As reported in The New England Journal of Medicine by Yuichiro Doki, MD, of Osaka University Graduate School of Medicine, Japan, and colleagues, 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.¹ A progression-free survival benefit was observed with nivolumab/chemotherapy but not nivolumab/ipilimumab in the PD-L1–positive population.

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. The chemotherapy-alone group received a 4-week cycle of fluorouracil at 800 mg/m² on days 1 to 5 and cisplatin at 80 mg/m² on day 1. 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. 

Survival Outcomes

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

In subgroup analyses of patients from Asian and non-Asian regions, hazard ratios for overall survival for nivolumab/chemotherapy vs chemotherapy were 0.57 (95% CI = 0.41–0.79) among patients from Asian regions and 0.48 (95% CI = 0.29–0.79) among those from non-Asian regions in the PD-L1–positive population and 0.74 (95% CI = 0.59–0.94) among patients from Asian regions and 0.74 (95% CI = 0.54–1.02) among those from non-Asian regions in the total population. Hazard ratios for nivolumab/ipilimumab vs chemotherapy were 0.66 (95% CI = 0.48–0.90) and 0.52 (95% CI = 0.32–0.86) in the PD-L1–positive population and 0.83 (95% CI = 0.66–1.04) and 0.69 (95% CI = 0.50–0.96), respectively.

Median progression-free survival in the nivolumab/chemotherapy group vs the 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 the 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 months; HR vs chemotherapy = 1.26, 95% CI = 1.04–1.52 months). Rates at 12 months were 26% in the PD-L1–positive population and 23% in the total population.

Adverse Events

The most common treatment-related adverse events of any grade were nausea (59%) and decreased appetite (43%) in the nivolumab/chemotherapy group, rash (17%) and pruritus and hypothyroidism (13% each) in the nivolumab/ipilimumab group, and nausea (52%) and decreased appetite (43%) in the chemotherapy group. 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. 

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.” 

DISCLOSURE: The study was funded by Bristol Myers Squibb and Ono Pharmaceutical. Dr. Doki has received research support from and/or served as a speaker for Abbott Japan, Ajinomoto Pharmaceuticals, Astellas Pharma, AstraZeneca, Chugai, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Intuitive Surgical, Johnson & Johnson, Kaken Pharmaceutical, Medtronic, Merck Sharp and Dohme, Nestle HealthCare Nutrition, Nippon Kayaku, Novartis, Olympus, Ono Pharmaceutical, Otsuka, Pfizer Japan, Sanofi Pasteur, Shionogi, Taiho Pharmaceutical, Takeda, Teijin Pharma, and Yakult Honsha.

REFERENCE

1. Doki Y, Ajani JA, Kato K, et al: Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med 386:449-462, 2022.