Department of Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Number 37, Guoxue Alley, Chengdu, 610041, Sichuan, People's Republic of China.
West China School of Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
Clin Drug Investig. 2019 Jan;39(1):27-43. doi: 10.1007/s40261-018-0719-0.
Neratinib is a novel pan-human epidermal growth factor receptor (HER) tyrosine kinase inhibitor that has shown promising activity against several types of malignancies, especially HER2-overexpressing breast cancer.
The objective of the current study was to provide a comprehensive insight into the efficacy and safety profiles of neratinib-based therapies.
Comprehensive literature searches of the PubMed, EMBASE, and Web of Science electronic databases were performed for all relevant clinical trials. Adverse events (AEs) of any grade and of grade 3 or higher were summarized and event rates were calculated. For controlled trials, odds ratios (ORs) were calculated to determine the role of neratinib in AEs. A random-effects model was applied if heterogeneity was observed (I ≥ 50%), otherwise a fixed-effects model was used. Kaplan-Meier survival curves were extracted for hazard ratio (HR) calculation, and survival outcomes were measured by progression-free survival (PFS) and overall survival (OS).
Twenty-three studies and 4896 patients were included in the analysis. The most frequently occurring all-grade AEs in neratinib monotherapy were diarrhea (83.9%), nausea (37.9%), and abdominal pain (28.4%). The most common AEs for grades 3 or 4 were diarrhea (25.1%), dyspnea (5.6%), and abnormalities in liver enzyme levels (4.2%). Diarrhea, the most common AE, can be mitigated by prophylactic loperamide. Neratinib demonstrated promising clinical activity as monotherapy in HER2-positive breast cancer; however, in contrast, the effect became much less significant among HER2-mutated breast cancer patients. Notably, neratinib-based combination therapy achieved a higher response rate than neratinib monotherapy.
Neratinib-based therapies led to a higher frequency of some AEs, although these were mostly tolerable. Most studies demonstrated that neratinib provides a benefit in survival outcome. When combined with other anticancer agents, neratinib may hold promise for treating breast cancer with central nervous system metastases.
奈拉替尼是一种新型的泛人表皮生长因子受体（HER）酪氨酸激酶抑制剂，对多种恶性肿瘤，特别是 HER2 过表达乳腺癌具有显著的疗效。
本研究旨在全面了解奈拉替尼为基础的治疗方案的疗效和安全性。
对 PubMed、EMBASE 和 Web of Science 电子数据库进行全面文献检索，检索所有相关的临床试验。总结所有等级和 3 级或更高等级的不良事件（AE），并计算发生率。对于对照试验，计算比值比（OR）以确定奈拉替尼在 AE 中的作用。如果观察到异质性（I≥50%），则应用随机效应模型，否则应用固定效应模型。提取危险比（HR）的 Kaplan-Meier 生存曲线，并通过无进展生存期（PFS）和总生存期（OS）来衡量生存结果。
纳入 23 项研究和 4896 例患者进行分析。奈拉替尼单药治疗最常发生的所有等级 AE 为腹泻（83.9%）、恶心（37.9%）和腹痛（28.4%）。最常见的 3 级或 4 级 AE 为腹泻（25.1%）、呼吸困难（5.6%）和肝酶水平异常（4.2%）。腹泻是最常见的 AE，可以通过预防性洛哌丁胺来缓解。奈拉替尼作为单药治疗 HER2 阳性乳腺癌具有显著的临床活性；然而，在 HER2 突变型乳腺癌患者中，效果明显减弱。值得注意的是，奈拉替尼为基础的联合治疗比奈拉替尼单药治疗的反应率更高。
奈拉替尼为基础的治疗方案导致某些 AE 的发生率更高，但这些 AE 大多是可耐受的。大多数研究表明，奈拉替尼在生存结果方面有获益。当与其他抗癌药物联合使用时，奈拉替尼可能在治疗伴有中枢神经系统转移的乳腺癌方面有潜力。
