Yuichiro Doki1, Jaffer A Ajani1, Ken Kato1, Jianming Xu1, Lucjan Wyrwicz1, Satoru Motoyama1, Takashi Ogata1, Hisato Kawakami1, Chih-Hung Hsu1, Antoine Adenis1, Farid El Hajbi1, Maria Di Bartolomeo1, Maria I Braghiroli1, Eva Holtved1, Sandra A Ostoich1, Hye R Kim1, Masaki Ueno1, Wasat Mansoor1, Wen-Chi Yang1, Tianshu Liu1, John Bridgewater1, Tomoki Makino1, Ioannis Xynos1, Xuan Liu1, Ming Lei1, Kaoru Kondo1, Apurva Patel1, Joseph Gricar1, Ian Chau1, Yuko Kitagawa1. 1. From Osaka University Graduate School of Medicine, Osaka (Y.D., T.M.), National Cancer Center Hospital (K. Kato), Toranomon Hospital (M.U.), and Keio University School of Medicine (Y.K.), Tokyo, Akita University Hospital, Akita (S.M.), Kanagawa Cancer Center, Kanagawa (T.O.), and Kindai University Faculty of Medicine, Osakasayama (H.K.) - all in Japan; University of Texas M.D. Anderson Cancer Center, Houston (J.A.A.); Fifth Medical Center, Chinese PLA General Hospital, Beijing (J.X.), and Zhongshan Hospital, Fudan University, Shanghai (T.L.); Klinika Onkologii i Radioterapii, Narodowy Instytut Onkologii, Warsaw, Poland (L.W.); National Taiwan University Hospital, Taipei (C.-H.H.), and E-Da Hospital and I-Shou University, Kaohsiung (W.-C.Y.) - both in Taiwan; Institut de Recherche en Cancérologie de Montpellier, INSERM, Université Montpellier, Institut du Cancer de Montpellier, Montpellier (A.A.), and Centre Oscar Lambret, Lille (F.E.H.) - both in France; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (M.D.B.); Institute of Cancer of São Paulo, University of São Paulo, São Paulo (M.I.B.); Odense University Hospital, Odense, Denmark (E.H.); Hospital Provincial del Centenario, Rosario, Argentina (S.A.O.); the Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea (H.R.K.); the Christie NHS Foundation Trust, Manchester (W.M.), the UCL Cancer Institute, University College London, London (J.B.), and the Royal Marsden Hospital (Surrey), Sutton (I.C.) - all in the United Kingdom; and Bristol Myers Squibb, Princeton, NJ (I.X., X.L., M.L., K. Kondo, A.P., J.G.).
Abstract
BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. CONCLUSIONS: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).
BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. CONCLUSIONS: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).