Kourie Hampig Raphael, Chaix Marie, Gombos Andrea, Aftimos Phillippe, Awada Ahmad
a Medical Oncology Clinic , Jules Bordet Institute, Free University of Brussels , Brussels , Belgium.
Expert Opin Drug Metab Toxicol. 2016 Aug;12(8):947-57. doi: 10.1080/17425255.2016.1198317. Epub 2016 Jun 27.
Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development.
This review article focuses on neratinib in the treatment of HER2-positive breast cancer - early and metastatic stage - and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug.
The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.
尽管有几种有效的HER2靶向治疗药物，但原发性和获得性耐药仍然影响着HER2阳性乳腺癌患者的预后。来那替尼是一种处于临床后期开发阶段的不可逆泛HER酪氨酸激酶抑制剂。
这篇综述文章聚焦于来那替尼在HER2阳性乳腺癌（早期和转移性）以及HER2突变型乳腺癌治疗中的应用，特别强调了该药物的药代动力学和药效学。
III期ExteNET试验表明，来那替尼可改善早期HER2阳性乳腺癌患者在基于曲妥珠单抗的辅助治疗后的2年无侵袭性疾病生存期，尤其是HER2+/HR+肿瘤患者。生存数据仍有待观察。来那替尼在高危患者中的研究作用，或者相反，在与其他抗HER2疗法联合且不进行化疗的降阶梯双药方案中的作用，都值得关注。II期试验表明，来那替尼在HER2阳性转移性乳腺癌患者以及携带HER2突变的肿瘤患者中，无论是作为单药治疗还是与其他化疗或内分泌药物联合使用，均具有疗效。来那替尼在HER2阳性患者治疗方案中的作用以及延缓中枢神经系统事件的发生，有待诸如NALA等正在进行的试验结果。腹泻是来那替尼的主要毒性反应，早期使用洛哌丁胺预防可有效控制。
