First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles The Lancet Year : 2021

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial

1 UCM - Universidad Complutense de Madrid = Complutense University of Madrid [Madrid]
2 TOI - The Oncology Institute "Prof. Dr. Ion Chiricuţă" [Cluj-Napoca, Romania]
3 IBIMA Plataforma BIONAND - Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina = Biomedical Research Institute of Málaga and Nanomedicine Platform
4 SF Nectarie Oncology Center [Craiova, Romania]
5 AC - Ambulatorium Chemioterapii [Bydgoszcz, Poland]
6 HNSDC - Hospital Nossa Senhora Da Conceição [Porto Alegre, Brazil]
7 IODC - Instituto Oncológico De Córdoba [Córdoba, Argentina]
8 CRCINA-ÉQUIPE 4 - Immunogenic Cell Death and Mesothelioma Therapy
9 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
10 VHIO - Vall d'Hebron Institute of Oncology [Barcelone]
11 Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe
12 OIB - Oncology Institute of Bucharest Professor Doctor Alexandru Trestioreanu [Bucharest, Romania]
13 S2C - Saitama Cancer Center [Saitama, Japan]
14 IMRC - Instituto Medico Rio Cuarto SA [Córdoba, Argentina]
15 FALP - Fundacion Arturo Lopez Perez [Santiago, Metropolitana, Chile]
16 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
17 Barretos Cancer Hospital [São Paulo, Brazil]
18 IAF - Instituto Alexander Fleming [Buenos Aires, Argentina]
19 Centre Léon Bérard [Lyon]
20 OncoThAI - Thérapies Assistées par Lasers et Immunothérapies pour l'Oncologie - U 1189
21 Université de Lille
22 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
23 Shanghai Jiao Tong University [Shanghai]
24 Austin Hospital [Melbourne]
25 OSU - Ohio State University [Columbus]
26 Bristol-Myers Squibb [Princeton]
27 German Center for Lung Research
Martin Reck

Abstract

Background: First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit. Methods: This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov, number NCT03215706. Findings: Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related. Interpretation: Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC. Funding: Bristol Myers Squibb.

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Cancer
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inserm-03349944 , version 1 (21-09-2021)

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Luis Paz-Ares, Tudor-Eliade Ciuleanu, Manuel Cobo, Michael Schenker, Bogdan Zurawski, et al.. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. The Lancet, 2021, 22 (2), pp.198-211. ⟨10.1016/S1470-2045(20)30641-0⟩. ⟨inserm-03349944⟩
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