Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial
Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial
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DOI：
10.1016/s1470-2045(11)70397-7
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发表时间：
2012-02-01
期刊：
影响因子：
51.1
通讯作者：
von Minckwitz, Gunter
中科院分区：
文献类型：
--
作者：
Untch, Michael;Loibl, Sibylle;von Minckwitz, Gunter
背景我们比较了拉帕替尼与曲妥珠单抗增加蒽环类紫杉烷为基础的新辅助chemotherapy.Methods的疗效和安全性，在GeparQuinto随机3期试验，未经治疗的HER 2阳性可手术或局部晚期乳腺癌患者在2007年11月7日和2010年7月9日之间入组。如果患者的肿瘤被分类为cT 3/4a-d，或激素受体（HR）阴性，HR阳性伴临床淋巴结阳性和cT 2疾病（cT 2 cN+），或HR阳性和病理淋巴结阳性的前哨淋巴结（cT 1疾病（cT 1 pN（SLN+）），则患者符合资格。患者被随机分配到1：1例接受新辅助治疗和4个周期EC的比率（表阿霉素[90 mg/m2静脉注射]+环磷酰胺[600 mg/m2静脉注射]，每3周一次）和4个周期的多西他赛（100 mg/m（2），静脉注射，每3周一次），或曲妥珠单抗（6 mg/kg静脉注射，起始负荷剂量为8 mg/kg，共8个周期，每3周一次）或拉帕替尼（1000-1250 mg/天口服）。采用Pocock最小化方法通过动态分配进行随机化，并根据参与研究中心、HR状态和疾病程度（cT 1 -3、cN 0 -2 vs T4或N3）对患者进行分层。主要终点是病理学完全缓解（定义为ypT 0和ypN 0），并在所有接受至少一个周期EC的患者中进行分析。参与者和研究者对治疗分配不设盲。评估手术结局的中心病理学家对分组设盲。ClinicalTrials.gov在620名符合条件的患者中，309名随机分配到曲妥珠单抗化疗组（ECH-TH组），311名随机分配到拉帕替尼化疗组（ECL-TL组）。ECH-TH组的2例患者和ECL-TL组的3例患者因撤回知情同意或立即手术而未开始治疗。ECH-TH组307例患者中有93例（30.3%）和ECL-TL组308例患者中有70例（22.7%）达到病理学完全缓解（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水肿（119 [39.1%] vs 88 [28.7%]）和呼吸困难（90 [29.6%] vs 66 [21.4%]）相关，ECL-TL与更多腹泻（231 [75.0%] vs 144 [47.4%]）和皮疹（169 [54.9%] vs 97 [31.9%]）相关。ECH-TH组43例（14.0%）患者和ECL-TL组102例（33.1%）患者停药。ECH-TH组报告了70例严重不良事件，ECL-TL组报告了87例严重不良事件。解释曲妥珠单抗和拉帕替尼的这种直接比较显示，化疗和拉帕替尼的病理完全缓解率显著低于化疗和曲妥珠单抗。除非长期结局数据显示不同的结果，否则拉帕替尼不应在临床试验之外作为抗HER 2单药治疗联合新辅助化疗使用。
Background We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy.Methods 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.Findings 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.Interpretation 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.