初步研究表明，免疫疗法联合化疗对于许多不同类型肿瘤的疗效令人鼓舞。2018年美国麻省医学会《新英格兰医学杂志》发表的IMpassion130研究中位随访12.9个月第一次中期分析报告证实，免疫检查点PD-L1靶向抑制剂阿特珠单抗＋白蛋白纳米紫杉醇一线治疗晚期三阴性乳腺癌患者，无进展生存显著较长，总生存相似。
IMpassion130: A Phase III, Multicenter, Randomized, Placebo-Controlled Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Nab-Paclitaxel Compared With Placebo With Nab-Paclitaxel for Patients With Previously Untreated Metastatic Triple-Negative Breast Cancer (NCT02425891)
2019年11月27日，英国《柳叶刀》肿瘤学分册在线发表英国伦敦大学玛丽王后学院、美国旧金山加利福尼亚大学（俗称加州大学旧金山分校）、纽约大学、基因泰克、哈佛大学达纳法伯癌症研究院、匹兹堡大学、德国癌症研究中心、海德堡大学、巴西南里奥格兰德天主教大学、拉丁美洲肿瘤学协作组、日本爱知癌症中心医院、法国巴黎居里研究院、欧仁马奎斯癌症中心、瑞士霍夫曼罗氏、澳大利亚墨尔本大学彼得麦卡伦癌症中心的IMpassion130研究中位随访18.5个月预设第二次中期分析报告，更新了阿特珠单抗＋白蛋白纳米紫杉醇一线治疗晚期三阴性乳腺癌患者的有效性和安全性数据。
该国际多中心随机双盲安慰剂对照三期临床研究于2015年6月23日～2017年5月24日从41个国家或地区246个学术型和社区型肿瘤医院入组年龄≥18岁、尚未治疗、有组织学检查记录、美国东部肿瘤学协作组（ECOG）体力状态评分0～1分、局部晚期或远处转移的三阴性乳腺癌患者902例，按1∶1随机分入两组，其中阿特珠单抗组451例、安慰剂组451例。并按是否用过紫杉类、是否肝转移、肿瘤浸润免疫细胞PD-L1表达对随机分组进行分层。每28天的第1、15天静脉注射840毫克阿特珠单抗或安慰剂，第1、8、15天静脉注射每平方米体表面积100毫克白蛋白纳米紫杉醇，直至疾病进展或毒性反应无法耐受。研究者、患者、资助者均不知治疗分组。共同主要研究终点为研究者根据实体肿瘤疗效评价标准1.1版，对意向治疗患者和PD-L1免疫细胞阳性肿瘤（肿瘤PD-L1表达率≥1%）亚组患者评定的无进展生存和总生存。第一次中期总生存分析已经报告了最终的无进展生存结果。根据预设统计学检验分层设计，只有当两组意向治疗患者的总生存显著不同时，才对PD-L1免疫细胞阳性亚组患者的总生存进行正式分析。对实际接受治疗的患者进行安全性分析。
结果，两组各有6例患者未接受治疗，根据截至2019年1月2日的数据，第二次中期分析时，451例阿特珠单抗组与451例安慰剂组患者相比：
中位随访：18.5比17.5个月（四分位：9.6～22.8比8.4～22.4）
中位总生存：21.0比18.7个月（95%置信区间：19.0～22.6比16.9～20.3）
分层风险比：0.86（95%置信区间：0.72～1.02，P=0.078）
对于369例PD-L1免疫细胞阳性患者，185例阿特珠单抗组与安慰剂184例组患者相比：
中位总生存：25.0比18.0个月（95%置信区间：19.6～30.7比13.6～20.1）
分层风险比：0.71（95%置信区间：0.54～0.94）
根据截至2018年9月3日可获得的最新安全性数据，453例阿特珠单抗组与437例安慰剂组患者相比，发生率最高的3～4级不良事件：
中性粒细胞比例减少：38比36例（8%比8%）
周围神经病变：25比12例（6%比3%）
中性粒细胞数量减少：22比16例（5%比4%）
疲劳：17比15例（4%比3%）
阿特珠单抗组患者治疗相关死亡2例（<1%，其中阿特珠单抗相关自身免疫性肝炎死亡1例、白蛋白纳米紫杉醇相关感染性休克死亡1例），安慰剂组患者肝功能衰竭死亡1例（<1%）。2018年4月17日主要临床数据截止以来，尚未收到新的治疗相关死亡报告。
因此，该研究第二次与第一次中期总生存分析结果一致，两组意向治疗患者的总生存相似。不过，对于PD-L1免疫细胞阳性患者，阿特珠单抗＋白蛋白纳米紫杉醇与单用白蛋白纳米紫杉醇相比，总生存获益具有临床意义。由于预设统计学检验分层设计，故无法对该阳性结果进行正式的统计学分析。对于PD-L1免疫细胞阳性晚期三阴性乳腺癌患者，通常束手无策，阿特珠单抗＋白蛋白纳米紫杉醇可以成为重要的治疗选择之一。
对此，美国德克萨斯大学MD安德森癌症中心发表同期评论：对晚期三阴性乳腺癌患者分而治之。
Lancet Oncol. 2019 Nov 27. [Epub ahead of print]
Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial.
Peter Schmid, Hope S Rugo, Sylvia Adams, Andreas Schneeweiss, Carlos H Barrios, Hiroji Iwata, Véronique Diéras, Volkmar Henschel, Luciana Molinero, Stephen Y Chui, Vidya Maiya, Amreen Husain, Eric P Winer, Sherene Loi, Leisha A Emens; IMpassion130 Investigators.
Queen Mary University of London, London, UK; University of California, San Francisco, CA, USA; New York University Langone Medical Center, New York, NY, USA; Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany; Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil; Latin American Cooperative Oncology Group, Porto Alegre, Brazil; Grupo Oncoclínicas, Porto Alegre, Brazil; Aichi Cancer Center Hospital, Nagoya, Japan; Institut Curie, Paris, France; Centre Eugène Marquis, Rennes, France; F Hoffmann-La Roche, Basel, Switzerland; Genentech, South San Francisco, CA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; University of Melbourne, Melbourne, VIC, Australia; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA.
BACKGROUND: Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer.
METHODS: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice-web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m 2 of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891.
FINDINGS: Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18.5 months (IQR 9.6-22.8) in the atezolizumab group and 17.5 months (8.4-22.4) in the placebo group. Median overall survival in the intention-to-treat patients was 21.0 months (95% CI 19.0-22.6) with atezolizumab and 18.7 months (16.9-20.3) with placebo (stratified hazard ratio [HR] 0.86, 95% CI 0.72-1.02, p=0.078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25.0 months (95% CI 19.6-30.7) with atezolizumab versus 18.0 months (13.6-20.1) with placebo (stratified HR 0.71, 0.54-0.94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3-4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018).
INTERPRETATION: Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need.
FUNDING: F Hoffmann-La Roche and Genentech.
DOI: 10.1016/S1470-2045(19)30689-8
Lancet Oncol. 2019 Nov 27. [Epub ahead of print]
Building momentum for subsets of patients with advanced triple-negative breast cancer.
Wendy A Woodward.
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
DOI: 10.1016/S1470-2045(19)30737-5
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