Léna Hervé, Greillier Laurent, Cropet Claire, Bylicki Olivier, Monnet Isabelle, Audigier-Valette Clarisse, Falchero Lionel, Vergnenègre Alain, Demontrond Pierre, Geier Margaux, Guisier Florian, Hominal Stéphane, Locher Chrystèle, Corre Romain, Chouaid Christos, Ricordel Charles
Service de Pneumologie, Centre Hospitalier Universitaire de Rennes, Université Rennes 1, INSERM, UMR_S 1242, Centre Eugène Marquis, Rennes, France.
Multidisciplinary Oncology and Therapeutic Innovations, Aix-Marseille University, APHM, INSERM, CNRS, CRCM, Hôpital Nord, Marseille, France.
Lancet Respir Med. 2025 Feb;13(2):141-152. doi: 10.1016/S2213-2600(24)00264-9. Epub 2024 Oct 29.
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.
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/m intravenous infusion every 3 weeks] or carboplatin [on day 1; area under the curve ≤700 mg] plus paclitaxel [90 mg/m 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.
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.
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.
Bristol-Myers Squibb.
抗程序性死亡蛋白-1（PD-1）抗体与抗细胞毒性T淋巴细胞相关抗原4（CTLA-4）抗体联合治疗在晚期非小细胞肺癌（NSCLC）患者中已显示出优于化疗的效果，但对于东部肿瘤协作组（ECOG）体能状态为0-1的老年患者（年龄≥70岁）或ECOG体能状态为2的患者，相关数据较少。我们旨在测试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岁及以上或ECOG体能状态为2的NSCLC患者中优于铂类双联化疗的效果。
这项开放标签、多中心、随机、对照、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，无已知致癌改变，年龄为70岁及以上且ECOG体能状态为0-2，或年龄小于70岁且ECOG体能状态为2。患者通过计算机生成的算法进行中心随机分组（1:1），按年龄（<70岁与≥70岁）、ECOG体能状态（0-1与2）和组织学类型（鳞状与非鳞状）分层，接受纳武利尤单抗加伊匹木单抗或铂类双联化疗（卡铂[曲线下面积≤700mg]加培美曲塞[500mg/m²静脉输注，每3周一次]或卡铂[第1天；曲线下面积≤700mg]加紫杉醇[90mg/m²静脉输注，在第1、5和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性分析人群中进行，该人群包括所有随机分组的患者。安全性在安全性分析集中进行分析，该集合包括所有随机分组且接受至少一剂研究治疗并至少有一次安全性随访的患者。该试验已在ClinicalTrials.gov注册，注册号为NCT03351361。
在预期事件发生33%后，基于预先计划的中期分析，该试验因无效而提前终止。在2018年2月12日至2020年12月15日期间，217例患者被随机分组，其中216例患者纳入最终分析，纳武利尤单抗加伊匹木单抗组109例，化疗组107例；中位年龄为74岁（四分位间距70-78岁）。纳武利尤单抗加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ECOG体能状态为0-1的70岁及以上患者（中位年龄76岁[四分位间距73-79岁]）中，纳武利尤单抗加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的患者（中位年龄69岁[四分位间距63-75岁]）中，纳武利尤单抗加伊匹木单抗组的中位总生存期为2.9个月（95%CI 1.4-4.8），化疗组为6.1个月（3.5-10.4）（HR 1.32[95%CI 0.82-2.11]）。未报告新的安全信号。最常见的3级或更严重不良事件在化疗组为中性粒细胞减少（103例患者中的28例[27%]），在纳武利尤单抗加伊匹木单抗组为内分泌紊乱（105例患者中的5例[5%]）、心脏疾病（10例[10%]患者）和胃肠道疾病（11例[11%]患者）。
该研究显示纳武利尤单抗加伊匹木单抗联合治疗在总体研究人群中无益处。由于提前终止，该试验对于主要和次要终点的检验效能不足；然而，在ECOG体能状态为0-1的老年NSCLC亚组中，纳武利尤单抗加伊匹木单抗与铂类双联化疗相比生存期更好这一发现值得进一步研究。
百时美施贵宝公司。
