BACKGROUND: Nivolumab plus ipilimumab showed promising efficacy for the 
treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor 
mutational burden has emerged as a potential biomarker of benefit. In this part 
of an open-label, multipart, phase 3 trial, we examined progression-free 
survival with nivolumab plus ipilimumab versus chemotherapy among patients with 
a high tumor mutational burden (≥10 mutations per megabase).
METHODS: We enrolled patients with stage IV or recurrent NSCLC that was not 
previously treated with chemotherapy. Those with a level of tumor programmed 
death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 
1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or 
chemotherapy; those with a tumor PD-L1 expression level of less than 1% were 
randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, 
nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was 
determined by the FoundationOne CDx assay.
RESULTS: Progression-free survival among patients with a high tumor mutational 
burden was significantly longer with nivolumab plus ipilimumab than with 
chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab 
plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free 
survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 
months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 
0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The objective response rate was 45.3% 
with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of 
nivolumab plus ipilimumab over chemotherapy was broadly consistent within 
subgroups, including patients with a PD-L1 expression level of at least 1% and 
those with a level of less than 1%. The rate of grade 3 or 4 treatment-related 
adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with 
chemotherapy. ical; CheckMate 227 ClinicalTrials.gov number, NCT02477826 .).
CONCLUSIONS: Progression-free survival was significantly longer with first-line 
nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a 
high tumor mutational burden, irrespective of PD-L1 expression level. The 
results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role 
of tumor mutational burden as a biomarker for patient selection. (Funded by 
Bristol-Myers Squibb and Ono Pharmaceut