Supplementary Material for: Neoadjuvant pyrotinib plus trastuzumab, docetaxel, and carboplatin in early or locally advanced HER2-positive breast cancer in China: a multicenter, randomized, double-blind, placebo-controlled phase 2 trial

INTRODUCTION This multicenter, randomized, double-blind, placebo-controlled phase 2 trial compared the efficacy, and safety of adding pyrotinib to trastuzumab, docetaxel, and carboplatin vs placebo, trastuzumab, docetaxel, and carboplatin in Chinese patients with HER2-positive early or locally advanced breast cancer (ClinicalTrials.gov identifier: NCT03756064). METHODS Sixty-nine women with HER2-positive early (T1-3, N0-1, M0) or locally advanced breast cancer (T2-3, N2 or N3, M0; T4, any N, M0) were recruited from Oct 1, 2019, to Jun 1, 2021. Before surgery, patients received 6 cycles of orally pyrotinib (400mg once per day), trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses), docetaxel (75 mg/m2), and carboplatin (AUC=6mg/ml·min) or orally placebo, trastuzumab, and docetaxel, and carboplatin every 3 weeks. The primary end point was independent review committee–assessed total pathologic complete response rate. The 2-sided Cochran-Mantel-Haenszel test, stratified by age, hormone receptor status, tumor stage, nodal status, cTNM stage, and Ki-67 level was used to compare rates between treatment groups. RESULTS In total, 69 female patients were randomized (pyrotinib, 36; and placebo, 33; median age, 53 [31-69] years). In the intention-to-treat population, total pathologic complete response rates were 65.5 % (19/29) in the pyrotinib group and 33.3% (10/30) in the placebo group (difference, 32.2%, p=0.013). Diarrhea was been reported in 86.1% of patients (31/36) in the pyrotinib group as the most common adverse events (AEs), and 15.2% of patients (5/33) in the placebo group. But no grade 4 or 5 AEs were reported. CONCLUSION Treatment with pyrotinib, trastuzumab, docetaxel, and carboplatin resulted in a statistically significant improvement in the total pathologic complete response rate vs placebo, trastuzumab, docetaxel, and carboplatin for the neoadjuvant treatment of HER2-positive early or locally advanced breast cancer in Chinese patients. Safety data were in line with the known pyrotinib safety profile and generally comparable between treatment groups.

引言 本项多中心、随机、双盲、安慰剂对照的Ⅱ期临床试验，对比了吡咯替尼（pyrotinib）联合曲妥珠单抗（trastuzumab）、多西他赛（docetaxel）与卡铂（carboplatin）方案，与安慰剂联合曲妥珠单抗、多西他赛与卡铂方案，针对中国HER2阳性早期或局部晚期乳腺癌患者的疗效与安全性（临床试验注册号：ClinicalTrials.gov标识符：NCT03756064）。
方法 本研究于2019年10月1日至2021年6月1日期间，共纳入69例HER2阳性早期（T1-3、N0-1、M0）或局部晚期乳腺癌（T2-3、N2或N3、M0；T4、任意N、M0）女性患者。术前患者每3周接受1个周期治疗，共6个周期：试验组口服吡咯替尼（400mg，每日1次）、曲妥珠单抗（负荷剂量8mg/kg，维持剂量6mg/kg）、多西他赛（75mg/m²）及卡铂（AUC=6mg/ml·min）；对照组口服安慰剂、曲妥珠单抗、多西他赛及卡铂。本试验的主要终点为独立审查委员会评估的总体病理完全缓解率。采用按年龄、激素受体状态、肿瘤分期、淋巴结状态、临床TNM分期及Ki-67水平分层的双侧Cochran-Mantel-Haenszel检验，对比两组间的疗效指标差异。
结果 总计69例女性患者被随机分组（吡咯替尼组36例，安慰剂组33例；中位年龄53岁[范围31~69岁]）。在意向治疗人群中，吡咯替尼组的总体病理完全缓解率为65.5%（19/29），安慰剂组为33.3%（10/30），组间差异为32.2%（p=0.013）。吡咯替尼组最常见的不良事件（AEs）为腹泻，发生率达86.1%（31/36）；安慰剂组腹泻发生率为15.2%（5/33）。两组均未报告4级或5级不良事件。
结论 针对中国HER2阳性早期或局部晚期乳腺癌患者的新辅助治疗中，吡咯替尼联合曲妥珠单抗、多西他赛及卡铂的治疗方案，相较于安慰剂联合曲妥珠单抗、多西他赛及卡铂方案，可显著提升总体病理完全缓解率，差异具有统计学意义。安全性数据符合已知的吡咯替尼安全谱，且两组不良事件整体发生率相当。