阿特珠单抗＋白蛋白结合型紫杉醇一线治疗晚期三阴性乳腺癌的结局

　　三阴性乳腺癌对现有靶向疗法无效，临床结局较差，化疗仍为主要的全身疗法，国际指南支持将紫杉类或蒽环类单药作为一线疗法，总生存时间各不相同，但是大多不到18个月。对于三阴性乳腺癌患者，细胞程序性死亡蛋白配体-1（PD-L1）主要表达于活化的抗原提呈细胞表面，受体为T淋巴细胞表面的细胞程序性死亡蛋白-1（PD-1），可以抑制T淋巴细胞增殖以及细胞因子产生，并且可以抑制抗癌免疫应答。因此，抑制PD-1和PD-L1可以作为三阴性乳腺癌的治疗策略。PD-L1选择性地靶向抑制剂阿特珠单抗可以防止PD-L1与PD-1受体结合，从而逆转T淋巴细胞抑制。阿特珠单抗已被批准单药治疗转移性尿路上皮癌和非小细胞肺癌。阿特珠单抗也被证实对其他实体瘤患者具有良好的安全性和临床活性，包括三阴性乳腺癌。化疗可以增强肿瘤抗原释放和免疫检查点抑制剂的抗肿瘤反应，尤其紫杉类可以激活Toll样受体活性并且促进树突细胞活性。白蛋白结合型纳米微粒紫杉醇已被晚期非小细胞肺癌患者1b期和3期研究、三阴性乳腺癌患者1b期研究证实可以增强阿特珠单抗的抗癌活性和安全性。乳腺癌患者1b期研究表明，同时给予白蛋白结合型纳米微粒紫杉醇不会削弱阿特珠单抗的免疫动力学效应。

　　2018年10月20日，美国麻省医学会《新英格兰医学杂志》在线发表英国伦敦玛丽王后大学、美国纽约大学、旧金山加利福尼亚大学、基因泰克、佛罗里达癌症研究所、哈佛大学达纳法伯癌症研究所、霍普金斯大学、德国海德堡大学、巴西南大河州天主教大学、圣保罗大学、日本爱知县癌症中心医院、法国居里研究所、韩国首尔大学、瑞士罗氏、澳大利亚墨尔本大学彼得麦卡勒姆癌症中心的研究报告，比较了白蛋白结合型纳米微粒紫杉醇＋阿特珠单抗或安慰剂治疗转移性三阴性乳腺癌的结局。

　　该国际随机双盲安慰剂对照3期研究（IMpassion130、NCT02425891）于2015年6月～2017年5月从41个国家246家医院入组902例未经治疗的转移性三阴性乳腺癌患者按1∶1随机分配接受白蛋白结合型纳米微粒紫杉醇＋阿特珠单抗（451例）或安慰剂（451例）直至疾病进展或发生无法耐受的毒性反应。分层因素为接受或非接受紫杉类新辅助或辅助治疗、入组时肝转移与否、入组时PD-L1表达阳性或阴性。两个主要终点为无进展生存（意向治疗人群和PD-L1阳性亚组）和总生存（意向治疗人群；如果结果显著，对PD-L1阳性亚组进行检验）。

　　结果，经过中位随访12.9个月，根据意向治疗分析中，阿特珠单抗组与安慰剂组相比：

• 中位无进展生存：7.2比5.5个月，进展或死亡风险减少20%（分层风险比：0.80，95%置信区间：0.69～0.92，P=0.002）

• PD-L1阳性肿瘤患者的中位无进展生存：7.5比5.0个月，进展或死亡风险减少38%（分层风险比：0.62，95%置信区间，0.49～0.78，P<0.001）

• 中位总生存：21.3比17.6个月，死亡风险减少16%（分层风险比：0.84，95%置信区间：0.69～1.02，P=0.08）

• PD-L1阳性肿瘤患者的中位总生存：25.0比15.5个月，死亡风险减少38%（分层风险比，0.62，95%置信区间，0.45～0.86）

• 导致任何药物停用的不良事件发生率：15.9%比8.2%（未见新的不良反应）

　　因此，该研究结果表明，对于意向治疗人群和PD-L1阳性亚组，阿特珠单抗＋白蛋白结合型纳米微粒紫杉醇显著延长了转移性三阴性乳腺癌患者的无进展生存，不良事件与两种药物的已知安全性特征一致。

相关阅读

N Engl J Med. 2018 Oct 20. [Epub ahead of print]

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer.

Peter Schmid, Sylvia Adams, Hope S. Rugo, Andreas Schneeweiss, Carlos H. Barrios, Hiroji Iwata, Véronique Diéras, Roberto Hegg, Seock-Ah Im, Gail Shaw Wright, Volkmar Henschel, Luciana Molinero, Stephen Y. Chui, Roel Funke, Amreen Husain, Eric P. Winer, Sherene Loi, Leisha A. Emens; IMpassion130 Trial Investigators.

Barts Cancer Institute, Queen Mary University of London, London; Perlmutter Cancer Center, New York University School of Medicine, New York; University of California, San Francisco, San Francisco; Genentech, South San Francisco, California; University Hospital Heidelberg, Heidelberg, Germany; Centro de Pesquisa em Oncologia, Hospital Sao Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre; University of Sao Paulo, Sao Paulo, Brazil; Aichi Cancer Center Hospital, Nagoya, Japan; Institut Curie, Paris; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea; Florida Cancer Specialists and Research Institute, New Port Richey; Roche, Basel, Switzerland; Dana-Farber Cancer Institute, Boston; Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia; Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore.

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.

FUND: F. Hoffmann-La Roche/Genentech

IMpassion130 ClinicalTrials.gov number: NCT02425891

DOI: 10.1056/NEJMoa1809615

第十五届全国乳腺癌会议

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