Three generations of tyrosine kinase inhibitors (TKI) have been approved for anaplastic lymphoma kinase (ALK) fusion–positive non–small cell lung cancer. However, none address the combined need for broad resistance coverage, brain activity, and avoidance of clinically dose-limiting TRK inhibition. NVL-655 is a rationally designed TKI with >50-fold selectivity for ALK over 96% of the kinome tested. In vitro, NVL-655 inhibits diverse ALK fusions, activating alterations, and resistance mutations, showing ≥100-fold improved potency against ALKG1202R single and compound mutations over approved ALK TKIs. In vivo, it induces regression across 12 tumor models, including intracranial and patient-derived xenografts. NVL-655 inhibits ALK over TRK with 22-fold to >874-fold selectivity. These preclinical findings are supported by three case studies from an ongoing first-in-human phase I/II trial of NVL-655 which demonstrate preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion–positive non–small cell lung cancer, including in patients with brain metastases and single or compound ALK resistance mutations. Significance: By combining broad activity against single and compound ALK resistance mutations, brain penetrance, and selectivity, NVL-655 addresses key limitations of currently approved ALK inhibitors and has the potential to represent a distinct advancement as a fourth-generation inhibitor for patients with ALK-driven cancers.

中文翻译：

---

NVL-655 是一种选择性和脑渗透性抑制剂，可抑制多种 ALK 突变癌蛋白，包括 Lorlatinib 耐药化合物突变


三代酪氨酸激酶抑制剂 （TKI） 已被批准用于间变性淋巴瘤激酶 （ALK） 融合阳性非小细胞肺癌。然而，没有一个能解决广泛耐药覆盖、大脑活动和避免临床剂量限制性 TRK 抑制的共同需求。NVL-655 是一种合理设计的 TKI，对 ALK 的选择性为 >50 倍，超过 96% 的激酶组测试。在体外，NVL-655 抑制多种 ALK 融合、激活改变和耐药突变，与已批准的 ALK TKI 相比，对ALKG1202R单一和复合突变的效力提高了 ≥ 100 倍。在体内，它诱导 12 种肿瘤模型的消退，包括颅内和患者来源的异种移植物。NVL-655 抑制 ALK 而不是 TRK，选择性是 22 倍至 >874 倍。这些临床前发现得到了正在进行的 NVL-655 首次人体 I/II 期试验的三个案例研究的支持，这些研究证明了在经过大量治疗的 ALK 融合阳性非小细胞肺癌患者中的初步概念验证临床活性，包括脑转移和单个或复合 ALK 耐药突变的患者。意义：NVL-655 结合对单一和复合 ALK 耐药突变的广泛活性、脑外显率和选择性，解决了目前批准的 ALK 抑制剂的关键局限性，并有可能代表作为 ALK 驱动癌症患者的第四代抑制剂的独特进步。