Pyrotinib是一种新型不可逆酪氨酸激酶抑制剂，显示出良好的抗肿瘤活性，可提高HER2阳性转移性乳腺癌（MBC）患者的总体反应率和无进展生存期（PFS）。但目前针对Pyrotinib或Pyrotinib加卡培他滨在HER2阳性MBC患者的生存数据仍较缺乏。因此，我们汇总了来自Pyrotinib或Pyrotinib加卡培他滨Ⅰ期试验的患者的更新个体数据，提供了一种不可逆酪氨酸激酶抑制剂在HER2阳性MBC患者中的长期结局和相关生物标记分析的累积评估。我们对来自个体受试者的更新生存数据进行了汇总分析，针对预测性生物标记进行了循环肿瘤DNA的下一代测序。共招募了66名患者，包括来自PyrotinibⅠb试验的38名患者和来自Pyrotinib加卡培他滨Ⅰc试验的28名患者。中位随访时间为84.2个月（95% CI：74.7-93.7个月）。在整个队列中，估计的中位PFS为9.2个月（95% CI：5.4-12.9个月），中位总生存期为31.0个月（95% CI：16.5-45.5个月） 。 Pyrotinib单药队列的中位PFS为8.2个月，Pyrotinib加卡培他滨组的中位PFS为22.1个月，Pyrotinib单药组的中位总生存期为27.1个月，Pyrotinib加卡培他滨组为37.4个月。生物标记分析表明，与没有或仅有一种基因突变的患者相比，患者在HER2相关信号网络（HER2绕过信号通路、PI3K/Akt/mTOR通路和TP53）中同时携带多条通路上的突变会使PFS和总生存期显著较差（中位PFS，7.3 vs 26.1个月，P = 0.003;中位总生存期，25.1 vs 48.0个月，P = 0.013）。“基于Pyrotinib联合方案的Ⅰ期试验的个体患者数据更新的生存结果显示出HER2阳性MBC的良好PFS和OS。 HER2相关信号网络中的多条通路上的并存突变可能是Pyrotinib在HER2阳性MBC中的潜在疗效和预后生物标记。”(NCT01937689，NCT02361112)。©2023年作者。

Pyrotinib, a novel irreversible tyrosine kinase inhibitor (TKI), has demonstrated promising antitumor activity to improve the overall response rate and progression-free survival (PFS) in patients with HER2-positive metastatic breast cancer (MBC). However, the survival data of pyrotinib or pyrotinib plus capecitabine in HER2-positive MBC remains scarce. Thus, we summarized the updated individual patient data from the phase I trials of pyrotinib or pyrotinib plus capecitabine, to provide a cumulative assessment on long-term outcomes and associated biomarker analysis of irreversible TKIs in HER2-positive MBC patients.We performed a pooled analysis of the phase I trials for pyrotinib or pyrotinib plus capecitabine based on the updated survival data from individual patients. Next-generation sequencing was performed on circulating tumor DNA for predictive biomarkers.A total of 66 patients were enrolled, including 38 patients from the phase Ib trial for pyrotinib and 28 patients from the phase Ic trial for pyrotinib plus capecitabine. The median follow-up duration was 84.2 months (95% CI: 74.7-93.7 months). The estimated median PFS in the entire cohort was 9.2 months (95% CI: 5.4-12.9 months) and median OS was 31.0 months (95% CI: 16.5-45.5 months). The median PFS was 8.2 months in the pyrotinib monotherapy cohort and 22.1 months in the pyrotinib plus capecitabine group, while the median OS was 27.1 months in the pyrotinib monotherapy group and 37.4 months in the pyrotinib plus capecitabine group. Biomarker analysis suggested that the patients harbored concomitant mutations from multiple pathways in HER2-related signaling network (HER2 bypass signaling pathways, PI3K/Akt/mTOR pathway and TP53) were observed with significantly poorer PFS and OS when compared to those with none or one genetic alteration (median PFS, 7.3 vs. 26.1 months, P = 0.003; median OS, 25.1 vs. 48.0 months, P = 0.013).The updated survival results based on individual patient data from the phase I trials of pyrotinib-based regimen revealed promising PFS and OS in HER2-positive MBC. Concomitant mutations from multiple pathways in HER2-related signaling network may be a potential efficacy and prognosis biomarker for pyrotinib in HER2-positive MBC.ClinicalTrials.gov. (NCT01937689, NCT02361112).© 2023. The Author(s).