Background

Combined treatment with anti-PD-1 and anti-CTLA-4 antibodies has shown superiority over chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC), but data for older patients (aged ≥70 years) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 or those with an ECOG performance status of 2 are scarce. 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.

Methods

This open-label, multicentre, randomised, controlled, phase 3 trial was done at 30 hospitals and cancer centres in France. 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. 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]). The primary endpoint was overall survival; secondary endpoints included progression-free survival and safety. All efficacy analyses were performed in the intention-to-treat population, which included all randomly assigned patients. 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. The trial is registered with ClinicalTrials.gov, NCT03351361.

Findings

The trial was stopped early for futility on the basis of a pre-planned interim analysis after 33% of the expected events had occurred. 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). Median overall survival was 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]). Among patients aged 70 years or older with an ECOG performance status of 0–1 (median age 76 years [IQR 73–79]), median overall survival was 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]). Among patients with an ECOG performance status of 2 (median age 69 years [IQR 63–75]), median overall survival was 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]). No new safety signals were reported. 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.

Interpretation

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

Funding

Bristol-Myers Squibb.

中文翻译：

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纳武利尤单抗加伊匹木单抗与基于卡铂的双药作为年龄≥ 或 ECOG 体能状态为 2 的晚期非小细胞肺癌患者的一线治疗 （GFPC 08–2015 ENERGY）：一项随机、开放标签的 3 期研究

 背景

在晚期非小细胞肺癌 （NSCLC） 患者中，抗 PD-1 和抗 CTLA-4 抗体的联合治疗优于化疗，但东部肿瘤合作组 （ECOG） 体能状态为 0-1 或 ECOG 体能状态为 2 的老年患者（≥70 岁）的数据很少。我们旨在测试 PD-1 抗体纳武利尤单抗和 CTLA-4 抗体 ipilimumab 作为 70 岁或以上或 ECOG 体能状态为 2 的 NSCLC 患者作为一线治疗的铂类双药化疗的优越性。

 方法

这项开放标签、多中心、随机、对照的 3 期试验在法国的 30 家医院和癌症中心进行。符合条件的患者患有经组织学证实的 IV 期 NSCLC，没有已知的致癌改变，年龄在 70 岁或以上，ECOG 体能状态为 0-2 岁，或小于 70 岁，ECOG 体能状态为 2。患者被随机分配 （1：1） 集中分配，使用按年龄 （<70 vs ≥70 岁）、ECOG 体能状态 （0-1 vs 2） 和组织学 （鳞状细胞与非鳞状细胞） 分层的算法，接受纳武利尤单抗加伊匹木单抗或铂类双药化疗（卡铂 [曲线下面积 ≤700 mg] 加培美曲塞 [500 mg/m²每 3 周静脉输注一次] 或卡铂 [第 1 天;曲线下面积 ≤700 mg] 加紫杉醇 [90 mg/m² 静脉输注，第 1 天、第 5 天和第 15 天，每 4 周一次]）。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。所有疗效分析均在意向治疗人群中进行，其中包括所有随机分配的患者。在安全性分析集中分析了安全性，其中包括所有随机分配的患者，这些患者接受了至少一剂研究治疗并且至少接受了一次安全性随访。该试用版已在 ClinicalTrials.gov NCT03351361注册。

 发现

在 33% 的预期事件发生后，根据预先计划的中期分析，该试验因无效而提前停止。2018 年 2 月 12 日至 2020 年 12 月 15 日期间，随机分配 217 例患者，其中 216 例患者纳入最终分析，其中纳武利尤单抗联合伊匹木单抗组 109 例，化疗组 107 例;中位年龄为 74 岁 （IQR 70-78）。纳武利尤单抗联合伊匹木单抗组的中位总生存期为 14·7 个月 （95% CI 8·0-19·7），化疗组为 9·9 个月 （7·7-12·3） （风险比 [HR] 0·85 [95% CI 0·62-1·16]）。在 70 岁或以上且 ECOG 体能状态为 0-1 （中位年龄 76 岁 [IQR 73-79]）的患者中，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% CI 18·1-36·0） 对 11·8 个月 （8·9-20·5;HR 0·64 [95% CI 0·46–0·96]）。在 ECOG 体能状态为 2 岁（中位年龄 69 岁 [IQR 63-75]）的患者中，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% CI 1·4-4·8），而化疗组为 6·1 个月 （3·5-10·4） （HR 1·32 [95% CI 0·82-2·11]）。没有报告新的安全信号。最常见的 3 级或更严重的不良事件是化疗组的中性粒细胞减少症（103 例患者中有 28 例 [27%]）和内分泌疾病（105 例患者中有 5 例 [5%]）、心脏疾病（10 例 [10%] 患者）和胃肠道疾病（11 例 [11%] 患者）在纳武利尤单抗加伊匹木单抗组中。

 解释

该研究表明，纳武利尤单抗加 ipilimumab 组合对整个研究人群没有益处。由于提前停止，该试验的主要和次要终点把握度不足;然而，在 ECOG 体能状态为 0-1 的老年 NSCLC 患者亚组中，与铂类双药相比，纳武利尤单抗联合伊匹木单抗的生存率更高，值得进一步研究。

 资金

 百时美施贵宝。