Guan Xiuwen, Ma Fei, Li Qiao, Chen Shanshan, Lan Bo, Fan Ying, Wang Jiayu, Luo Yang, Cai Ruigang, Zhang Pin, Li Qing, Xu Binghe
Department of Medical Oncology and State Key Laboratory of Molecular Oncology, National Cancer Center / Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17, PanjiayuanNanli, Chaoyang District, Beijing, 100021, China.
Biomark Res. 2023 Feb 20;11(1):21. doi: 10.1186/s40364-023-00453-0.
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).
吡咯替尼是一种新型不可逆酪氨酸激酶抑制剂（TKI），已显示出有前景的抗肿瘤活性，可提高HER2阳性转移性乳腺癌（MBC）患者的总体缓解率和无进展生存期（PFS）。然而，吡咯替尼或吡咯替尼联合卡培他滨治疗HER2阳性MBC的生存数据仍然稀缺。因此，我们总结了吡咯替尼或吡咯替尼联合卡培他滨I期试验的最新个体患者数据，以对HER2阳性MBC患者中不可逆TKI的长期结局和相关生物标志物分析进行累积评估。
我们基于个体患者的更新生存数据，对吡咯替尼或吡咯替尼联合卡培他滨的I期试验进行了汇总分析。对循环肿瘤DNA进行下一代测序以寻找预测性生物标志物。
共纳入66例患者，其中38例来自吡咯替尼Ib期试验，28例来自吡咯替尼联合卡培他滨Ic期试验。中位随访时间为84.2个月（95%CI：74.7 - 93.7个月）。整个队列的估计中位PFS为9.2个月（95%CI：5.4 - 12.9个月），中位总生存期（OS）为31.0个月（95%CI：16.5 - 45.5个月）。吡咯替尼单药治疗组的中位PFS为8.2个月，吡咯替尼联合卡培他滨组为22.1个月；吡咯替尼单药治疗组的中位OS为27.1个月，吡咯替尼联合卡培他滨组为37.4个月。生物标志物分析表明，与无或有一个基因改变的患者相比，HER2相关信号网络中存在多个途径伴随突变（HER2旁路信号途径、PI3K/Akt/mTOR途径和TP53）的患者，其PFS和OS明显较差（中位PFS，7.3个月对26.1个月，P = 0.003；中位OS，25.1个月对48.0个月，P = 0.013）。
基于吡咯替尼方案I期试验个体患者数据的更新生存结果显示，HER2阳性MBC患者的PFS和OS前景良好。HER2相关信号网络中多个途径的伴随突变可能是吡咯替尼治疗HER2阳性MBC的潜在疗效和预后生物标志物。
ClinicalTrials.gov.（NCT01937689，NCT02361112）
