For decades, despite the poor survival outcomes, the standard treatment for advanced or metastatic esophageal squamous-cell carcinoma was based on chemotherapy (i.e. fluoropyrimidine plus platinum). However, significant clinical benefit was recently reported with programmed death 1 (PD-1) inhibitors in combination with chemotherapy over chemotherapy alone.
On February 3, CheckMate 648 trial (NCT03143153) was published in the New England Journal of Medicine; this randomized, open-label, phase 3 trial randomly assigned patients with unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma to receive nivolumab 240 mg/q2w plus chemotherapy (consisting of a 4-week cycle of fluorouracil 800 mg/m² on days 1 through 5 and cisplatin 80 mg/m² on day 1); nivolumab 3 mg/kg/q2w plus ipilimumab 1 mg/kg/q6w; or chemotherapy alone. Treatment continued until disease progression, unacceptable toxic effects, withdrawal of consent, or the end of the trial. Patients could receive immunotherapy for a maximum of 2 years. The primary end points were overall survival (OS) and progression-free survival (PFS), as determined by blinded independent central review. Hierarchical testing was performed first in patients with PD-L1 positive (expression of 1% or greater) and then in the overall population.
A total of 970 patients underwent randomization. Demographic and baseline clinical characteristics were balanced across groups in the overall population and in patients with tumor-cell PD-L1 ≥ 1%. Most of the patients (70%) were from Asian countries, and 49% had PD-L1 ≥ 1%. The primary reason for treatment discontinuation was disease progression in 59% of the patients who received nivolumab plus chemotherapy, 54% for those treated with nivolumab plus ipilimumab, and 63% who received chemotherapy alone.
At a 13-month minimum follow-up, OS was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with PD-L1 positive (median, 15.4 vs. 9.1 months; HR, 0.54; 99.5% CI, 0.37 to 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 to 0.96; P = 0.002). A longer OS was observed with nivolumab plus ipilimumab than with chemotherapy among patients with PD-L1 positive (median, 13.7 vs. 9.1 months; HR, 0.64; CI 98.6%, 0.46 to 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 to 0.98; P = 0.01).
Among patients with tumor-cell PD-L1 ≥ 1%, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (HR, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002), but not with the dual immune checkpoint blockade as compared with chemotherapy.
As expected, objective response was higher with nivolumab plus chemotherapy than with chemotherapy alone among patients with tumor-cell PD-L1 expression of 1% or greater (53% vs. 20%), as well as in the overall population (47% vs. 27%), and the median duration of response was longer (8.4 vs. 5.7 months and 8.2 vs. 7.1 months, respectively).
The percentage of patients with tumor-cell PD-L1 expression of 1% or greater who had an objective response was higher with nivolumab plus ipilimumab than with chemotherapy (35% vs. 20%), and the median duration of response was 11.8 months and 5.7 months, respectively.
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.
In summary, first-line treatment of advanced esophageal squamous-cell carcinoma comprising nivolumab with chemotherapy or ipilimumab resulted in a significant overall survival benefit and durable responses as compared with chemotherapy alone.
1. Doki Y, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med 2022; 386:449-462.