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编者按：磷脂酰肌醇3-激酶（PI3K）通路激活是曲妥珠单抗HER2靶向疗法耐药的重要机制。瑞士诺华的阿尔卑利昔（BYL719 ）属于PI3K催化亚基α（PIK3CA）口服抑制剂，瑞士罗氏的曲妥珠单抗-恩坦辛（T-DM1）属于单克隆抗体与细胞有丝分裂抑制剂的缀合物，两者联合对于曲妥珠单抗＋紫杉类治疗失败后的转移性乳腺癌可能有效。 2018年5月30日，施普林格·自然旗下《乳腺癌研究与治疗》在线发表芝加哥西北大学范伯格医学院罗伯特·卢里综合癌症中心的研究报告，评定了BYL719＋T-DM1对于曲妥珠单抗和紫杉醇耐药HER2阳性转移性乳腺癌患者的安全性和疗效。 该I期非盲单组单中心研究于2014年5月～2015年2月选择17例曲妥珠单抗等药物治疗失败后的HER2阳性转移性乳腺癌患者，接受BYL719每天150～400mg＋T-DM1每3周3.6mg/kg的治疗。通过描述统计对限制剂量的毒性反应、最大耐受剂量、不良事件、总缓解率、临床获益率（完全缓解＋部分缓解＋疾病稳定>6个月）进行评定，通过生存曲线法计算无进展生存。 结果发现，限制剂量的毒性反应为斑丘疹，BYL719每天最大耐受剂量为250mg。最常见的毒性反应包括疲乏、皮疹、胃肠副作用、血小板减少、贫血、肝酶升高、高血糖。 可评价疗效患者14例，总有效率43%、临床获益率71%。其中，既往T-DM1治疗失败患者10例，总有效率30%、临床获益率60%。中位无进展生存为8.1个月。 因此，该研究表明，BYL719＋T-DM1可耐受，并且证实对于曲妥珠单抗耐药的HER2阳性转移性乳腺癌有效。此外，对于T-DM1耐药乳腺癌也有效。这些数据表明，PIK3CA抑制剂可以针对抗HER2疗法的重要耐药通路，为进一步研究PI3K抑制剂对于难治型HER2阳性转移性乳腺癌的作用以验证上述结果提供了依据。 相关阅读 Breast Cancer Res Treat. 2018 May 30. Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy. Sarika Jain, Ami N. Shah, Cesar A. Santa-Maria, Kalliopi Siziopikou, Alfred Rademaker, Irene Helenowski, Massimo Cristofanilli, William J. Gradishar. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, USA. PURPOSE: Activation of the phosphoinositide 3-kinase (PI3K) pathway is an important resistance mechanism to anti-HER2 therapies. This study aimed to assess the safety and activity of alpelisib (a PI3Kα isoform-specific inhibitor) with T-DM1 in trastuzumab- and taxane-resistant HER2-positive MBC. METHODS: Patients with HER2-positive MBC that had progressed on trastuzumab-based therapy were treated with alpelisib daily and T-DM1 3.6 mg/kg every 3 weeks. The dose-limiting toxicity (DLT), maximum tolerated dose (MTD), adverse events, overall response rate (ORR), and clinical benefit rate (CBR = CR + PR + SD > 6 months) were assessed with descriptive statistics. Progression-free survival (PFS) was calculated by the Kaplan-Meier method. RESULTS: Seventeen patients were enrolled with a median of 3 prior therapies for metastatic disease. The DLT was a maculopapular rash and MTD was 250 mg alpelisib daily. The most frequently occurring toxicities included fatigue, rash, gastrointestinal side effects, thrombocytopenia, anemia, elevated liver enzymes, and hyperglycemia. Fourteen patients were evaluable for response with an ORR of 43%. In patients with prior treatment and progression on T-DM1 (n = 10), the ORR was 30%. The CBR was 71% in evaluable patients and 60% in those with prior T-DM1. The median PFS was 8.1 months. CONCLUSIONS: The combination of alpelisib and T-DM1 is tolerable and demonstrates activity in trastuzumab-resistant HER2-positive MBC. Furthermore, activity was observed in T-DM1-resistant disease. These data suggest that PIK3CA inhibition targets an important resistance pathway to anti-HER2 therapy, providing rationale for further study of PI3K inhibition in refractory HER2-positive MBC to validate these results. KEYWORDS: Alpelisib; HER2-positive; T-DM1; PI3-Kinase; PIK3CA DOI: 10.1007/s10549-018-4792-0
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