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SCI 19 July 2019 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
Background 背景 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. 临床前和临床证据表明，同时阻断VEGF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、抗肿瘤活性，并具有较低的毒性。我们此项研究的目的是评估ramucirumab (IgG1 VEGFR-2拮抗剂)联合pembrolizumab (IgG4 PD-1拮抗剂)在经治的晚期胃或胃食管交界腺癌、NSCLC或尿路上皮癌患者中的安全性和初步抗肿瘤活性。 Methods 方法 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. 我们在美国、法国、德国、西班牙和英国的16个学术医疗中心、医院和诊所进行了多队列、非随机、开放标签、1a/b期试验。我们招募了组织学证实为胃或胃食管交界腺癌(A组和B组)、NSCLC(C组)或尿路上皮癌(D组)的 18岁或以上的成年患者，他们先前接受过一线或二线治疗(胃或胃食管交界腺癌)或一至三线治疗(NSCLC和尿路上皮癌),且这些治疗方案中包括铂类(所有肿瘤类型)或fluoropyrimidine或两者均有(胃或胃食管交界腺癌)。入选标准包括未可估测疾病和东部肿瘤合作组评分为0到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. 先前未经治疗的胃或胃食管交界腺癌和NSCLC患者也被纳入研究(在另外两个单独的队列中);这些队列的结果将另行报告。第一个21天的治疗周期是剂量限制毒性的观察期(1a期;)，然后是1b期的队列扩展阶段。Pembrolizumab为第1天静脉注射200毫克, ramucirumab为A组第1天和第8天分别以8mg/kg的剂量静脉注射，B组第1天以10mg/kg的速度静脉注射，B组、C组和D组每3周注射一次。 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. 主要终点是ramucirumab联合pembrolizumab的安全性和耐受性，这将通过1a期和1b期不良事件的发生率以及1a期的剂量限制毒性来评估。对所有接受至少一剂药物进行研究治疗的患者进行安全性和活动分析。该试验已在ClinicalTrials.gov上注册，编号为NCT02443324，已不再登记患者。 Findings 结果 Between July 30, 2015 and June 24, 2016, we enrolled and treated 92 patients (41 with gastric or gastrooesophageal 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. 我们于2015年7月30日至2016年6月24日，登记并治疗92例患者(41例为胃或胃食管交界腺癌，27例为NSCLC，24例为尿路上皮癌)。中位随访32.8个月(IQR 28.1-33.6)。在治疗的第一个周期(1a期;n=11) 1例胃食管交界腺癌患者接受8 mg/kg剂量的ramucirumab后，出现3级安全性事件包括腹痛、结肠炎、肝炎、间质性肺病、黄疸和4级安全新事件胆汁淤积，后于治疗第40天死亡;死亡被认为与疾病进展有关。 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. 没有发生其他的剂量限制毒性，因此决定在1b期将维持ramucirumab和pembrolizumab的全部计划剂量 (n=81)。92例患者中有75例(82%)发生治疗相关不良事件，最常见的是疲劳(33例[36%])，主要为1级或2级的严重程度。22例患者(24%)有至少1种治疗相关的3级或更严重的不良事件，最常见的是高血压(6例;7%)及结肠炎(5例;5%)。92例患者中53例(58%)发生严重不良事件，22例(24%)被认为与治疗有关。 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. 最常见的与治疗相关的严重不良事件是胃或胃食管交界腺癌患者的腹痛(41例患者中有3例[7%]);NSCLC(27例中有2例[7%])和尿路上皮癌(24例中有2例[8%])患者出现虚弱和心肌梗死。92例患者中有6例(7%)因治疗相关的不良事件而停止治疗，1例死亡(胃或胃食管交界腺癌患者出现肺脓毒血症)被认为与治疗有关。 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. 41例胃或胃食管交界腺癌患者中有3例(7%; 95% CI 1.5–19.9) 达到客观反应，27例NSCLC患者中有8例(30%, 13.8-50.2)，尿路上皮癌组有3例(13%, 2.7–32.4)达到。 Interpretation 意义 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. Ramucirumab联合pembrolizumab在经治的晚期胃或胃食管交界腺癌、NSCLC和尿路上皮癌患者中显示出可控的安全性，且具有良好的抗肿瘤活性。 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. 我们的研究结果为支持同时抑制VEGF-VEGFR2和PD-1-PD-L1通路的疗法提供了更多的证据。无论化疗与否，这种联合疗法都可以进一步探究，特别是对于那些单药检查点抑制剂在化疗中没有额外获益的肿瘤患者。 喜欢SCI天天读的理由 陪您一起学习SCI医学论文 每天5分钟，让自己的英语牛逼起来 特殊福利让您惊喜连连 |
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