拉帕替尼联合曲妥珠单抗治疗人表皮生长因子受体 2 阳性早期乳腺癌（NeoALTTO）：一项随机、开放标签、多中心、III 期临床试验。
Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial.
机构信息
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
出版信息
Lancet. 2012 Feb 18;379(9816):633-40. doi: 10.1016/S0140-6736(11)61847-3. Epub 2012 Jan 17.
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/kg [DOSAGE ERROR CORRECTED], 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/m(2)) 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.
背景
抗 HER2 单克隆抗体曲妥珠单抗和酪氨酸激酶抑制剂拉帕替尼在 HER2 过表达乳腺癌的模型中具有互补的作用机制和协同的抗肿瘤活性。我们认为，两种抗 HER2 药物联合使用会优于单一药物治疗。
方法
本项平行组、随机、开放标签、3 期研究于 2008 年 1 月 5 日至 2010 年 5 月 27 日进行，来自 23 个国家的患有 HER2 阳性原发性乳腺癌且肿瘤直径大于 2 厘米的女性患者被随机分配接受口服拉帕替尼（1500mg）、静脉注射曲妥珠单抗（负荷剂量 4mg/kg[剂量错误修正]，后续剂量 2mg/kg）或拉帕替尼（1000mg）加曲妥珠单抗治疗。治疗分配采用分层、随机分组，有四个分层因素。单独使用抗 HER2 治疗 6 周；然后在方案中加入每周紫杉醇（80mg/m2）治疗 12 周，然后进行确定性手术。手术后，患者接受辅助化疗，然后在新辅助阶段相同的靶向治疗持续到 52 周。主要终点是病理完全缓解（pCR）率，按意向治疗进行分析。该试验在 ClinicalTrials.gov 上注册，编号为 NCT00553358。
结果
154 例患者接受拉帕替尼治疗，149 例患者接受曲妥珠单抗治疗，152 例患者接受联合治疗。接受拉帕替尼和曲妥珠单抗治疗的患者 pCR 率显著高于接受曲妥珠单抗单药治疗的患者（152 例患者中有 78 例[51.3%；95%CI 43.1-59.5%]，149 例患者中有 44 例[29.5%；22.4-37.5%]；差异为 21.1%，9.1-34.2，p=0.0001）。我们没有记录到接受拉帕替尼（154 例患者中有 38 例[24.7%；18.1-32.3%]）和曲妥珠单抗（差异-4.8%，-17.6-8.2，p=0.34）治疗的患者之间 pCR 有显著差异。没有发生重大心脏功能障碍。腹泻 3 级的发生率在接受拉帕替尼（36 例[23.4%]）和拉帕替尼加曲妥珠单抗（32 例[21.1%]）治疗的患者中高于接受曲妥珠单抗（3 例[2.0%]）治疗的患者。同样，接受拉帕替尼（27 例[17.5%]）和拉帕替尼加曲妥珠单抗（15 例[9.9%]）治疗的患者中，3 级肝酶改变的发生率高于接受曲妥珠单抗（11 例[7.4%]）治疗的患者。
结论
HER2 的双重抑制可能是 HER2 阳性乳腺癌新辅助治疗的一种有效方法。
资金来源
葛兰素史克公司。
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