KEYNOTE-598 Trial: Addition of Ipilimumab to Pembrolizumab in Previously Untreated Patients With Metastatic NSCLC and High PD-L1 Expression

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As reported in the Journal of Clinical Oncology by Michael Boyer, MBBS, PhD, and colleagues, an interim analysis in the phase III KEYNOTE-598 trial showed no improvement in overall or progression-free survival with the addition of ipilimumab to pembrolizumab in previously untreated patients with metastatic non–small cell lung cancer (NSCLC), a PD-L1 tumor proportion score (TPS) ≥ 50%, and no targetable EGFR or ALK aberrations. 

Study Details

In the double-blind trial, 568 patients from sites in 24 countries were randomly assigned between January 2018 and August 2019 to receive ipilimumab at 1 mg/kg (n = 284) or placebo (n = 284) every 6 weeks for up to 18 doses, with all patients receiving pembrolizumab at 200 mg every 3 weeks for up to 35 doses. The primary endpoints were overall survival and progression-free survival.

Michael Boyer, MBBS, PhD

Michael Boyer, MBBS, PhD

Overall and Progression-Free Survival

As of data cutoff for the first interim analysis (September 2020), median follow-up was 20.6 months (range = 12.4–31.7 months). The external data and safety monitoring committee recommended that the study be stopped for futility and that patients discontinue ipilimumab and placebo.

Median overall survival was 21.4 months (95% confidence interval [CI] = 16.6 months–not reached) in the pembrolizumab/ipilimumab group vs 21.9 months (95% CI = 18.0 months–not reached) in the pembrolizumab group (hazard ratio [HR] = 1.08, 95% CI = 0.85–1.37, P = .74), with similar outcomes among patient subgroups; 12-month rates were 63.6% vs 67.9%.

Median progression-free survival was 8.2 months (95% CI = 6.0–10.5 months) in the combination group vs 8.4 months (95% CI = 6.3–10.5 months) in the pembrolizumab group (HR = 1.06, 95% CI = 0.86–1.30, P = .72), with results generally consistent among subgroups; 12-month rates were 41.3% vs 42.1%.

Objective response was observed in 45.4% of patients in each group, with complete response in 4.6% of the combination group vs 2.8% of the pembrolizumab group. Median durations of response were 16.1 months (range = 1.1+ to 26.0 months) vs 17.3 months (range = 2.0+ to 29.4+ months).


  • The addition of ipilimumab to pembrolizumab did not improve progression-free or overall survival.
  • Combination treatment was associated with greater toxicity.

Adverse Events

Grade 3 to 5 adverse events occurred in 62.4% of patients in the combination group vs 50.2% of the pembrolizumab group. Adverse events led to discontinuation of pembrolizumab and ipilimumab in 30.9% and ipilimumab only in 6.4% in the combination group, and to discontinuation of pembrolizumab and placebo in 17.1% and placebo only in 3.2% in the pembrolizumab group. Immune-mediated adverse events and infusion-related reactions occurred in 44.7% vs 32.4% of patients and were grade ≥ 3 in 20.2% vs 7.8%.

Death due to immune-mediated adverse events occurred in six patients (2.1%) in the combination group and no patients in the pembrolizumab group. Overall, adverse events led to death in 13.1% vs 7.5% of patients. Death considered related to treatment occurred in seven patients (2.5%) in the combination group (vs no patients in the pembrolizumab group), with causes consisting of myocarditis in two patients and adrenal insufficiency, cholestatic jaundice, disease progression, lymphocytic hypophysitis, and pneumonitis in one patient each.

The investigators concluded, “Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or ALK aberrations. These data do not support use of pembrolizumab/ipilimumab in place of pembrolizumab monotherapy in this population.”

Dr. Boyer, of Chris O’Brien Lifehouse and The University of Sydney, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit

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