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对于人类表皮生长因子受体HER2阳性且激素受体阳性晚期乳腺癌绝经患者，HER2靶向治疗可显著提高内分泌治疗的临床获益。HER2双靶向药物与HER2单靶向药物相比，临床获益也可显著提高。不过，对于术前新辅助或术后辅助或转移后曲妥珠单抗＋化疗失败后不再考虑或无法耐受化疗的HER2阳性且激素受体阳性晚期乳腺癌绝经患者，HER2双靶向药物＋内分泌治疗的有效性和安全性尚不明确。 2020年8月21日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表英国伦敦大学皇家马斯登医院、巴西圣保罗妇女保健中心、爱因斯坦医院、韩国首尔大学、国家癌症中心、俄罗斯阿尔汉格尔斯克肿瘤医院、莫斯科布洛欣癌症研究中心、保加利亚索非亚医科大学、美国南加利福尼亚大学、芝加哥西北大学、罗伯特卢里综合癌症中心、日本爱知癌症中心、瑞士诺华的ALTERNATIVE研究报告更新，对拉帕替尼＋曲妥珠单抗＋芳香酶抑制剂、曲妥珠单抗＋芳香酶抑制剂、拉帕替尼＋芳香酶抑制剂三种方案一线或二线治疗HER2阳性且激素受体阳性晚期乳腺癌曲妥珠单抗＋化疗失败患者的有效性和安全性进行了比较。 ALTERNATIVE (EGF114299): A Phase III Trial to Compare the Safety and Efficacy of Lapatinib Plus Trastuzumab Plus an Aromatase Inhibitor (AI) vs. Trastuzumab Plus an AI vs. Lapatinib Plus an AI as 1st- or 2nd- Line Therapy in Postmenopausal Subjects With Hormone Receptor+, HER2-positive Metastatic Breast Cancer (MBC) Who Received Prior Trastuzumab and Endocrine Therapies (NCT01160211) 该国际多中心非盲随机平行对照三期临床研究于2011年5月5日～2016年3月11日从29个国家地区112家医院入组曲妥珠单抗＋化疗失败后不再考虑化疗的HER2阳性且激素受体阳性晚期乳腺癌绝经患者355例，按1∶1∶1的比例随机分为三组：
芳香酶抑制剂为研究者自行选择的来曲唑、阿那曲唑、依西美坦三者之一。 主要终点为研究者评定的无进展生存（拉帕替尼＋曲妥珠单抗＋芳香酶抑制剂、曲妥珠单抗＋芳香酶抑制剂两组相比）。次要终点为无进展生存（其他组相比）、总生存、客观缓解比例、临床获益比例、安全性。 三组患者基线特征分布平衡。 结果，该研究达到主要终点。拉帕替尼＋曲妥珠单抗＋芳香酶抑制剂、曲妥珠单抗＋芳香酶抑制剂两组相比，中位无进展生存将近2倍（11个月比5.6个月），进展或死亡风险显著减少38%（风险比：0.62，95%置信区间：0.45～0.88，P=0.0063）。预设亚组分析的无进展生存获益也显著改善。客观缓解比例、临床获益比例、总生存也有利于拉帕替尼＋曲妥珠单抗＋芳香酶抑制剂。 拉帕替尼＋芳香酶抑制剂、曲妥珠单抗＋芳香酶抑制剂相比，中位无进展生存将近1.5倍（8.3比5.6个月），进展或死亡风险减少15%（风险比：0.85，95%置信区间：0.62～1.17，P=0.3159）。 拉帕替尼＋曲妥珠单抗＋芳香酶抑制剂、曲妥珠单抗＋芳香酶抑制剂、拉帕替尼＋芳香酶抑制剂相比，发生比例≥15%的不良事件：
三组患者报告的严重不良事件发生比例相似，拉帕替尼＋曲妥珠单抗＋芳香酶抑制剂的不良事件所致停药比例较低。 因此，该研究结果表明，对于HER2阳性且激素受体阳性晚期乳腺癌曲妥珠单抗＋化疗失败后不再考虑或无法耐受化疗的绝经患者，拉帕替尼＋曲妥珠单抗双靶向药物阻断＋芳香酶抑制剂与曲妥珠单抗＋芳香酶抑制剂相比，无进展生存获益显著较大。该联合方案为此类患者提供了有效而安全的化疗替代方案。 J Clin Oncol. 2020 Aug 21. Online ahead of print. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. The Royal Marsden NHS Foundation Trust, London, United Kingdom; Novartis Pharmaceuticals UK Limited, Frimley, United Kingdom; Centro de Referência da Saúde da Mulher, Sao Paulo, Brazil; Hospital Israelita Albert Einstein, Sao Paulo, Brazil; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; National Cancer Center, Gyeonggi-do, Korea; Regional Oncology Dispensary, Arkhangelsk, Russia; N.N. Blokhin Russian Cancer Research Center, Moscow, Russia; University Cancer Center Hospital, Sofia, Bulgaria; University of Southern California, Los Angeles, Los Angeles, CA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL; Aichi Cancer Center Hospital, Aichi, Japan; Novartis Pharma AG, Basel, Switzerland. PURPOSE: Human epidermal growth factor receptor 2 (HER2) targeting plus endocrine therapy (ET) improved clinical benefit in HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) versus ET alone. Dual HER2 blockade enhances clinical benefit versus single HER2 blockade. The ALTERNATIVE study evaluated the efficacy and safety of dual HER2 blockade plus aromatase inhibitor (AI) in postmenopausal women with HER2-positive/HR-positive MBC who received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy. This updated article reflects minor numerical corrections in some secondary efficacy analyses that resulted from programming errors and that do not change the major conclusions of the study. METHODS: Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) plus TRAS plus AI, TRAS plus AI, or LAP plus AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP plus TRAS plus AI versus TRAS plus AI. Secondary end points were PFS (comparison of other arms), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. RESULTS: Three hundred fifty-five patients were included in this analysis: LAP plus TRAS plus AI (n = 120), TRAS plus AI (n = 117), and LAP plus AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP plus TRAS plus AI versus TRAS plus AI (median PFS, 11 v 5.6 months; hazard ratio, 0.62 [95% CI, 0.45 to 0.88]; P = .0063). A consistent PFS benefit was observed in predefined subgroups. ORR, CBR, and OS also favored LAP plus TRAS plus AI. The median PFS with LAP plus AI versus TRAS plus AI was 8.3 versus 5.6 months (hazard ratio, 0.85 [95% CI, 0.62 to 1.17]; P = .3159). Common adverse events (AEs; ≥ 15%) with LAP plus TRAS plus AI, TRAS plus AI, and LAP plus AI were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively), mostly grade 1 or 2. Serious AEs were reported similarly across the 3 groups, and AEs leading to discontinuation were lower with LAP plus TRAS plus AI. CONCLUSION: Dual HER2 blockade with LAP plus TRAS plus AI showed superior PFS benefit versus TRAS plus AI in patients with HER2-positive/HR-positive MBC. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population. PMID: 32822287 DOI: 10.1200/JCO.20.01894
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