Bonnefoi H, Jacot W, Saghatchian M, Moldovan C, Venat-Bouvet L, Zaman K, Matos E, Petit T, Bodmer A, Quenel-Tueux N, Chakiba C, Vuylsteke P, Jerusalem G, Brain E, Tredan O, Messina C G M, Slaets L, Cameron D
Department of Medical Oncology, Institut Bergonié Comprehensive Cancer Centre, Université de Bordeaux, INSERM U916, Bordeaux
Department of Medical Oncology, Centre Val D'Aurelle-Paul Lamarque, Montpellier.
Ann Oncol. 2015 Feb;26(2):325-32. doi: 10.1093/annonc/mdu551. Epub 2014 Dec 1.
Neoadjuvant trials conducted using a double HER2 blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological complete response (pCR) rates, but at the cost of important toxicity. We hypothesised that this toxicity might be due to a specific interaction between paclitaxel and lapatinib. This trial assesses the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab.
Patients with stage IIA to IIIC HER2-positive breast cancer received six cycles of chemotherapy (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, cyclophosphamide). They were randomised 1 : 1 : 1 to receive during the first three cycles either lapatinib (1000 mg orally daily), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or trastuzumab + lapatinib at the same dose. The primary end point was pCR rate defined as ypT0/is. Secondary end points included safety and toxicity. pCR rate defined as ypT0/is ypN0 was assessed as an exploratory analysis. In June 2012, arm A was closed for futility based on the results from other studies.
From October 2010 to January 2013, 128 patients were included in 14 centres. The percentage of the 122 assessable patients with pCR in the breast, and pCR in the breast and nodes, was numerically highest in the lapatinib + trastuzumab group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%), and lowest in the lapatinib group (46% and 36%). Frequency (%) of the most common grade 3-4 toxicities in the lapatinib /trastuzumab/lapatinib + trastuzumab arms were: febrile neutropenia 23/15/10, diarrhoea 9/2/18, infection (other) 9/4/8, and hepatic toxicity 0/2/8.
This study demonstrates a numerically modest pCR rate increase with double anti-HER2 blockade plus chemotherapy, but suggests that the use of docetaxel rather than paclitaxel may not reduce toxicity.
NCT00450892.
使用拉帕替尼和曲妥珠单抗双重HER2阻断联合不同含紫杉醇化疗方案进行的新辅助试验显示出较高的病理完全缓解（pCR）率，但代价是严重的毒性。我们推测这种毒性可能是由于紫杉醇与拉帕替尼之间的特定相互作用。本试验评估多西他赛与拉帕替尼和曲妥珠单抗联合使用的毒性和活性。
IIA至IIIC期HER2阳性乳腺癌患者接受六个周期的化疗（三个周期的多西他赛，随后三个周期的氟尿嘧啶、表柔比星、环磷酰胺）。他们被1:1:1随机分组，在前三个周期接受拉帕替尼（每日口服1000mg）、曲妥珠单抗（4mg/kg负荷剂量，随后每周2mg/kg）或相同剂量的曲妥珠单抗+拉帕替尼。主要终点是定义为ypT0/is的pCR率。次要终点包括安全性和毒性。定义为ypT0/is ypN0的pCR率作为探索性分析进行评估。2012年6月，根据其他研究结果，A组因无效而关闭。
从2010年10月到2013年1月，14个中心纳入了128例患者。在可评估的122例患者中，拉帕替尼+曲妥珠单抗组乳腺pCR以及乳腺和淋巴结pCR的百分比在数值上最高（分别为60%和56%），曲妥珠单抗组居中（52%和52%），拉帕替尼组最低（46%和36%）。拉帕替尼/曲妥珠单抗/拉帕替尼+曲妥珠单抗组中最常见的3-4级毒性的频率（%）为：发热性中性粒细胞减少23/15/10、腹泻9/2/18、感染（其他）9/4/8和肝毒性0/2/8。
本研究表明，双重抗HER2阻断加化疗在数值上使pCR率适度增加，但表明使用多西他赛而非紫杉醇可能不会降低毒性。
NCT00450892。
