Nivolumab plus ipilimumab versus carboplatin-based doublet as first-line treatment for patients with advanced non-small-cell lung cancer aged ≥70 years or with an ECOG performance status of 2 (GFPC 08-2015 ENERGY): a randomised, open-label, phase 3 study.

We aimed to test the superiority of the PD-1 antibody nivolumab and the CTLA-4 antibody ipilimumab over platinum-based doublet chemotherapy as first-line treatment in patients with NSCLC aged 70 years or older or with an ECOG performance status of 2.

我们的目标是测试PD-1抗体纳武利尤单抗和CTLA-4抗体伊匹木单抗作为一线治疗在70岁或以上年龄的NSCLC患者或ECOG表现状态为2的患者中相对于基于铂的双药化疗的优越性。

Methods

This open-label, multicentre, randomised, controlled, phase 3 trial was done at 30 hospitals and cancer centres in France.

这是一项开放标签、多中心、随机对照的III期临床试验，在法国的30家医院和癌症中心进行。

Eligible patients had stage IV histologically proven NSCLC, with no known oncogenic alterations, and were either aged 70 years or older with ECOG performance status of 0-2 or younger than 70 years with an ECOG performance status of 2.

符合条件的患者患有IV期组织学证实的非小细胞肺癌（NSCLC），没有已知的肿瘤驱动基因改变，并且年龄要么是70岁或以上且ECOG体能状态评分为0-2，要么是小于70岁且ECOG体能状态评分为2。

Patients were randomly assigned (1:1) centrally, using a computer-generated algorithm stratified by age (<70 vs ≥70 years), ECOG performance status (0-1 vs 2), and histology (squamous vs non-squamous) to receive nivolumab plus ipilimumab or platinum-based doublet chemotherapy (carboplatin [area under the curve ≤700 mg] plus pemetrexed [500 mg/m2 intravenous infusion every 3 weeks] or carboplatin [on day 1; area under the curve ≤700 mg] plus paclitaxel [90 mg/m2 as intravenous infusion on days 1, 5, and 15, every 4 weeks]).

患者被随机分配（1:1），使用计算机生成的算法，根据年龄（<70岁与≥70岁）、ECOG表现状态（0-1与2）和组织学类型（鳞状与非鳞状）进行分层，接受纳武利尤单抗加伊匹木单抗或基于铂的双药化疗（卡铂[曲线下面积≤700 mg]加培美曲塞[500 mg/m2静脉输注，每3周一次]或卡铂[第1天；曲线下面积≤700 mg]加紫杉醇[每4周一次，第1、5、15天静脉输注90 mg/m2]）。

The primary endpoint was overall survival; secondary endpoints included progression-free survivaland safety.

主要终点是总生存期；次要终点包括无进展生存期和安全性。

All efficacy analyses were performed in the intention-to-treatpopulation, which included all randomly assigned patients.

所有疗效分析均在意向治疗人群中进行，该人群包括所有随机分配的患者。

Safety was analysed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study treatment and who had at least one safety follow-up.

安全性分析在安全性分析集中进行，该集包括所有随机分配的患者，这些患者至少接受了一次研究治疗，并且至少有一次安全随访。

The trial is registered with ClinicalTrials.gov, NCT03351361.

该试验已在ClinicalTrials.gov注册，注册号为NCT03351361。

Results

The trial was stopped early for futility on the basis of a pre-planned interim analysis after 33% of the expected events had occurred.

基于预先计划的中期分析，在预期事件发生33%后，该试验因无效而提前终止。

Between Feb 12, 2018, and Dec 15, 2020, 217 patients were randomly assigned, of whom 216 patients were included in the final analysis, with 109 patients in the nivolumab plus ipilimumab group and 107 in the chemotherapy group; median age was 74 years (IQR 70-78).

2018年2月12日至2020年12月15日期间，共有217名患者被随机分配，其中216名患者被纳入最终分析，其中109名患者在纳武单抗联合伊匹木单抗组，107名在化疗组；中位年龄为74岁（四分位数间距70-78岁）。

Median overall survivalwas 14·7 months (95% CI 8·0-19·7) in the nivolumab plus ipilimumab group and 9·9 months (7·7-12·3) in chemotherapy group (hazard ratio[HR] 0·85 [95% CI 0·62-1·16]).

纳武单抗联合伊匹木单抗组的中位总生存期为14.7个月（95%置信区间8.0-19.7），化疗组为9.9个月（7.7-12.3）（风险比[HR] 0.85 [95%置信区间0.62-1.16]）。

Among patients aged 70 years or older with an ECOG performance status of 0-1 (median age 76 years [IQR 73-79]), median overall survivalwas longer in the nivolumab plus ipilimumab group than the chemotherapy group: 22·6 months (95% CI 18·1-36·0) versus 11·8 months (8·9-20·5; HR 0·64 [95% CI 0·46-0·96]).

在年龄≥70岁且ECOG表现状态为0-1的患者中（中位年龄76岁，四分位数间距73-79岁），纳武利尤单抗联合伊匹木单抗组的中位总生存期长于化疗组：22.6个月（95%置信区间18.1-36.0）对比11.8个月（8.9-20.5；风险比0.64 [95%置信区间0.46-0.96]）。

Among patients with an ECOG performance status of 2 (median age 69 years [IQR 63-75]), median overall survivalwas 2·9 months (95% CI 1·4-4·8) in the nivolumab plus ipilimumab group versus 6·1 months (3·5-10·4) in the chemotherapy group (HR 1·32 [95% CI 0·82-2·11]).

在ECOG表现状态为2的患者中（中位年龄69岁，四分位数间距63-75岁），纳武利尤单抗联合伊匹木单抗组的中位总生存期为2.9个月（95%置信区间1.4-4.8），而化疗组为6.1个月（3.5-10.4；风险比1.32 [95%置信区间0.82-2.11]）。

No new safety signals were reported.

未报告新的安全信号。

The most frequent grade 3 or worse adverse events were neutropenia (28 [27%] of 103 patients) in the chemotherapy group and endocrine disorders (five [5%] of 105 patients), cardiac disorders (ten [10%] patients), and gastrointestinal disorders (11 [11%] patients) in the nivolumab plus ipilimumab group.

化疗组中最常见的3级或更严重的不良事件是中性粒细胞减少症（103名患者中有28例[27%]），而在纳武单抗联合伊匹木单抗组中最常见的3级或更严重的不良事件是内分泌疾病（105名患者中有五例[5%]）、心脏疾病（十例[10%]患者）和胃肠道疾病（11例[11%]患者）。

interpretation

The study showed no benefit of nivolumab plus ipilimumab combination in the overall study population.

该研究显示，在整个研究人群中，纳武利尤单抗联合伊匹木单抗的组合疗法并无益处。

As a result of early stopping, the trial was underpowered for primary and secondary endpoints; however, the finding of better survival with nivolumab plus ipilimumab compared with platinum doublet in the subgroup of older patients with NSCLC with an ECOG performance status of 0-1 warrants further study.

由于早期停止试验，该试验对于主要和次要终点的统计功效不足；然而，在非小细胞肺癌老年患者亚组中，与铂类双药化疗相比，纳武利尤单抗联合伊匹木单抗显示出更好的生存率，其中老年患者的ECOG表现状态为0-1，这一发现值得进一步研究。

funding

Bristol-Myers Squibb.

百时美施贵宝。