Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial.
Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial.
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DOI：
10.1016/s0140-6736(11)61847-3
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发表时间：
2012-02-18
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影响因子：
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通讯作者：
NeoALTTO Study Team
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作者：
Baselga J;Bradbury I;Eidtmann H;Di Cosimo S;de Azambuja E;Aura C;Gómez H;Dinh P;Fauria K;Van Dooren V;Aktan G;Goldhirsch A;Chang TW;Horváth Z;Coccia-Portugal M;Domont J;Tseng LM;Kunz G;Sohn JH;Semiglazov V;Lerzo G;Palacova M;Probachai V;Pusztai L;Untch M;Gelber RD;Piccart-Gebhart M;NeoALTTO Study Team
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 过表达乳腺癌模型中具有互补的作用机制和协同抗肿瘤活性。我们认为两种抗 HER2 药物一起使用会比单药治疗更好。在这个平行组中，2008年1月5日至2010年5月27日期间进行的随机、开放标签3期研究中，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厘米的女性被随机分配接受口服拉帕替尼（1500 mg）、静脉注射曲妥珠单抗（负荷剂量4 mg/kg，后续剂量2 mg/kg）或拉帕替尼（1000 mg）组。加曲妥珠单抗。治疗分配是通过分层、排列组随机化进行的，具有四个分层因素。前 6 周仅进行抗 HER2 治疗；然后每周一次紫杉醇 (80 mg/m2) 添加到治疗方案中，持续 12 周，然后进行最终手术。手术后，患者接受辅助化疗，随后接受与新辅助阶段相同的靶向治疗至52周。主要终点是病理完全缓解率 (pCR)，按意向治疗进行分析。该试验已在 ClinicalTrials.gov 注册，NCT00553358。 154 名患者接受了拉帕替尼治疗，149 名患者接受了曲妥珠单抗治疗，152 名患者接受了联合治疗。拉帕替尼联合曲妥珠单抗组（152 名患者中的 78 名 [51·3%；95% CI 43·1–59·5]）的 pCR 率显着高于单独给予曲妥珠单抗的组（149 名患者中的 44 名 [29·5%；22·4–37·5]；差异 21·1%、9·1–34·2、 p=0·0001）。我们记录拉帕替尼组（154 名患者中的 38 名 [24·7%，18·1–32·3]）和曲妥珠单抗组（差异 -4·8%，-17·6 至 8·2，p=0·34）之间的 pCR 没有显着差异。没有发生严重的心脏功能障碍。拉帕替尼组（36 名患者[23·4%]）和拉帕替尼加曲妥珠单抗组（32 名患者[21·1%]）的 3 级腹泻频率高于曲妥珠单抗组（3 名患者[2·0%]）。同样，拉帕替尼 (27 [17·5%]) 和拉帕替尼加曲妥珠单抗 (15 [9·9%]) 的 3 级肝酶改变比曲妥珠单抗 (11 [7·4%]) 更频繁。 HER2 的双重抑制可能是新辅助治疗 HER2 阳性乳腺癌的有效方法。葛兰素史克。
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. 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, 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. 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%]). Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting. GlaxoSmithKline.