Nivolumab combination therapy may improve outcomes in patients with advanced esophageal squamous-cell carcinoma, according to an open-label, phase 3 trial published in the New England Journal of Medicine.

Adults with previously untreated esophageal squamous-cell carcinoma that was unresectable, recurrent, or metastatic were randomly assigned 1:1:1 to receive standard of care fluoropyrimidine-plus platinum-based chemotherapy, nivolumab plus chemotherapy, or nivolumab plus ipilimumab ( Identifier: NCT03143153). Nivolumab is a programmed death 1 (PD-1) inhibitor, and ipilimumab is often used with nivolumab for chemotherapy-resistant colorectal cancer.

The primary outcomes assessed were overall survival and progression-free survival. Outcomes were calculated in patients with tumor-cell programmed death ligand 1 (PD-L1) expression greater than 1% and in the overall patient population.

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Overall, 970 patients were included in the study: 321 patients in the nivolumab plus chemotherapy group, 325 in the nivolumab plus ipilimumab group, and 324 in the chemotherapy alone group. The majority of patients (70%) were from countries within Asia; in total, 49% of patients exhibited PD-L1 expression of 1% or greater. 

Patients receiving nivolumab combination therapy had extended overall survival. While this was true in the overall population, the difference was even larger in the subset of patients with PD-L1 expression of 1% or greater.

Table 1: Rates of Overall Survival Based on Treatment Regimen

Treatment RegimenOverall survival
PD-L1 over 1%Overall population
Nivolumab + Chemotherapy15.4 months*13.2 months*
Nivolumab + Ipilimumab13.7 months*12.7 months*
Chemotherapy9.1 months10.7 months

* Indicates statistical significance

Progression-free survival was significantly extended in the nivolumab plus chemotherapy group compared with the chemotherapy alone group; however, this difference was not observed in the nivolumab plus ipilimumab group.

Study results were limited by the trial’s open-label design. Patient responses to questionnaires and adverse events may have been affected by participant knowledge of the type of treatment received.

The results of the study suggest that nivolumab combination therapy is an appropriate choice for the first-line treatment of advanced squamous-cell carcinoma.


Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386(5):449-462. doi: 10.1056/NEJMoa2111380