Purpose: The emergence of secondary mutations is a cause of resistance to current KIT inhibitors used in the treatment of patients with gastrointestinal stromal tumors (GIST). AZD3229 is a selective inhibitor of wild-type KIT and a wide spectrum of primary and secondary mutations seen in patients with GIST. The objective of this analysis is to establish the pharmacokinetic–pharmacodynamic (PKPD) relationship of AZD3229 in a range of mouse GIST tumor models harboring primary and secondary KIT mutations, and to benchmark AZD3229 against other KIT inhibitors. Experimental Design: A PKPD model was developed for AZD3229 linking plasma concentrations to inhibition of phosphorylated KIT using data generated from several in vivo preclinical tumor models, and in vitro data generated in a panel of Ba/F3 cell lines. Results: AZD3229 drives inhibition of phosphorylated KIT in an exposure-dependent manner, and optimal efficacy is observed when >90% inhibition of KIT phosphorylation is sustained over the dosing interval. Integrating the predicted human pharmacokinetics into the mouse PKPD model predicts that an oral twice daily human dose greater than 34 mg is required to ensure adequate coverage across the mutations investigated. Benchmarking shows that compared with standard-of-care KIT inhibitors, AZD3229 has the potential to deliver the required target coverage across a wider spectrum of primary or secondary mutations. Conclusions: We demonstrate that AZD3229 warrants clinical investigation as a new treatment for patients with GIST based on its ability to inhibit both ATP-binding and A-loop mutations of KIT at clinically relevant exposures.

中文翻译：

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AZD3229（一种新型选择性 KIT 抑制剂）在一系列 GIST 小鼠异种移植模型中的药代动力学-药效学 (PKPD) 关系。

目的：继发性突变的出现是对当前用于治疗胃肠道间质瘤 (GIST) 患者的 KIT 抑制剂产生耐药性的原因。AZD3229 是野生型 KIT 和 GIST 患者中广泛的原发性和继发性突变的选择性抑制剂。该分析的目的是在一系列具有原发性和继发性 KIT 突变的小鼠 GIST 肿瘤模型中建立 AZD3229 的药代动力学-药效学 (PKPD) 关系，并将 AZD3229 与其他 KIT 抑制剂进行对比。实验设计：使用几个体内临床前肿瘤模型产生的数据和一组 Ba/F3 细胞系产生的体外数据，为 AZD3229 开发了 PKPD 模型，将血浆浓度与磷酸化 KIT 的抑制联系起来。结果：AZD3229 以暴露依赖性方式驱动对磷酸化 KIT 的抑制，当超过 90% 的 KIT 磷酸化抑制持续超过给药间隔时，观察到最佳疗效。将预测的人体药代动力学整合到小鼠 PKPD 模型中预测，需要每天口服两次大于 34 mg 的人体剂量，以确保对所研究的突变进行足够的覆盖。基准测试表明，与标准护理 KIT 抑制剂相比，AZD3229 有可能在更广泛的初级或次级突变范围内提供所需的目标覆盖率。结论：我们证明 AZD3229 作为 GIST 患者的新疗法值得临床研究，因为它能够在临床相关暴露下抑制 KIT 的 ATP 结合和 A 环突变。