• Luis Paz-Ares, Tudor-Eliade Ciuleanu, Manuel Cobo, Michael Schenker, Bogdan Zurawski, Juliana Menezes, Eduardo Richardet, Jaafar Bennouna, Enriqueta Felip, Oscar Juan-Vidal, Aurelia Alexandru, Hiroshi Sakai, Alejo Lingua, Pamela Salman, SouquetPierre-JeanPJHôpital Lyon Sud, Lyon, Pierre Bénite, France., Pedro De Marchi, Claudio Martin, Maurice Pérol, Arnaud Scherpereel, Shun Lu, Thomas John, David P Carbone, Stephanie Meadows-Shropshire, Shruti Agrawal, Abderrahim Oukessou, Jinchun Yan, and Martin Reck.
• Hospital Universitario 12 de Octubre, CNIO-H12o Lung Cancer Unit, Universidad Complutense & CiberOnc, Madrid, Spain. Electronic address: lpazaresr@seom.org.
• Lancet Oncol. 2021 Feb 1; 22 (2): 198-211.

BackgroundFirst-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.MethodsThis 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.FindingsBetween 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.InterpretationNivolumab 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.FundingBristol Myers Squibb.Copyright © 2021 Elsevier Ltd. All rights reserved.

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