阿替利珠单抗联合白蛋白紫杉醇治疗晚期三阴性乳腺癌。
Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer.
机构信息
From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).
出版信息
N Engl J Med. 2018 Nov 29;379(22):2108-2121. doi: 10.1056/NEJMoa1809615. Epub 2018 Oct 20.
BACKGROUND
Unresectable locally advanced or metastatic triple-negative (hormone-receptor-negative and human epidermal growth factor receptor 2 [HER2]-negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)-paclitaxel may enhance the anticancer activity of atezolizumab.
METHODS
In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1-positive subgroup) and overall survival (tested in the intention-to-treat population; if the finding was significant, then it would be tested in the PD-L1-positive subgroup).
RESULTS
Each group included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median progression-free survival was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); among patients with PD-L1-positive tumors, the median progression-free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, the median overall survival was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD-L1-positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel.
CONCLUSIONS
Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1-positive subgroup. Adverse events were consistent with the known safety profiles of each agent. (Funded by F. Hoffmann-La Roche/Genentech; IMpassion130 ClinicalTrials.gov number, NCT02425891 .).
背景
不可切除的局部晚期或转移性三阴性（激素受体阴性和人表皮生长因子受体 2 [HER2]阴性）乳腺癌是一种侵袭性疾病，预后不良。纳米白蛋白结合紫杉醇（nab-紫杉醇）可能增强阿替利珠单抗的抗癌活性。
方法
在这项 3 期试验中，我们将未经治疗的转移性三阴性乳腺癌患者随机分配（1:1 比例）接受阿替利珠单抗加 nab-紫杉醇或安慰剂加 nab-紫杉醇；患者继续接受干预，直到疾病进展或出现不可接受的毒性水平。分层因素为接受或未接受新辅助或辅助紫杉烷治疗、基线时是否存在肝转移以及基线时程序性死亡配体 1（PD-L1）表达（阳性与阴性）。两个主要终点是无进展生存期（在意向治疗人群和 PD-L1 阳性亚组中）和总生存期（在意向治疗人群中进行测试；如果发现有意义，则在 PD-L1 阳性亚组中进行测试）。
结果
每组包括 451 名患者（中位随访时间 12.9 个月）。在意向治疗分析中，阿替利珠单抗加 nab-紫杉醇组的中位无进展生存期为 7.2 个月，而安慰剂加 nab-紫杉醇组为 5.5 个月（进展或死亡风险比，0.80；95%置信区间[CI]，0.69 至 0.92；P=0.002）；在 PD-L1 阳性肿瘤患者中，中位无进展生存期分别为 7.5 个月和 5.0 个月（风险比，0.62；95%CI，0.49 至 0.78；P<0.001）。在意向治疗分析中，阿替利珠单抗加 nab-紫杉醇组的中位总生存期为 21.3 个月，安慰剂加 nab-紫杉醇组为 17.6 个月（死亡风险比，0.84；95%CI，0.69 至 1.02；P=0.08）；在 PD-L1 阳性肿瘤患者中，中位总生存期分别为 25.0 个月和 15.5 个月（风险比，0.62；95%CI，0.45 至 0.86）。未发现新的不良反应。接受阿替利珠单抗加 nab-紫杉醇治疗的患者中有 15.9%和接受安慰剂加 nab-紫杉醇治疗的患者中有 8.2%发生导致任何药物停药的不良事件。
结论
阿替利珠单抗加 nab-紫杉醇延长了转移性三阴性乳腺癌患者的无进展生存期，无论是在意向治疗人群还是 PD-L1 阳性亚组中。不良事件与每种药物的已知安全性特征一致。（由 F. Hoffmann-La Roche/Genentech 资助；IMpassion130 临床试验.gov 编号，NCT02425891 。）。
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