【原】拉曲芳、拉芳的无进展生存获益显著优于曲芳

　　HER2靶向治疗＋内分泌治疗，与单用内分泌治疗相比，可以提高HER2阳性伴激素受体阳性转移性乳腺癌的临床获益。而双HER2阻断与单HER2阻断相比，也可提高临床获益。那么，双HER2阻断＋内分泌治疗的临床获益如何？

　　2017年12月15日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表英国伦敦皇家马斯登医院、英国诺华、巴西女性健康咨询中心、圣保罗爱因斯坦医院、韩国国家癌症中心、首尔大学医学院、俄罗斯癌症研究中心、阿尔汉格尔斯克地区肿瘤医院、保加利亚索非亚大学癌症中心医院、美国南加利福尼亚大学、美国西北大学、日本爱知癌症中心医院、瑞士诺华的研究报告，评估了双HER2阻断＋芳香酶抑制剂（来曲唑、阿那曲唑或依西美坦）对于绝经后女性HER2阳性伴激素受体阳性转移性乳腺癌既往已经接受内分泌治疗和新（辅助）一线曲妥珠单抗＋化疗的有效性和安全性。

　　该Ⅲ期随机研究（ALTERNATIVE）将既往已经接受内分泌治疗和新（辅助）一线曲妥珠单抗＋化疗的绝经后HER2阳性伴激素受体阳性转移性乳腺癌女性，按1∶1∶1随机分配接受拉曲芳（拉帕替尼每天1000mg＋曲妥珠单抗＋芳香酶抑制剂）、曲芳（曲妥珠单抗＋芳香酶抑制剂）或拉芳（拉帕替尼每天1500mg＋芳香酶抑制剂）。愿意继续接受化疗的患者被排除。主要终点为拉曲芳与曲芳相比的无进展生存（根据研究者评定）。次要终点为其他相比的无进展生存、总生存、总缓解率、临床获益率和安全性。

　　结果，符合分析条件的患者共355例，其中拉曲芳120例、曲芳117例、拉芳118例，各基线特征相似。

• 拉曲芳与曲芳相比，中位无进展生存显著延长（11比5.7个月，风险比：0.62，95%置信区间：0.45～0.88，P=0.0064）。
  

• 拉芳与曲芳相比，中位无进展生存也显著延长（8.3比5.7个月，风险比：0.71，95%置信区间：0.51～0.98，P=0.0361）。
  

• 预设亚组的无进展生存获益一致。拉曲芳的总缓解率、临床获益率和总生存率也较高。
  

• 拉曲芳、曲芳、拉芳的常见（≥15%）不良事件分别为腹泻（69%、9%、51%）、皮疹（36%、2%、28%）、恶心（22%、9%、22%）、甲沟炎（30%、0%、15%），大多数为1或2级。

• 各组严重不良事件发生率相似，拉曲芳组导致停药的不良事件发生率较低。

　　因此，对于HER2阳性伴激素受体阳性转移性乳腺癌患者，拉曲芳、拉芳的无进展生存获益，显著优于曲芳，而且为不能或不愿接受化疗的患者人群，提供了安全有效的替代方案。

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J Clin Oncol. 2017 Dec 15. [Epub 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: 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; Novartis Pharmaceuticals UK Limited, Frimley, United Kingdom; Centro de Referência da Saúde da Mulher; Hospital Israelita Albert Einstein, Sao Paulo, Brazil; Seoul National University College of Medicine, Seoul; National Cancer Center, Gyeonggi-do, Korea; Regional Oncology Dispensary, Arkhangelsk; N.N. Blokhin Russian Cancer Research Center, Moscow, Russia; University Cancer Center Hospital, Sofia, Bulgaria; University of Southern California, Los Angeles, CA; Aichi Cancer Center Hospital, Aichi, Japan; Novartis Pharma AG, Basel, Switzerland; Northwestern University, Chicago, IL.

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.

METHODS: Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) + TRAS + AI, TRAS + AI, or LAP + AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP + TRAS + AI versus TRAS + AI. Secondary end points were PFS (comparison of other arms), overall survival, overall response rate, clinical benefit rate, and safety.

RESULTS: Three hundred fifty-five patients were included in this analysis: LAP + TRAS + AI (n = 120), TRAS + AI (n = 117), and LAP + AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP + TRAS + AI versus TRAS + AI (median PFS, 11 v 5.7 months; hazard ratio, 0.62; 95% CI, 0.45 to 0.88; P = .0064). Consistent PFS benefit was observed in predefined subgroups. Overall response rate, clinical benefit rate, and overall survival also favored LAP + TRAS + AI. The median PFS with LAP + AI versus TRAS + AI was 8.3 versus 5.7 months (hazard ratio, 0.71; 95% CI, 0.51 to 0.98; P = .0361). Common adverse events (AEs; ≥ 15%) with LAP + TRAS + AI, TRAS + AI, and LAP + 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 three groups, and AEs leading to discontinuation were lower with LAP + TRAS + AI.

CONCLUSION: Dual HER2 blockade with LAP + TRAS + AI showed superior PFS benefit versus TRAS + 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: 29244528

DOI: 10.1200/JCO.2017.74.7824