Kaiser Permanente Medical Center, Vallejo, CA, USA.
US Oncology Research, The Woodlands, TX, USA; Virginia Cancer Specialists Research Institute, Fairfax, VA, USA.
Lancet. 2016 Apr 30;387(10030):1837-46. doi: 10.1016/S0140-6736(16)00587-0. Epub 2016 Mar 10.
Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population.
In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993.
Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12·6 months (95% CI 9·7-16·4) for atezolizumab versus 9·7 months (8·6-12·0) for docetaxel (hazard ratio [HR] 0·73 [95% CI 0·53-0·99]; p=0·04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-γ-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event.
Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy.
F Hoffmann-La Roche/Genentech Inc.
先前接受过治疗的晚期或转移性非小细胞肺癌（NSCLC）患者的预后较差。抗程序性死亡配体 1（PD-L1）抗体阿特珠单抗对癌症具有临床活性，包括 NSCLC，特别是对肿瘤细胞、肿瘤浸润免疫细胞或两者均表达 PD-L1 的癌症。我们评估了 PD-L1 肿瘤细胞和肿瘤浸润免疫细胞表达水平以及意向治疗人群中阿特珠单抗与多西他赛治疗先前治疗的 NSCLC 的疗效和安全性。
在这项开放标签、2 期随机对照试验中，在欧洲和北美 13 个国家的 61 个学术医疗中心和社区肿瘤学实践中招募了先前接受过铂类化疗进展的 NSCLC 患者。主要纳入标准为东部合作肿瘤学组表现状态 0 或 1，根据实体瘤反应评估标准 1.1（RECIST v1.1）可测量疾病，以及足够的血液学和终末器官功能。患者按 PD-L1 肿瘤浸润免疫细胞状态、组织学和先前的治疗线进行分层，并通过交互式语音或网络系统按 1:1 的比例随机分配（1:1），采用排列块随机化（块大小为 4）接受静脉注射阿特珠单抗 1200mg 或多西他赛 75mg/m²，每 3 周一次。通过免疫组织化学在肿瘤细胞（PD-L1 表达肿瘤细胞 TC3≥50%、TC2≥5%和<50%、TC1≥1%和<5%和 TC0<1%）和肿瘤浸润免疫细胞（肿瘤面积的百分比：IC3≥10%、IC2≥5%和<10%、IC1≥1%和<5%和 IC0<1%）上对基线 PD-L1 表达进行评分。意向治疗人群和 PD-L1 亚组的主要终点是总生存期，在 173 例死亡时进行评估。在探索性分析中评估了生物标志物。我们评估了所有接受至少一剂研究药物的患者的安全性。该研究在 ClinicalTrials.gov 注册，编号为 NCT01903993。
患者于 2013 年 8 月 5 日至 2014 年 3 月 31 日期间入组。144 名患者被随机分配至阿特珠单抗组，143 名患者被分配至多西他赛组。142 名患者接受了至少一剂阿特珠单抗治疗，135 名患者接受了多西他赛治疗。意向治疗人群的总生存期为阿特珠单抗组的 12.6 个月（95%CI 9.7-16.4）与多西他赛组的 9.7 个月（8.6-12.0）（风险比[HR]0.73 [95%CI 0.53-0.99]；p=0.04）。总生存期的改善与 PD-L1 表达的增加相关（TC3 或 IC3 HR 0.49 [0.22-1.07；p=0.068]，TC2/3 或 IC2/3 HR 0.54 [0.33-0.89；p=0.014]，TC1/2/3 或 IC1/2/3 HR 0.59 [0.40-0.85；p=0.005]，TC0 和 IC0 HR 1.04 [0.62-1.75；p=0.871]）。在我们的探索性分析中，具有高 T 效应干扰素-γ相关基因表达的预先存在免疫的患者，阿特珠单抗的总生存期得到改善。阿特珠单抗组有 11 名（8%）患者因不良事件停止治疗，多西他赛组有 30 名（22%）患者停止治疗。阿特珠单抗组有 16 名（11%）患者出现与治疗相关的 3-4 级不良事件，多西他赛组有 52 名（39%）患者出现与治疗相关的 3-4 级不良事件，阿特珠单抗组有 1 名（1%）患者因治疗相关不良事件死亡，多西他赛组有 3 名（2%）患者因治疗相关不良事件死亡。
与多西他赛相比，阿特珠单抗显著改善了先前治疗的 NSCLC 患者的生存。改善与肿瘤细胞和肿瘤浸润免疫细胞上的 PD-L1 免疫组织化学表达相关，表明 PD-L1 表达对阿特珠单抗获益有预测作用。阿特珠单抗耐受性良好，其安全性与化疗不同。
罗氏/基因泰克公司。
