Zongertinib (BI 1810631) 是一种不可逆 HER2 TKI，可避免 EGFR 信号转导并改善临床前模型和 HER2 驱动癌症患者的治疗反应。
Zongertinib (BI 1810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2-driven cancers.
发表日期：2024 Sep 09
作者：
Birgit Wilding, Lydia Woelflingseder, Anke Baum, Krzysztof Chylinski, Gintautas Vainorius, Neil Gibson, Irene C Waizenegger, Daniel Gerlach, Martin Augsten, Fiona Spreitzer, Yukina Shirai, Masachika Ikegami, Sylvia Tilandyova, Dirk Scharn, Mark A Pearson, Johannes Popow, Anna C Obenauf, Noboru Yamamoto, Shunsuke Kondo, Frans L Opdam, Annemarie Bruining, Shinji Kohsaka, Norbert Kraut, John V Heymach, Flavio Solca, Ralph A Neumuller
来源：
Cancer Discovery
摘要：
2-4% 的非小细胞肺癌 (NSCLC) 发生 HER2 突变，导致预后不良。 ERBB 靶向酪氨酸激酶抑制剂已被批准用于治疗其他 HER2 依赖性癌症，但由于剂量限制性毒性或效力欠佳，对 HER2 突变非小细胞肺癌无效。我们报告了 zongertinib (BI 1810631) 的发现，这是一种共价 HER2 抑制剂。 Zongertinib 有效且选择性地阻断 HER2，同时保留 EGFR，并抑制依赖于 HER2 致癌驱动事件的细胞的生长，包括对曲妥珠单抗 deruxtecan 耐药的 HER2 依赖性人类癌细胞。 Zongertinib 在 HER2 依赖性人 NSCLC 异种移植模型中显示出有效的抗肿瘤活性，并增强抗体药物偶联物和 KRASG12C 抑制剂的活性，且不会引起明显的毒性。 zongertinib 的临床前疗效转化为 HER2 依赖性肿瘤患者的客观反应，包括胆管癌（SDC4-NRG1 融合）和乳腺癌（V777L HER2 突变），从而支持 zongertinib 正在进行的临床开发。
Mutations in HER2 occur in 2-4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2 mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently and selectively blocks HER2, while sparing EGFR, and inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. Zongertinib displays potent anti-tumor activity in HER2-dependent human NSCLC xenograft models and enhances the activities of antibody-drug conjugates and KRASG12C inhibitors, without causing obvious toxicities. The preclinical efficacy of zongertinib translates in objective responses in patients with HER2-dependent tumors, including cholangiocarcinoma (SDC4-NRG1 fusion) and breast cancer (V777L HER2 mutation) thus supporting the ongoing clinical development of zongertinib.