Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial
Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial
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DOI：
10.1016/s1470-2045(16)30098-5
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发表时间：
2016-07-01
期刊：
影响因子：
51.1
通讯作者：
Calvo, Emiliano
中科院分区：
文献类型：
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作者：
Antonia, Scott J.;Lopez-Martin, Jose A.;Calvo, Emiliano
背景铂类化疗失败后小细胞肺癌（SCLC）的治疗是有限的。我们评估了nivolumab和nivolumab加ipilimumab在SCLC患者中的安全性和活性，这些患者在一个或多个先前的regiments.Methods后进展，该1/2期多中心，多臂，开放标签试验的SCLC队列在6个国家的23个站点（学术中心和医院）进行。符合条件的患者年龄≥ 18岁，患有局限期或广泛期SCLC，并且在至少一种既往含铂方案后发生疾病进展。患者每2周接受纳武单抗（静脉内3 mg/kg体重）（给予直至疾病进展或不可接受的毒性），或每3周接受纳武单抗加伊匹单抗（静脉内lmg/kg加lmg/kg、lmg/kg加3 mg/kg或3 mg/kg加lmg/kg），持续4个周期，随后每2周接受纳武单抗3 mg/kg。将患者分配至nivolumab单一疗法或在nivolumab/ipilimumab组合的剂量递增安全性阶段中评估，所述nivolumab/ipilimumab组合从nivolumab lmg/kg加ipilimumab lmg/kg开始。根据耐受性，然后将患者分配至nivolumab 1 mg/kg + ipilimumab 3 mg/kg或nivolumab 3 mg/kg + ipilimumab 1 mg/kg。主要终点是研究者评估的客观缓解。所有分析均包括在数据库锁定前至少90天入组的患者。这项试验正在进行中;在这里，我们报告了SCLC队列的中期分析。在2013年11月18日至2015年7月28日期间，招募并治疗了216名患者（98名患者接受nivolumab 3 mg/kg治疗，3名患者接受nivolumab 1 mg/kg + ipilimumab 1 mg/kg治疗，61名患者接受nivolumab 1 mg/kg + ipilimumab 3 mg/kg治疗，54名患者接受nivolumab 3 mg/kg + ipilimumab 1 mg/kg治疗）。ClinicalTrials.gov 2015年11月6日数据库锁定时，继续参与研究的患者的中位随访时间（包括死亡或停止治疗的患者）为198.5天（IQR 163.0-464.0）nivolumab 3 mg/kg，302天（IQR不可计算）纳武单抗1 mg/kg+伊匹单抗1 mg/kg，361.0天对于纳武单抗1 mg/kg加伊匹单抗3 mg/kg，为273.0-470.0天，对于纳武单抗3 mg/kg加伊匹单抗1 mg/kg，为260.5天（248.0-288.0天）。在接受纳武单抗3 mg/kg的98名患者中的10名（10%）、接受纳武单抗1 mg/kg加伊匹单抗1 mg/kg的3名患者中的1名（33%）、接受纳武单抗1 mg/kg加伊匹单抗3 mg/kg的61名患者中的14名（23%）和接受纳武单抗3 mg/kg加伊匹单抗1 mg/kg的54名患者中的10名（19%）中实现客观应答。3级或4级治疗相关不良事件发生在纳武单抗3 mg/kg组中的13名（13%）患者中，在纳武单抗1 mg/kg加伊匹单抗3 mg/kg组中的18名（30%）患者中，以及在纳武单抗3 mg/kg加伊匹单抗1 mg/kg组中的10名（19%）患者中;最常报告的3级或4级治疗相关不良事件为脂肪酶升高（无vs 5例[8%] vs无）和腹泻（无vs 3例[5%] vs 1例[2%]）。纳武单抗1 mg/kg加伊匹单抗1 mg/kg队列中没有患者发生3级或4级治疗相关不良事件。nivolumab 3 mg/kg组中有6名（6%）患者，nivolumab 1 mg/kg + ipilimumab 3 mg/kg组中有7名（11%）患者，nivolumab 3 mg/kg + ipilimumab 1 mg/kg组中有4名（7%）患者因治疗相关不良事件而停止治疗。两名接受nivolumab 1 mg/kg + ipilimumab 3 mg/kg的患者死于治疗相关不良事件（重症肌无力和肾衰竭恶化），1名接受nivolumab 3 mg/kg加ipilimumab 1 mg/kg的患者死于治疗-解释纳武单抗单一疗法和纳武单抗加伊匹单抗显示抗肿瘤活性，在先前治疗的患有肺炎的患者中具有持久的应答和可管理的安全性概况。SCLC。这些数据表明，对于治疗选择有限的患者人群，可能存在一种新的治疗方法，并支持在SCLC的3期随机对照试验中评估nivolumab和nivolumab + ipilimumab。
Background Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens.Methods The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394.Findings Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198.5 days (IQR 163.0-464.0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361.0 days (273.0-470.0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260.5 days (248.0-288.0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis.Interpretation Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC.