Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer A Phase 1 Study
Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer A Phase 1 Study
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DOI：
10.1001/jamaoncol.2018.4224
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发表时间：
2019-01-01
期刊：
影响因子：
28.4
通讯作者：
Schmid, Peter
中科院分区：
文献类型：
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作者：
Emens, Leisha A.;Cruz, Cristina;Schmid, Peter
Atezolizumab（抗程序性细胞死亡配体1 [PD-L1]）在多种癌症类型中具有良好的耐受性和临床活性。其在转移性三阴性乳腺癌（mTNBC）中的安全性和临床活性尚未报道。目的评估单药atezolizumab在mTNBC患者中的安全性、临床活性和生物标志物。设计、环境和参与者：2013年1月至2016年2月，在美国和欧洲学术医疗中心，mTNBC女性（由研究者评估定义）入组了一项多队列开放标签一期研究。中位随访为25.3个月（范围0.4-45.6个月）。符合条件的患者，无论采用何种治疗方法，均具有实体肿瘤反应评价标准（1.1版）可测量的疾病；东部肿瘤合作集团业绩状况0 ~ 1；以及用于评估免疫细胞（IC） PD-L1表达的代表性肿瘤样本。干预措施：Atezolizumab每3周静脉注射一次，直到出现不可接受的毒副作用或丧失临床获益。主要结局和测量主要结局是安全性和耐受性。活性和探索性结果包括客观缓解率（ORR）、缓解持续时间、无进展生存期（PFS）和总生存期（OS）。对所有患者和关键患者亚组的结果进行评估。结果116例可评估患者（中位年龄53岁[范围29-82岁]）中，73例（63%）发生治疗相关不良事件；58例（79%）为1 ~ 2级。大多数不良事件发生在治疗的第一年内。一线患者的orr（21例中有5例[24%]）高于二线或以上患者（94例中有6例[6%]）。中位缓解持续时间为21个月（范围，3至>= 38个月）。RECIST组的中位PFS为1.4 （95% CI, 1.3-1.6）个月，irRC组的中位PFS为1.9 （95% CI, 1.4-2.5）个月。在一线患者中，中位OS为17.6个月（95% CI， 10.2个月至不可估计）。PD-L1表达至少1%肿瘤浸润性ic的患者orr较高，OS较长（12%[11 / 91];10.1 [95% CI, 7.0-13.8]个月），而ic低于1%的患者（0 / 21;6.0 [95% CI, 2.6-12.6]个月）。高水平的ic（约10%）与较高的orr和较长的OS独立相关。结论和相关性单药atezolizumab耐受性良好，在疾病稳定或应答的mTNBC患者和早期治疗中提供持久的临床益处。
IMPORTANCE Atezolizumab (anti-programmed cell death ligand 1 [PD-L1]) is well tolerated and clinically active in multiple cancer types. Its safety and clinical activity in metastatic triple-negative breast cancer (mTNBC) has not been reported.OBJECTIVE To evaluate the safety, clinical activity, and biomarkers associated with the use of single-agent atezolizumab in patients with mTNBC.DESIGN, SETTING, AND PARTICIPANTS Women with mTNBC (defined by investigator assessment) were enrolled between January 2013 and February 2016 in a multicohort open-label, phase 1 study at US and European academic medical centers. Median follow-up was 25.3 months (range, 0.4-45.6 months). Eligible patients regardless of line of therapy had measurable disease by Response Evaluation Criteria in Solid Tumors, version 1.1; Eastern Cooperative Oncology Group performance status of 0 to 1; and a representative tumor sample for assessment of immune cell (IC) PD-L1 expression.INTERVENTIONS Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects or loss of clinical benefit.MAIN OUTCOMES AND MEASURES Primary outcome was safety and tolerability. Activity and exploratory outcomes included objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Outcomes were assessed in all patients and in key patient subgroups.RESULTS Among 116 evaluable patients (median age, 53 years [range, 29-82 years]), treatment-related adverse events occurred in 73 (63%); 58 (79%) were grade 1 to 2. Most adverse events occurred within the first treatment year. The ORRs were numerically higher in first-line (5 of 21 [24%]) than in second-line or greater patients (6 of 94 [6%]). Median duration of response was 21 months (range, 3 to >= 38 months). Median PFS was 1.4 (95% CI, 1.3-1.6) months by RECIST and 1.9 (95% CI, 1.4-2.5) months by irRC. In first-line patients, median OS was 17.6 months (95% CI, 10.2 months to not estimable). Patients with PD-L1 expression of at least 1% tumor-infiltrating ICs had higher ORRs and longer OS (12%[11 of 91]; 10.1 [95% CI, 7.0-13.8] months, respectively) than those with less than 1% ICs (0 of 21; 6.0 [95% CI, 2.6-12.6] months, respectively). High levels of ICs (>10%) were independently associated with higher ORRs and longer OS.CONCLUSIONS AND RELEVANCE Single-agent atezolizumab was well tolerated and provided durable clinical benefit in patients with mTNBC with stable or responding disease and in earlier lines of treatment.