Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden

M. D. Hellmann, T. E. Ciuleanu, A. Pluzanski, J. S. Lee, G. A. Otterson, C. Audigier-Valette, E. Minenza, H. Linardou, S. Burgers, P. Salman, H. Borghaei, S. S. Ramalingam, J. Brahmer, M. Reck, K. J. O'Byrne, W. J. Geese, G. Green, H. Chang, J. Szustakowski, P. BhagavatheeswaranD. Healey, Y. Fu, F. Nathan, L. Paz-Ares

Research output: Contribution to journalArticlepeer-review

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)2093-2104
Number of pages12
JournalNew England Journal of Medicine
Volume378
Issue number22
DOIs
StatePublished - May 31 2018

ASJC Scopus subject areas

  • Medicine(all)

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