Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial
Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial
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DOI：
10.1016/s1470-2045(19)30458-9
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发表时间：
2019-08-01
期刊：
影响因子：
51.1
通讯作者：
Chau, Ian
中科院分区：
文献类型：
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作者：
Herbst, Roy S.;Arkenau, Hendrik-Tobias;Chau, Ian
背景：临床前和临床证据表明，同时阻断血管内皮生长因子受体-2(VEGFR-2)和PD-1或PD-L1可增强抗原特异性T细胞的迁移和抗肿瘤活性，并具有良好的毒性。在这项研究中，我们旨在评估Ramucirumab(一种IgG1VEGFR-2拮抗剂)与pembrolizumab(一种IgG4PD-1拮抗剂)联合治疗晚期胃或胃食道交界部腺癌、非小细胞肺癌或尿路上皮癌的安全性和初步抗肿瘤活性。方法我们在美国、法国、德国、西班牙和英国的16个学术医疗中心、医院和诊所进行了一项多队列、非随机、开放标签的1a/b期试验。我们招募了18岁或以上的成年患者，他们的组织学确诊为胃或胃食道交界处腺癌(A和B组)、非小细胞肺癌(C组)或尿路上皮癌(D组)，他们的疾病在以前的一到两个疗程(对于胃或胃-食道交界部腺癌)或一到三个先前的治疗(对于非小细胞肺癌和尿路上皮癌)的治疗下进展(对于所有的肿瘤类型)或氟嘧啶(对于胃或胃-食道交界腺癌)。资格标准包括是否存在可测量的疾病和东部合作肿瘤学小组的绩效状态为0-1。以前未经治疗的胃或胃食道交界部腺癌和非小细胞肺癌的患者也被纳入(在另外两个单独的队列中)；这些队列的结果将分别报告。第一个21天的治疗周期是剂量限制毒性观察期(1a阶段；安全磨合)，随后是1b阶段队列扩大阶段。培溴利珠单抗200 mg于第1天静脉注射，雷穆鲁单抗静脉滴注于第1、8天，A组为8 mg/kg，B、C、D组为10 mg/kg，每3周一次，直至达到疾病进展或其他停药标准。主要终点是Ramucirumab和Pembrolizumab联合使用的安全性和耐受性，通过1a和1b阶段的不良事件发生率和1a阶段的剂量限制毒性来评估。安全性和活动度分析集包括所有接受至少一剂研究治疗的患者。这项试验在ClinicalTrials.gov注册，编号NCT02443324，不再招募患者。2015年7月30日至2016年6月24日，我们招募并治疗了92名患者(41例胃或胃食道交界腺癌，27例非小细胞肺癌，24例尿路上皮癌)。中位随访时间为32.8个月(IQR 28.1~33.6)。在第一周期(1a期安全磨合；n=11)，1例胃-食管交界腺癌患者接受8 mg/kg的Ramucirumab治疗，出现3级腹痛、结肠炎、肝炎、间质性肺疾病、黄疸和4级胆汁淤积，并于治疗第40天死亡；死亡被认为与进展性疾病有关。没有发生额外的剂量限制毒性，并决定将Ramucirumab和Pembrolizumab的全部计划剂量维持在1b阶段(n=81)。92名患者中有75名(82%)发生了与治疗相关的不良事件，其中最常见的是疲劳(33名患者[36%])，主要是1级或2级严重程度。22名患者(24%)有一个或多个3级或更严重的与治疗相关的不良事件，最常见的是高血压(6名患者；7%)和结肠炎(5名患者；5%)。在92名患者中，53名(58%)发生了严重的不良事件，22名(24%)患者被认为与治疗有关。最常见的与治疗相关的严重不良事件是胃或胃-食道交界部腺癌患者的腹痛(3例[7%])，非小细胞肺癌患者的虚弱和心肌梗死(2例[7%])，尿路上皮癌患者的结肠炎(2例[8%])。92名患者中有6名(7%)因与治疗相关的不良事件而停止治疗，1名死亡(胃或胃-食道交界部腺癌患者死于肺部败血症)被认为与治疗有关。在41例胃或胃-食道交界区腺癌队列中，达到客观有效的患者数为3例(7%；95%可信区间1.5-19.9)，27例非小细胞肺癌队列中有8例(30%；13.8-50.2)，尿路上皮癌队列中有3例(13%，2.7-32.4)。解释Ramucirumab联合培溴珠单抗在先前治疗的晚期胃或胃-食道交界区腺癌、非小细胞肺癌和尿路上皮癌患者中显示出良好的抗肿瘤活性。我们的结果有助于提供越来越多的证据，支持对VEGF-VEGFR2和PD-1-PD-L1通路的双重抑制。无论有没有化疗，这种组合都可以进一步探索，特别是对于那些单剂检查点抑制剂没有显示出比化疗有额外好处的肿瘤患者。版权所有(C)2019爱思唯尔有限公司。保留所有权利。
Background Pre-clinical and clinical evidence suggests that simultaneous blockade of VEGF receptor-2 (VEGFR-2) and PD-1 or PD-L1 enhances antigen-specific T-cell migration, antitumour activity, and has favourable toxicity. In this study, we aimed to assess the safety and preliminary antitumour activity of ramucirumab (an IgG1 VEGFR-2 antagonist) combined with pembrolizumab (an IgG4 PD-1 antagonist) in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, or urothelial carcinoma.Methods We did a multicohort, non-randomised, open-label, phase 1a/b trial at 16 academic medical centres, hospitals, and clinics in the USA, France, Germany, Spain, and the UK. We enrolled adult patients aged 18 years or older with histologically confirmed gastric or gastro-oesophageal junction adenocarcinoma (cohorts A and B), non-small-cell lung cancer (cohort C), or urothelial carcinoma (cohort D), whose disease had progressed on one or two lines of previous therapy (for those with gastric or gastro-oesophageal junction adenocarcinoma) or one to three lines of previous therapy (for those with non-small-cell lung cancer and urothelial carcinoma) that included platinum (for all tumour types) or fluoropyrimidine or both (for gastric or gastro-oesophageal junction adenocarcinoma). Eligibility criteria included presence of measurable disease and an Eastern Cooperative Oncology Group performance status of 0-1. Patients with previously untreated gastric or gastro-oesophageal junction adenocarcinoma and non-small-cell lung cancer were also