美国《临床肿瘤杂志》2017年5月12日在线先发
http://ascopubs.org/doi/full/10.1200/JCO.2016.69.6179
在人表皮生长因子受体 2 阳性转移性乳腺癌患者中对一种新型不可逆泛ErbB受体酪氨酸激酶*制剂抑**吡咯替尼的 Ⅰ 期研究和生物标志物分析
马飞，李俏，陈闪闪，等，徐兵河（通讯作者）（所有作者均来自国家癌症中心/中国医学科学院协和医学院肿瘤医院）
目的
吡咯替尼是一种不可逆的泛ErbB*制剂抑**，这项Ⅰ期研究在人表皮生长因子受体2阳性转移性乳腺癌患者中，评价了吡咯替尼的安全性、耐受性、药代动力学、抗肿瘤活性及（治疗）预测性生物标记。
患者及方法
对既往未用过HER2的络氨酸激酶*制剂抑**患者给予连续口服吡咯替尼每日一次。计划的递增剂量为80、160、240、320、400和480mg。对于药代动力学分析，于第1天和第28天按时采集血液标本。对循环肿瘤DNA和肿瘤标本中的基因组DNA实施二代测序。
结果
共入组38例患者。剂量限制性毒性为发生于2例口服480mg吡咯替尼患者中的3级腹泻，最大耐受剂量为400mg。常见的吡咯替尼相关不良反应包括腹泻(44.7%[17/38])、恶心(13.2%[5/38])、口腔溃疡(13.2%[5/38])、疲乏(10.5%[4/38])及白细胞减少(10.5%[4/38])。腹泻为唯一的3级不良反应。药代动力学分析提示吡咯替尼存在剂量依赖性。总有效率为50.0%（18/30），临床获益率（完全缓解+部分缓解+疾病稳定≥24周）为61.1%（22/36）。中位疾病无进展生存期为35.4周(95%CI，23.3-40.0周)。在未用过曲妥珠单抗的患者中，总有效率为83.3%（10/12），用过者为33.3%（8/24）。初步结果表明，循环肿瘤DNA中PIK3CA及TP53突变可以预测吡咯替尼疗效(P=0.013)，而保存的肿瘤组织中的PIK3CA及TP53突变的疗效预测作用不明显（P=0.474）。
结论
在HER2阳性转移性乳腺癌患者中持续每日一次吡咯替尼治疗耐受性好、且显示了明显的抗肿瘤活性，确立的最大耐受剂量为400mg，腹泻为剂量限制性毒性。吡咯替尼明显的抗肿瘤活性及可接受的耐受性需要在II期研究中进一步评价。
ORIGINAL REPORTS Breast Cancer
Phase I Study and Biomarker Analysis of Pyrotinib, a Novel Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer
Fei Ma, Qiao Li, Shanshan Chen, Wenjie Zhu, Ying Fan, Jiayu Wang, Yang Luo, Puyuan Xing, Bo Lan, Meiying Li, Zongbi Yi, Ruigang Cai, Peng Yuan, Pin Zhang, Qing Li, and Binghe Xu
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Abstract
Purpose
This phase I study assessed the safety, tolerability, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer.
Patients and Methods
Pyrotinib was administered continuously, orally, once per day to patients who did not have prior exposure to tyrosine kinase inhibitors of HER2. Planned dose escalation was 80, 160, 240, 320, 400, and 480 mg. For pharmacokinetic analysis, timed blood samples were collected on day 1 and day 28. Next-generation sequencing was performed on circulating tumor DNA and genomic DNA from tumor samples.
Results
Thirty-eight patients were enrolled. The dose-limiting toxicity was grade 3 diarrhea, which occurred in two patients administered 480 mg of pyrotinib; thus, the maximum tolerated dose was 400 mg. Common pyrotinib-related adverse events included diarrhea (44.7% [17 of 38]), nausea (13.2% [five of 38]), oral ulceration (13.2% [five of 38]), asthenia (10.5% [four of 38]), and leukopenia (10.5% [four of 38]). The only grade 3 adverse event was diarrhea.
Pharmacokinetic analyses indicated that pyrotinib exposure was dose dependent. The overall response rate was 50.0% (18 of 36), and the clinical benefit rate (complete response + partial response + stable disease ≥ 24 weeks) was 61.1% (22 of 36). The median progression-free survival was 35.4 weeks (95% CI, 23.3 to 40.0 weeks). The overall response rate was 83.3% (10 of 12) in trastuzumab-naive patients and 33.3% (eight of 24) in trastuzumab-pretreated patients. Preliminary results suggest that PIK3CA and TP53 mutations in circulating tumor DNA (P = .013) rather than in archival tumor tissues (P = .474) may predict the efficacy of pyrotinib.
Conclusion
Continuous once-per-day pyrotinib was well tolerated and demonstrated promising antitumor activity in HER2-positive patients with metastatic breast cancer. The maximum tolerated dose was established as 400 mg. Diarrhea was the dose-limiting toxicity. The promising antitumor activity and acceptable tolerability of pyrotinib warrant its further evaluation in a phase II study.
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《壹篇》系主要面向医务人员的公益性头条号，不以营利为目的，不进行任何有偿咨询和服务，不出售任何产品，与ASCO、CSCO等所有专业学会和机构没有任何关系和联系，也不代表任何官方学会发声。
文章图片均来自网络，不做商业用途，若有版权争议请与《壹篇》联系。
坚持点赞、赞赏和转发是一种态度和支持。