Esophagus to Small Intestine

N Engl J Med. 2022;386(5):449–62

Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators

Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma

Background: First-line chemotherapy for advanced esophageal squamous-cell carcinoma (ESCC) results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival (OS) benefit over chemotherapy in previously treated patients with advanced ESCC.
Methods: In this open-label, phase 3 trial, the authors randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were OS and progression-free survival (PFS), 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% 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, OS was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of ≥ 1% (median, 15.4 vs. 9.1 months; hazard ratio [HR] = 0.54; 99.5% confidence interval [CI]: 0.37–0.80; p < 0.001) and in the overall population (median, 13.2 vs. 10.7 months; HR = 0.74; 99.1% CI: 0.58–0.96; p = 0.002). OS was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of ≥ 1% (median, 13.7 vs. 9.1 months; HR = 0.64; 98.6% CI: 0.46–0.90; p = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; HR = 0.78; 98.2% CI: 0.62–0.98; p = 0.01). Among patients with tumor-cell PD-L1 expression of ≥ 1%, a significant PFS benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (HR for disease progression or death = 0.65; 98.5% CI: 0.46–0.92; 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.

DOI:  DOI: 10.1056/NEJMoa2111380