Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.
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DOI：
10.1016/s0140-6736(16)00561-4
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发表时间：
2016-05-07
期刊：
影响因子：
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通讯作者：
Dreicer R
中科院分区：
文献类型：
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作者：
Rosenberg JE;Hoffman-Censits J;Powles T;van der Heijden MS;Balar AV;Necchi A;Dawson N;O'Donnell PH;Balmanoukian A;Loriot Y;Srinivas S;Retz MM;Grivas P;Joseph RW;Galsky MD;Fleming MT;Petrylak DP;Perez-Gracia JL;Burris HA;Castellano D;Canil C;Bellmunt J;Bajorin D;Nickles D;Bourgon R;Frampton GM;Cui N;Mariathasan S;Abidoye O;Fine GD;Dreicer R
铂类化疗失败后，转移性尿路上皮癌患者的治疗选择有限。这项多中心、单臂2期试验在该人群中评估了阿替唑单抗，一种可选择性结合程序化死亡配体1(PD-L1)的人源化IgG1单抗。310例患者接受阿替唑单抗治疗，每3周1次，每次1200 mg。免疫组织化学方法前瞻性检测肿瘤浸润性免疫细胞(IC)上PD-L1的表达。共同的主要终点是RECIST v1.1和免疫改良RECIST的客观应答率。采用分层检验程序，在α水平为0.05的情况下，检验客观有效率是否显著高于历史对照的10%。探索性分析包括评估癌症基因组图谱(TCGA)分子亚型、CD8+T细胞渗透、突变负荷和临床结果之间的关系。经独立综述，IC2/3组客观有效率为26%(95%可信区间18~36)，IC1/2/3组客观有效率为18%(95%可信区间13~24)，所有患者客观有效率为15%(95%可信区间11~19)。中位随访时间为11.7个月，84%的应答者观察到持续反应。未达到应答持续时间的中位数(范围2.0*，13.7*个月，*经审查)。中位总生存期IC2/3组为11.4个月(95%CI 9·0~不可估量)，IC1/2/3组为8.8个月(95%CI 7·1~10·6)，全部患者为7·9个月(95%CI 6·6~9·3)。与治疗相关的3-4级不良事件发生率为16%，免疫介导的3-4级不良事件发生率为5%。探索性分析显示，TCGA亚型和突变负荷可以独立预测对阿替唑单抗的反应。阿替唑珠单抗在该人群中表现出持久的活性和良好的耐受性。免疫细胞上PD-L1的表达与免疫应答有关。这是首次报道TCGA亚型与免疫检查点抑制反应的相关性，并证明突变负荷作为晚期尿路上皮癌对这类药物反应的生物标记物的重要性。F.霍夫曼-拉罗氏有限公司
Patients with metastatic urothelial carcinoma have limited treatment options after failure of platinum-based chemotherapy. This multicenter, single-arm phase 2 trial evaluated atezolizumab, an engineered humanized IgG1 monoclonal antibody that binds selectively to programmed death–ligand 1 (PD-L1), in this population. Three hundred and ten patients received atezolizumab (1200 mg, every 3 weeks). PD-L1 expression on tumor-infiltrating immune cells (IC) was prospectively assessed by immunohistochemistry. The co-primary endpoints were the objective response rate by RECIST v1.1 and immune modified RECIST. A hierarchical testing procedure was used to test whether the objective response rate was significantly higher than the historical control of 10% at alpha level of 0·05. Exploratory analyses included assessing the association between The Cancer Genome Atlas (TCGA) molecular subtypes, CD8+ T cell infiltration, mutation load, and clinical outcomes. By independent review, objective response rates were 26% (95% CI 18 to 36) in the IC2/3 group, 18% (95% CI 13 to 24) in the IC1/2/3 group and 15% (95% CI 11 to 19) in all patients. With a median follow-up of 11·7 months, ongoing responses were observed in 84% of responders. The median duration of response was not reached (range 2·0*, 13·7* months, *censored). The median overall survival was 11·4 months (95% CI 9·0 to not estimable) in the IC2/3 group, 8·8 months (95% CI 7·1 to 10·6) in the IC1/2/3, and 7·9 months (95% CI 6·6 to 9·3) in all patients. Grade 3–4 related treatment-related adverse events occurred in 16% and grade 3–4 immune-mediated adverse events occurred in 5% of treated patients. Exploratory analyses showed TCGA subtypes and mutation load to be independently predictive for response to atezolizumab. Atezolizumab demonstrated durable activity and good tolerability in this population. PD-L1 expression on immune cells was associated with response. This is the first report to show the association of TCGA subtypes with response to immune checkpoint inhibition and demonstrate the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma. F. Hoffmann-La Roche Ltd.