As reported in The New England Journal of Medicine by Doki et al, the phase III CheckMate 648 trial has shown improved overall survival with nivolumab combined with chemotherapy or ipilimumab vs chemotherapy alone in patients with previously untreated advanced esophageal squamous cell carcinoma, in both the PD-L1–positive and total populations. A progression-free survival benefit was observed with nivolumab plus chemotherapy but not nivolumab plus ipilimumab in the PD-L1–positive population.  

Study Details

In the open-label trial, 970 patients with unresectable advanced, recurrent, or metastatic disease from sites in 26 countries were randomly assigned 1:1:1 between June 2017 and November 2019 to receive nivolumab plus chemotherapy (n = 321), nivolumab plus ipilimumab (n = 325), or chemotherapy alone. In the nivolumab/chemotherapy group, patients received nivolumab at 240 mg every 2 weeks; chemotherapy consisted of a 4-week cycle of fluorouracil at 800 mg/m² on days 1 to 5 and cisplatin at 80 mg/m² on day 1. The nivolumab/ipilimumab group received nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks. Treatment continued until disease progression or unacceptable toxicity. Patients could receive nivolumab or nivolumab plus ipilimumab for a maximum of 2 years.

The primary endpoints were overall survival and progression-free survival on blinded independent central review, with hierarchical testing performed first in patients with tumor cell PD-L1 expression ≥ 1% (PD-L1–positive) and then in the overall population. Proportions of patients who were PD-L1–positive were 49% in the nivolumab/chemotherapy group, 49% in the nivolumab/ipilimumab group, and 48% in the chemotherapy group.

Overall and Progression-Free Survival

At a 13-month minimum follow-up, median overall survival in the nivolumab/chemotherapy group vs chemotherapy group was 15.4 months (95% confidence interval [CI] =11.9–19.5 months) vs 9.1 months (95% CI = 7.7–10.0 months) in the PD-L1–positive population (hazard ratio [HR] = 0.54, 99.5% CI = 0.37–0.80, P < .001) and 13.2 months (95% CI = 11.1–15.7 months) vs 10.7 months (95% CI = 9.4–11.9 months) in the total population (HR = 0.74, 99.1% CI = 0.58–0.96, P = .002). Rates at 1 year were 58% vs 37% in the PD-L1–positive population and 54% vs 44% in the total population.

Median overall survival in the nivolumab/ipilimumab group was 13.7 months (95% CI = 11.2–17.0 months) in the PD-L1–positive population (HR vs chemotherapy group = 0.64, 98.6% CI = 0.46–0.90, P = .001) and 12.7 months (95% CI = 11.3–15.5 months) in the total population (HR vs chemotherapy group = 0.78, 98.2% CI = 0.62–0.98, P = .01). Rates at 1 year in the nivolumab/ipilimumab group were 57% in the PD-L1–positive group and 54% in the total population.

Median progression-free survival in the nivolumab/chemotherapy group vs chemotherapy group was 6.9 months (95% CI = 5.7–8.3 months) vs 4.4 months (95% CI = 2.9–5.8 months) in the PD-L1–positive population (HR = 0.65, 98.5% CI = 0.46–0.92, P= .002) and 5.8 months (95% CI = 5.6–7.0 months) vs 5.6 months (95% CI =4.3–5.9 months) in the total population (HR = 0.81, 98.5% CI = 0.64–1.04, P = .04, not meeting a prespecified significance boundary of .015.) Rates at 12 months were 25% vs 10% in the PD-L1–positive population and 24% vs 16% in the total population.

Median progression-free survival in the nivolumab/ipilimumab group was 4.0 months (95% CI = 2.4–4.9 months) in the PD-L1–positive population (HR vs chemotherapy = 1.02, 98.5% CI = 0.73–1.43, P = .90). Since the difference did not meet the criterion for significance, comparison in the total population was not formally tested. Median progression-free survival in the total population was 2.9 months (95% CI = 2.7–4.2; HR vs chemotherapy = 1.26, 95% CI = 1.04–1.52). Rates at 12 months were 26% in the PD-L1–positive population and 23% in the total population.

Adverse Events

Treatment-related grade 3 or 4 adverse events occurred in 47% of the nivolumab/chemotherapy group, 32% of the nivolumab/ipilimumab group, and 36% of the chemotherapy group. Treatment-related serious adverse of any grade occurred in 24%, 32%, and 16%, respectively.

Treatment-related adverse events led to discontinuation of any component of study treatment in 34%, 18%, and 19%, respectively. Treatment-related death occurred in 2% of each group.

The investigators concluded: “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.”

Ken Kato, MD, PhD, Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Bristol Myers Squibb and Ono Pharmaceutical. For full disclosures of the study authors, visit nejm.org.