enrolled (in two additional separate cohorts); the results for these cohorts will be reported separately. The first 21-day treatment cycle was a dose-limiting toxicity observation period (phase 1a; safety run-in), followed by a phase 1b cohort expansion stage. Pembrolizumab 200 mg was administered intravenously on day 1, and intravenous ramucirumab was administered at 8 mg/kg on days 1 and 8 for cohort A or at 10 mg/kg on day 1 for cohorts B, C, and D, every 3 weeks, until disease progression or other discontinuation criteria were met. The primary endpoint was the safety and tolerability of ramucirumab in combination with pembrolizumab assessed by the incidence of adverse events in both phase 1a and 1b and as dose-limiting toxicities during phase 1a. The safety and activity analysis set included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02443324, and is no longer enrolling patients.Findings Between July 30, 2015 and June 24, 2016, we enrolled and treated 92 patients (41 with gastric or gastro-oesophageal junction adenocarcinoma, 27 with non-small-cell lung cancer, and 24 with urothelial carcinoma). Median follow-up was 32.8 months (IQR 28.1-33.6). During the first cycle of treatment (phase 1a safety run-in; n=11), one patient with gastro-oesophageal junction adenocarcinoma who received the 8 mg/kg dose of ramucirumab had grade 3 abdominal pain, colitis, hepatitis, interstitial lung disease, and jaundice, and grade 4 cholestasis, and died on treatment on day 40; the death was deemed related to progressive disease. No additional dose-limiting toxicities occurred and the decision was made to maintain the full planned doses of ramucirumab and pembrolizumab in phase 1b (n=81). Treatment-related adverse events occurred in 75 (82%) of 92 patients, the most common of which was fatigue (in 33 patients [36%]), predominantly of grade 1 or 2 severity. 22 patients (24%) had one or more treatment-related adverse events of grade 3 or worse, most commonly hypertension (six patients; 7%) and colitis (five patients; 5%). Serious adverse events occurred in 53 (58%) of 92 patients, and were deemed related to treatment in 22 (24%) patients. The most common treatment-related serious adverse events were abdominal pain in patients with gastric or gastro-oesophageal junction adenocarcinoma (in three [7%] of 41 patients); asthenia and myocardial infarction in patients with non-small-cell lung cancer (two [7%] of 27 patients), and colitis in patients with urothelial carcinoma (two [8%] of 24 patients). Six (7%) of 92 patients discontinued treatment because of treatment-related adverse events, and one death (from pulmonary sepsis in a patient with gastric or gastro-oesophageal junction adenocarcinoma) was deemed related to treatment. The number of patients achieving an objective response was three (7%; 95% CI 1.5-19.9) of 41 in the gastric or gastro-oesophageal junction adenocarcinoma cohort, eight (30%; 13.8-50.2) of 27 in the non-small-cell lung cancer cohort, and three (13%, 2.7-32.4) in the urothelial carcinoma cohort.Interpretation Ramucirumab in combination with pembrolizumab showed a manageable safety profile with favourable antitumour activity in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, and urothelial carcinoma. Our results contribute to the growing evidence that supports dual inhibition of the VEGF-VEGFR2 and PD-1-PD-L1 pathways. This combination could be further explored with or without chemotherapy, especially for patients with tumours for which single-agent checkpoint inhibitors have shown no additional benefit over chemotherapy. Copyright (C) 2019 Elsevier Ltd. All rights reserved.