Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden

Hellmann MD, Ciuleanu TE, Pluzanski A, et al. N Engl J Med. 2018 Apr 16 [Epub ahead of print]. [CrossRef] [PubMed]

Nivolumab, a PD-1 inhibitor, plus ipilimumab, an activator of cytotoxic T cells, have shown promise for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial.  In this open-label, multipart, phase 3 trial, the authors examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase). Patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy. 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. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection.