Doki, Yuichiro; Ajani, Jaffer A; Kato, Ken; Xu, Jianming; Wyrwicz, Lucjan; Motoyama, Satoru; Ogata, Takashi; ... CheckMate 648 Trial Investigators; + view all Doki, Yuichiro; Ajani, Jaffer A; Kato, Ken; Xu, Jianming; Wyrwicz, Lucjan; Motoyama, Satoru; Ogata, Takashi; Kawakami, Hisato; Hsu, Chih-Hung; Adenis, Antoine; El Hajbi, Farid; Di Bartolomeo, Maria; Braghiroli, Maria I; Holtved, Eva; Ostoich, Sandra A; Kim, Hye R; Ueno, Masaki; Mansoor, Wasat; Yang, Wen-Chi; Liu, Tianshu; Bridgewater, John; Makino, Tomoki; Xynos, Ioannis; Liu, Xuan; Lei, Ming; Kondo, Kaoru; Patel, Apurva; Gricar, Joseph; Chau, Ian; Kitagawa, Yuko; CheckMate 648 Trial Investigators; - view fewer (2022) Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. New England Journal of Medicine , 386 (5) pp. 449-462. 10.1056/NEJMoa2111380.

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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.).

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