Prolonging Survival in Advanced Esophageal Squamous Cell Carcinoma With Immune Checkpoint Inhibitors

Abstract

Doki Y, Ajani A, Xu L, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med 2022;386:449–462. Prognosis among patients with advanced esophageal squamous cell cancer (SCC) receiving chemotherapy is poor, with life expectancy averaging less than 1 year. Treatment with nivolumab, an anti–programmed death-1 monoclonal antibody, has been found to prolong survival compared with chemotherapy in previously treated advanced esophageal SCC. In other solid tumors, the combination of nivolumab with ipilimumab (an anti–cytotoxic T-lymphocyte antigen 4 antibody) has been found to improve survival compared with chemotherapy or nivolumab alone. Checkmate-648 was a global, randomized, open-label phase 3 trial that evaluated the efficacy of nivolumab combination therapies compared with chemotherapy alone in advanced, incurable esophageal SCC. The primary end point was overall and progression-free survival, with subset analyses performed in patients with programmed death ligand 1 (PD-L1) expression ≥1%. The trial randomized 970 patients to receive nivolumab plus chemotherapy (constituting cisplatin and fluorouracil, n = 321), nivolumab plus ipilimumab (n = 325), or chemotherapy alone (n = 324). At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy compared with chemotherapy alone, in both patients with PD-L1 expression ≥1% (15.4 vs 9.1 months) and in the overall population (13.2 vs 10.7 months). Progression-free survival in patients with PD-L1 expression ≥1% was also longer with nivolumab plus chemotherapy compared with chemotherapy alone (6.9 vs 4.4 months). Similarly, the dual immune checkpoint inhibitor combination of nivolumab and ipilimumab improved survival compared with chemotherapy alone in both patients with PD-L1 expression ≥1% (13.7 vs 9.1 months) and in the overall population (12.7 vs 10.7 months), although there was no significant difference in progression-free survival. Treatment-related adverse events, leading to drug discontinuation, were higher with nivolumab plus chemotherapy (34%) than nivolumab plus ipilimumab (18%) and chemotherapy alone (19%). Health-related quality of life was maintained in all groups during the treatment period. In summary, first-line treatment with nivolumab-based regimens prolonged survival by 2.0–6.3 months in patients with advanced esophageal SCC compared with chemotherapy alone. However, the trial was not designed to examine differences between nivolumab plus chemotherapy vs nivolumab plus ipilimumab. Future studies should aim to address this, in addition to identifying key prognostic markers that will aid personalizing immunotherapy for patients with esophageal SCC. The results of ongoing studies evaluating the role of immune checkpoint inhibitors in the neoadjuvant setting of operable esophageal cancer are also awaited (ClinicalTrials.gov, Numbers: NCT03604991, NCT03399071, and NCT04592913).