Addition of Ipilimumab to Nivolumab in Previously Treated, Immunotherapy-Naive Patients With Stage IV Squamous NSCLC

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As reported in JAMA Oncology by Scott N. Gettinger, MD, and colleagues, the phase III Lung Cancer Master Protocol S1400I trial showed no improvement in overall survival with the addition of ipilimumab to nivolumab in previously treated, immune checkpoint inhibitor–naive patients with stage IV squamous non–small cell lung cancer (NSCLC).

Scott N. Gettinger, MD

Scott N. Gettinger, MD

Study Details

In the open-label trial—conducted through the National Clinical Trials Network and led by the SWOG Cancer Research Network—252 eligible patients with disease progression after standard platinum-based chemotherapy were randomly assigned between December 2015 and April 2018 to receive nivolumab at 3 mg/kg every 2 weeks with (n = 125) or without (n = 127) ipilimumab at 1 mg/kg every 6 weeks until disease progression or intolerable toxicity. The primary endpoint was overall survival.

Overall Survival

The study was closed for futility at a preplanned interim analysis. Median follow-up for surviving patients was 29.5 months. Median overall survival was 10 months (95% confidence interval [CI] = 8.0–14.4 months) in the combination group vs 11 months (95% CI = 8.6–13.7 months) in the nivolumab group (hazard ratio [HR] = 0.87, 95% CI = 0.66–1.16, P = .34), with 1- and 2-year rates of 45% vs 44% and 28% vs 22%.

Median investigator-assessed progression-free survival was 3.8 months (95% CI = 2.7–4.4 months) in the combination group vs 2.9 months (95% CI = 1.8–4.0 months) in the nivolumab group (HR = 0.80, 95% CI = 0.61–1.03, P = .09), with 1- and 2-year rates of 17% vs 10% and 12% vs 5%. Objective response was observed in 18% vs 17% of patients, with median response durations of 28.4 months (95% CI = 4.9 months–not reached) vs 9.7 months (95% CI = 4.2–23.1 months).


  • The addition of ipilimumab to nivolumab did not significantly prolong overall survival.
  • The trial was closed for futility at a preplanned interim analysis.

Adverse Events

Grade ≥ 3 treatment-related adverse events occurred in 39.5% of patients in the combination group vs 33.3% of the nivolumab group, with the most common including fatigue (8.9% vs 5.7%) and pneumonitis (7.3% vs 4.9%). Immune-related adverse events of any grade occurred in 66% vs 59% of patients; the most common were rash (24%), dyspnea (19%), diarrhea (18%), and hypothyroidism (18%) in the combination group, and diarrhea (21%), dyspnea (20%), and hypothyroidism (11%) in the nivolumab group.

Adverse events led to treatment discontinuation in 25% vs 15% of patients. Treatment-related deaths occurred in three patients in the combination group (due to dyspnea, respiratory failure, and death–not otherwise specified) and in one patient in the nivolumab group (due to pneumonitis).

The investigators concluded: “In this phase III randomized clinical trial, ipilimumab added to nivolumab did not improve outcomes in patients with advanced, pretreated, immune checkpoint inhibitor–naive squamous NSCLC.”

Dr. Gettinger, of Yale Cancer Center, is the corresponding author for the JAMA Oncology article.

Disclosure: This study was supported by grants from the Foundation for the National Institutes of Health to SWOG. For full disclosures of the study authors, visit

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