Helios-Klinikum, Berlin-Buch, Berlin, Germany.
Lancet Oncol. 2012 Feb;13(2):135-44. doi: 10.1016/S1470-2045(11)70397-7. Epub 2012 Jan 17.
We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy.
In the GeparQuinto randomised phase 3 trial, patients with untreated HER2-positive operable or locally advanced breast cancer were enrolled between Nov 7, 2007, and July 9, 2010. Patients were eligible if their tumours were classified as cT3/4a-d, or hormone receptor (HR)-negative, HR-positive with clinically node-positive and cT2 disease (cT2 cN+), or HR-positive and pathologically node-positive in the sentinel lymph node for those with cT1 disease (cT1 pN(SLN+)). Patients were randomly assigned in a 1:1 ratio to receive neoadjuvant treatment with four cycles of EC (epirubicin [90 mg/m(2) intravenously] plus cyclophosphamide [600 mg/m(2) intravenously], every 3 weeks), and four cycles of docetaxel (100 mg/m(2) intravenously every 3 weeks) with either trastuzumab (6 mg/kg intravenously, with a starting loading dose of 8 mg/kg, for eight cycles, every 3 weeks) or lapatinib (1000-1250 mg per day orally) throughout all cycles before surgery. Randomisation was done by dynamic allocation with the minimisation method of Pocock and patients were stratified by participating site, HR status, and extent of disease (cT1-3 cN0-2 vs T4 or N3). The primary endpoint was pathological complete response (defined as ypT0 and ypN0) and was analysed in all patients who received at least one cycle of EC. Participants and investigators were not masked to treatment assignment. Pathologists in centres assessing surgery outcomes were masked to group assignment. This trial is registered with ClinicalTrials.gov, number NCT00567554.
Of 620 eligible patients, 309 were randomly assigned to chemotherapy with trastuzumab (ECH-TH group) and 311 to chemotherapy with lapatinib (ECL-TL group). Two patients in the ECH-TH group and three patients in the ECL-TL group did not start treatment because of withdrawal of consent or immediate surgery. 93 (30·3%) of 307 patients in the ECH-TH group and 70 (22·7%) of 308 patients in the ECL-TL group had a pathological complete response (odds ratio [OR] 0·68 [95%CI 0·47-0·97]; p=0·04). Chemotherapy with trastuzumab was associated with more oedema (119 [39·1%] vs 88 [28·7%]) and dyspnoea (90 [29·6%] vs 66 [21·4%]), and ECL-TL with more diarrhoea (231 [75·0%] vs 144 [47·4%]) and skin rash (169 [54·9%] vs 97 [31·9%]). 43 (14·0%) patients discontinued in the ECH-TH group and 102 (33·1%) in the ECL-TL group. 70 serious adverse events were reported in the ECH-TH group and 87 in the ECL-TL group.
This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab. Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy.
GlaxoSmithKline, Roche, and Sanofi-Aventis.
我们比较了曲妥珠单抗与拉帕替尼联合蒽环类紫杉类新辅助化疗的疗效和安全性。
在 GeparQuinto 随机 3 期试验中，招募了未经治疗的 HER2 阳性可手术或局部晚期乳腺癌患者，纳入时间为 2007 年 11 月 7 日至 2010 年 7 月 9 日。符合条件的患者肿瘤分类为 cT3/4a-d，或激素受体（HR）阴性，HR 阳性且临床淋巴结阳性和 cT2 疾病（cT2 cN+），或 HR 阳性且前哨淋巴结有病理淋巴结阳性的 cT1 疾病（cT1 pN(SLN+)）。患者按 1:1 的比例随机分配接受新辅助治疗，共 4 个周期的 EC（表柔比星[90 mg/m2]静脉注射+环磷酰胺[600 mg/m2]静脉注射，每 3 周 1 次），和 4 个周期的多西他赛（100 mg/m2 静脉注射，每 3 周 1 次）联合曲妥珠单抗（6 mg/kg 静脉注射，起始负荷剂量为 8 mg/kg，共 8 个周期，每 3 周 1 次）或拉帕替尼（每天 1000-1250 mg 口服），所有周期均在手术前进行。随机化采用 Pocock 的动态分配和最小化方法，患者按参与地点、HR 状态和疾病程度（cT1-3 cN0-2 与 T4 或 N3）分层。主要终点为病理完全缓解（定义为 ypT0 和 ypN0），并在至少接受 1 个 EC 周期的所有患者中进行分析。参与者和研究者未对治疗分配进行盲法，评估手术结果的中心病理学家对分组分配进行盲法。本试验在 ClinicalTrials.gov 注册，编号为 NCT00567554。
在 620 名合格患者中，309 名随机分配接受曲妥珠单抗化疗（ECH-TH 组），311 名接受拉帕替尼化疗（ECL-TL 组）。ECH-TH 组中有 2 名患者和 ECL-TL 组中有 3 名患者因撤回同意或立即手术而未开始治疗。ECH-TH 组中有 93（30.3%）名患者和 ECL-TL 组中有 70（22.7%）名患者发生病理完全缓解（比值比[OR]0.68[95%CI 0.47-0.97]；p=0.04）。曲妥珠单抗化疗与更多的水肿（119[39.1%]比 88[28.7%]）和呼吸困难（90[29.6%]比 66[21.4%]）相关，而 ECL-TL 与更多的腹泻（231[75.0%]比 144[47.4%]）和皮疹（169[54.9%]比 97[31.9%]）相关。ECH-TH 组中有 43（14.0%）名患者停止治疗，ECL-TL 组中有 102（33.1%）名患者停止治疗。ECH-TH 组报告了 70 例严重不良事件，ECL-TL 组报告了 87 例。
本研究直接比较了曲妥珠单抗和拉帕替尼，结果表明化疗联合拉帕替尼的病理完全缓解率明显低于化疗联合曲妥珠单抗。除非长期结果数据显示不同结果，否则拉帕替尼不应在临床试验之外用于与新辅助化疗联合的曲妥珠单抗单一抗 HER2 治疗。
葛兰素史克、罗氏和赛诺菲-安万特。
