Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
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DOI：
10.1016/s0140-6736(16)32517-x
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发表时间：
2017-01-21
期刊：
影响因子：
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通讯作者：
OAK Study Group
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作者：
Rittmeyer A;Barlesi F;Waterkamp D;Park K;Ciardiello F;von Pawel J;Gadgeel SM;Hida T;Kowalski DM;Dols MC;Cortinovis DL;Leach J;Polikoff J;Barrios C;Kabbinavar F;Frontera OA;De Marinis F;Turna H;Lee JS;Ballinger M;Kowanetz M;He P;Chen DS;Sandler A;Gandara DR;OAK Study Group
Atezolizumab是一种人源化抗程序性死亡配体1（PD-L1）单克隆抗体，可抑制PD-L1和程序性死亡-1（PD-1）以及PD-L1和B7-1相互作用，从而重振抗癌免疫力。我们在既往接受过治疗的非小细胞肺癌患者中评估了其与多西他赛相比的疗效和安全性。我们在31个国家的194个学术或社区肿瘤中心进行了一项随机、开放标签、3期试验（OAK）。我们入组的患者患有鳞状或非鳞状非小细胞肺癌，年龄≥ 18岁，根据实体瘤疗效评价标准有可测量的疾病，东部肿瘤协作组体能状态为0或1。患者既往接受过1 - 2种细胞毒性化疗方案（一种或多种含铂联合治疗）治疗IIIB或IV期非小细胞肺癌。排除有自身免疫性疾病史的患者和既往接受过多西他赛、CD 137激动剂、抗CTLA 4或靶向PD-L1和PD-1通路治疗的患者。通过交互式语音或网络应答系统，通过排列区组随机化（区组大小为8），将患者随机（1：1）分配至每3周一次静脉注射atezolizumab 1200 mg或多西他赛75 mg/m2。共同主要终点为意向治疗（ITT）和PD-L1表达人群TC 1/2/3或IC 1/2/3（肿瘤细胞或肿瘤浸润免疫细胞上PD-L1 ≥1%）的总生存期。在1225例入组患者中的前850例中进行了主要疗效分析。本研究已在ClinicalTrials.gov注册，编号。在2014年3月11日至2015年4月29日期间，招募了1225名患者。在主要人群中，425例患者被随机分配接受atezolizumab治疗，425例患者被分配接受多西他赛治疗。在ITT和PD-L1表达人群中，atezolizumab组的总生存期显著延长。在ITT人群中，与多西他赛相比，atezolizumab组的总生存期有所改善（中位总生存期为13.8个月[95% CI 11.8 - 15.7] vs 9.6个月[8.6 - 11.2];风险比[HR] 0.73 [95% CI 0.62 - 0.87]，p= 0.0003）。与多西他赛相比，atezolizumab（n=241）改善了TC 1/2/3或IC 1/2/3人群的总生存期（n=222; atezolizumab组的中位总生存期为15.7个月[95% CI 12.6 - 18.0]，多西他赛组为10.3个月[8.8 - 12.0]; HR 0.74 [95% CI 0.58 - 0.93]; p=0·0102）。PD-L1低水平或不可检测亚组（TC 0和IC 0）的患者在atezolizumab治疗后的生存期也有所改善（中位总生存期12.6个月vs 8.9个月; HR 0.75 [95% CI 0.59 - 0.96]）。鳞状（HR 0.73 [95% CI 0.54 - 0.98]; atezolizumab组n=112，多西他赛组n= 110）或非鳞状（0.73 [0.60 - 0.89]; n=313和n=315）组织学患者的总生存期改善相似。atezolizumab组（609例患者中的90例[15%]）发生治疗相关3级或4级不良事件的患者少于多西他赛组（578例患者中的247例[43%]）。多西他赛组报告了1例呼吸道感染导致的治疗相关死亡。据我们所知，OAK是第一项报告PD-L1靶向治疗结果的随机化III期研究，atezolizumab治疗与多西他赛相比，在既往接受过治疗的非小细胞肺癌患者中，无论PD-L1表达或组织学如何，总生存期均得到临床相关改善，具有有利的安全性特征。
Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7–1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number . Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8–15·7] vs 9·6 months [8·6–11·2]; hazard ratio [HR] 0·73 [95% CI 0·62–0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6–18·0] with atezolizumab vs 10·3 months [8·8–12·0] with docetaxel; HR 0·74 [95% CI 0·58–0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59–0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54–0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60–0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile.