK融合的晚期实体瘤患者，且不限定组织学类型。尽管由正常NTRK靶向抑制引起的神经毒性值得关注，但两种药物的安全性特征均较为可控。此外，TRK抑制剂治疗期间可能出现靶向及脱靶耐药机制，但可通过联合疗法及新一代TRK抑制剂应对。近期，基于显示临床疗效和安全性的数据，FDA批准第二代TRK抑制剂瑞波替尼用于NTRK融合患者，这为治疗NTRK变异癌症提供了新选择。本综述总结了当前关于TRK抑制剂在组织学非依赖性治疗中应用的证据，并从实践角度详细阐述了其安全性特征与耐药机制。
肿瘤(癌症)患者之家