编译：孙莉
来源：桓兴医讯
背景（Background）
以铂类为基础的化疗失败后，小细胞肺癌的治疗选择有限。我们对经过一个或更多方案治疗后进展的小细胞肺癌患者，评估行纳武单抗治疗与纳武单抗联合伊匹单抗治疗的安全性及有效性。
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.
方法（Methods）
在6个国家23家站点（学术医疗中心与医院）进行了这项小细胞肺癌队列多中心、多臂、开放标签、I/II期试验。符合条件的患者为：≥18岁、局限期或广泛期小细胞肺癌、至少先前一个含铂类方案治疗后疾病进展。患者接受纳武单抗（3mg/Kg，静脉给药）每两周一次（直至疾病进展或无法耐受毒性反应），或纳武单抗联合伊匹单抗（1mg/Kg联合1mg/Kg、1mg/Kg联合3mg/Kg、或3mg/Kg联合1mg/Kg，静脉给药）每三周一次，共4个周期，随后给予纳武单抗3mg/Kg 每两周一次。将患者随机分配至纳武单抗单药治疗组或者在纳武单抗联合伊匹单抗剂量递增的安全阶段评估，纳武单抗1mg/Kg联合伊匹单抗1mg/Kg起始。根据耐受性，随后将患者分配至纳武单抗1mg/Kg联合伊匹单抗3mg/Kg组或纳武单抗3mg/Kg联合伊匹单抗1mg/Kg组。主要终点是研究人员评估的客观缓解。所有分析纳入了数据库锁定之前90天以上入组的患者。这项试验仍在进行。在此，我们报告小细胞肺癌队列一项中期分析结果。这项研究在ClinicalTrials.gov注册，注册号NCT01928394。
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.
结果（Findings）
2013年11月18日至2015年7月28日，共216名患者入组治疗（98名患者纳武单抗3mg/Kg，3名患者纳武单抗1mg/Kg联合伊匹单抗1mg/Kg,61名患者纳武单抗1mg/Kg联合伊匹单抗3mg/Kg,54名患者纳武单抗3mg/Kg联合伊匹单抗1mg/Kg）。2015年11月6日数据库锁定时，患者在继续研究（包括死亡或终止治疗的患者）中，纳武单抗3mg/Kg组中位随访时间198.5天（IQR163.0-464.0），纳武单抗1mg/Kg联合伊匹单抗1mg/Kg组中位时间302天（IQR不可计算），纳武单抗1mg/Kg联合伊匹单抗3mg/Kg组中位时间361.0天（273.0-470.0），纳武单抗3mg/Kg联合伊匹单抗1mg/Kg组中位时间260.5天（248.0-288.0）。98名接受纳武单抗3mg/Kg的患者中有10名（10%）达到客观缓解，3名接受纳武单抗1mg/Kg联合伊匹单抗1mg/Kg的患者中有1名（33%），61名接受纳武单抗1mg/Kg联合伊匹单抗3mg/Kg的患者中有14名（23%），54名接受纳武单抗3mg/Kg联合伊匹单抗1mg/Kg的患者中有10名（19%）。纳武单抗3mg/Kg队列中发生13例（13%）3或4级治疗相关不良事件，纳武单抗1mg/Kg联合伊匹单抗3mg/Kg队列中有18例（30%），纳武单抗3mg/Kg联合伊匹单抗1mg/Kg队列中有10例（19%）；最常见报道的3或4级治疗相关不良事件是脂肪酶升高（分别是：没有、5例[8%]和没有）、腹泻（分别是：没有、3例[5%]和1例[2%]）。纳武单抗1mg/Kg联合伊匹单抗1mg/Kg患者队列中无3或4级治疗相关不良事件。纳武单抗3mg/Kg组中6名（6%）患者、纳武单抗1mg/Kg联合伊匹单抗3mg/Kg组中7名（11%）、纳武单抗3mg/Kg联合伊匹单抗1mg/Kg组中4名（7%）分别因为治疗相关不良反应而终止治疗。2名接受纳武单抗1mg/Kg联合伊匹单抗3mg/Kg治疗的患者死于治疗相关不良反应（重症肌无力和肾衰竭恶化），1名接受纳武单抗3mg/Kg联合伊匹单抗1mg/Kg治疗的患者死于治疗相关肺炎。
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.
推论（Interpretation）
在既往治疗过的小细胞肺癌患者中，纳武单抗单药治疗与纳武单抗联合伊匹单抗治疗显示出具有持久的抗肿瘤活性和可控的安全性。这些数据表明，对治疗选择有限的患者群，这可能是一有潜力的新的治疗方案，并且这些数据支持在小细胞肺癌患者中进行III期随机对照试验，以对纳武单抗和纳武单抗联合伊匹单抗进行评价。
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.
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