Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial.
Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial.
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铂衰竭后转移性尿路上皮癌的AVELUMAB（标枪实体瘤）：汇总的结果是两个开放标签1期试验的两个膨胀队列的结果。
DOI：
10.1016/s1470-2045(17)30900-2
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发表时间：
2018-01
期刊：
影响因子：
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通讯作者：
Apolo AB
中科院分区：
文献类型：
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作者：
Patel MR;Ellerton J;Infante JR;Agrawal M;Gordon M;Aljumaily R;Britten CD;Dirix L;Lee KW;Taylor M;Schöffski P;Wang D;Ravaud A;Gelb AB;Xiong J;Rosen G;Gulley JL;Apolo AB
抗程序性死亡配体 1 (PD-L1) 和抗程序性死亡 1 药物的批准扩大了局部晚期或转移性尿路上皮癌患者的治疗选择。 Avelumab 是一种人单克隆抗 PD-L1 抗体，在这种疾病中显示出良好的抗肿瘤活性和安全性。我们的目的是评估接受 avelumab 治疗的患者（铂类治疗后和未接受顺铂治疗）的安全性，并评估该药物在铂类治疗后患者中的抗肿瘤活性。在这项来自 1 期剂量扩展 JAVELIN 实体瘤研究的两个队列的汇总分析中，来自美国、欧洲和亚洲 80 个癌症治疗中心或医院的年龄在 18 岁及以上、经组织学或细胞学证实为局部晚期或转移性尿路上皮癌且在至少一次铂类化疗后病情进展的患者入组。符合条件的患者具有足够的终末器官功能、东部肿瘤合作组表现状态为 0 或 1、预期寿命至少 3 个月、至少有一个可测量的病变。先前可能在围手术期接受过治疗的不符合顺铂治疗条件的患者，包括未接受过铂类治疗的患者，也符合资格。未选择 PD-L1 表达的患者每 2 周接受一次 avelumab（10 mg/kg，1 小时静脉输注），直至确认疾病进展、出现不可接受的毒性或其他停药标准。该疗效扩展队列的主要终点是经独立审查判定的最佳总体缓解（根据 RECIST 1.1 版）。对所有接受至少一剂 avelumab 的患者进行安全性分析。在接受至少一剂 avelumab 的铂后患者中评估抗肿瘤活性。该试验已在 ClinicalTrials.gov 注册，编号 NCT01772004；该转移性尿路上皮癌患者队列的招募工作已结束，试验正在进行中。 2014年9月3日至2016年3月15日期间，筛选了329名晚期转移性尿路上皮癌患者纳入本研究； 249 名患者符合资格并接受了中位 12 周的 avelumab 治疗 (IQR 6·0–19·7)，并随访中位 9·9 个月 (4·3–12·1)。安全性和抗肿瘤活性在 2016 年 6 月 9 日数据截止时进行了评估。在 161 名接受至少 6 个月随访的铂后患者中，27 名患者记录了完全或部分缓解的最佳总体缓解（17%；95% CI 11-24），其中 9 名（6%）完全缓解和 18 名（11%）部分缓解。最常见的治疗相关不良事件（≥10% 患者中的任何级别）是输液相关反应（73 [29%]；均为 1-2 级）和疲劳（40 [16%]）。 249 名患者中有 21 名 (8%) 发生了 3 级或更严重的治疗相关不良事件，其中最常见的是疲劳（4 名 [2%]），以及乏力、脂肪酶升高、低磷酸盐血症和肺炎，各有两名 (1%) 患者出现。 249 名患者中有 19 名（8%）发生了与 avelumab 治疗相关的严重不良事件，并发生了 1 名治疗相关死亡（肺炎）。 Avelumab 在治疗铂类难治性转移性尿路上皮癌患者中显示出抗肿瘤活性；所有接受 avelumab 治疗的患者均报告了可控的安全性。这些数据为 avelumab 治疗转移性尿路上皮癌提供了基本原理，并在此基础上获得了美国 FDA 的加速批准。
The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0–19·7) and followed up for a median of 9·9 months (4·3–12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11–24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1–2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis). Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis.