柳叶刀: HER2靶向药物联合用于早期乳腺癌新辅助治疗效果显著
丁香园 · 2012/02/21
抗HER2分子靶向治疗药物曲妥单抗和拉帕替尼在治疗HER2过表达的乳腺癌中机制互补,具有协同效应,以往的研究中,拉帕替尼联合曲妥珠单抗在解救治疗中获得了可喜结果。在新辅助化疗没有重大疗效突破的现状下,引入靶向药物成为关注重点。

导读:一项由在麻省总医院,哈佛医学院等多家单位进行的中心开放性随机III期临床试验中,研究人员将拉帕替尼和曲妥单抗联合应用于HER2阳性的早期乳腺癌新辅助治疗,取得了显著疗效。他们发现,联合使用HER2靶向药物作为新辅助疗法治疗早期乳腺癌疗效优于单一靶向药物治疗。

三不同治疗组间病理完全缓解(pCR)率比较

抗HER2分子靶向治疗药物曲妥单抗和拉帕替尼在治疗HER2过表达的乳腺癌中机制互补,具有协同效应,以往的研究中,拉帕替尼联合曲妥珠单抗在解救治疗中获得了可喜结果。在新辅助化疗没有重大疗效突破的现状下,引入靶向药物成为关注重点。一项由在麻省总医院,哈佛医学院等多家单位进行的中心开放性随机III期临床试验(NeoALTTO)中,研究人员将拉帕替尼和曲妥单抗联合应用于HER2阳性的早期乳腺癌新辅助治疗,取得了显著疗效。该研究结果已发表于2月18日的《柳叶刀》(The Lancet)杂志上。

本临床试验中,研究人员于两年间(2008.1.5-2010.5.27)从23国家里共招募455例HER2阳性早期乳腺癌志愿者,瘤体直径大于2cm,她们被随机分配到拉帕替尼组(154例;1500mg),曲妥单抗组(149例;前期量用量4 mg/m2,随后2 mg/kg),拉帕替尼联合曲妥单抗(152例;1000mg)组,采用分层,区组随机法给药。确定性手术之前,患者接受新辅助治疗,头6周抗HER2治疗,接着12周紫杉醇(80 mg/m2)治疗;手术后,患者接受辅助化疗,共52周。主要终点为病理完全缓解(pCR)率,采取意向性分析;本研究已通过临床试验注册、授权(NO. NCT00553358)。

结果显示,联合治疗组pCR率为51.3%(78/152;95% CI 43.1-59.5),显著高于两单独治疗组(p=0.0001),曲妥单抗组(29.5% [44/149;22.4-37.5]),拉帕替尼组(24.7% [38/154;18.1-32.3);而两单独治疗组相比,不存在显著差别(p=0.34)。拉帕替尼组和联合治疗组中常见Ⅲ级腹泻,Ⅲ级肝酶增高;未出现心功能紊乱。

因此,作者在文中指出,联合使用HER2靶向药物作为新辅助疗法治疗早期乳腺癌疗效优于单一靶向药物治疗。但由于腹泻及肝损害等毒性反应发生率明显高于曲妥单抗组,似乎未达理想目的,该疗法能否在临床推广尚待证明。

 

Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial

José Baselga, Ian Bradbury, Holger Eidtmann, Serena Di Cosimo, Evandro de Azambuja, Claudia Aura, Henry Gómez, Phuong Dinh, Karine Fauria, et al.

Background: The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy.

Methods: In this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/m2, subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m2) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358.

Findings: 154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51•3%; 95% CI 43•1—59•5]) than in the group given trastuzumab alone (44 of 149 patients [29•5%; 22•4—37•5]; difference 21•1%, 9•1—34•2, p=0•0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24•7%, 18•1—32•3]) and the trastuzumab (difference −4•8%, −17•6 to 8•2, p=0•34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23•4%]) and lapatinib plus trastuzumab (32 [21•1%]) than with trastuzumab (three [2•0%]). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (27 [17•5%]) and lapatinib plus trastuzumab (15 [9•9%]) than with trastuzumab (11 [7•4%]).

Interpretation: Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting.

Funding: GlaxoSmithKline.

文献链接:http://www.biodiscover.com/news/unclass/library/11111

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