Nivolumab Plus Ipilimumab in Advanced NSCLC: Outcomes by PD-L1 and Tumor Mutational Burden Status


Key Points

  • Response rates were higher in PD-L1–positive patients and in those with tumor mutational burden ≥ 10 mut/Mb.
  • Response rates were high in patients with tumor mutational burden ≥ 10 mut/Mb irrespective of PD-L1 status.

As reported in the Journal of Clinical Oncology by Ready et al, the phase II CheckMate 568 trial has shown that higher tumor mutational burden is associated with response, irrespective of programmed cell death ligand 1 (PD-L1) expression in first-line nivolumab plus low-dose ipilimumab treatment of advanced non–small cell lung cancer (NSCLC). Response rates were also higher in patients with PD-L1–positive vs –negative tumors.

Study Details

In the study, 288 patients with recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks.

The primary endpoint was objective response rate in patients with ≥ 1% vs < 1% tumor PD-L1 expression. Efficacy on the basis of tumor mutational burden was a secondary endpoint.

Response Rates

Among patients with tumor available for testing, 252 (88%) of 288 were evaluable for PD-L1 expression and 98 (82%) of 120 were evaluable for tumor mutational burden.

The objective response rate among all 288 treated patients was 30%, including rates of 41% among 138 with ≥ 1% PD-L1 expression and 15% among 114 with < 1% PD-L1 expression. Response rates increased with higher tumor mutational burden, plateauing at ≥ 10 mutations/megabase (mut/Mb). Among 48 patents with tumor mutational burden ≥ 10 mut/Mb, response rates were 48% among those with PD-L1 expression ≥ 1% and 47% among those with expression < 1%. Among 50 patients with tumor mutational burden < 10 mut/Mb, respective response rates were 18% and 5%. Median progression-free survival was 7.1 months among patients with tumor mutational burden ≥ 10 mut/Mb vs 2.6 months among those with tumor mutational burden < 10 mut/Mb.

Adverse Events

Grade 3 or 4 treatment-related adverse events occurred in 29% of patients, and treatment-related adverse events led to discontinuation of treatment in 16%. The most common treatment-related immune-mediated adverse events of any grade were skin reactions (30%), with the most common grade 3 or 4 events being gastrointestinal toxicities (5%). Four treatment-related deaths were reported within 100 days of the last dose of study drug, with causes consisting of cardiac arrhythmia, pneumonitis, hypoxia, and other.

The investigators concluded, “Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. Tumor mutational burden of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups, and was thus identified as a potentially relevant cutoff in the assessment of tumor mutational burden as a biomarker for first-line nivolumab plus ipilimumab.”

Neal Ready, MD, PhD, of Duke University Medical Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Bristol-Myers Squibb and ONO Pharmaceutical. The study authors' full disclosures can be found at

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.