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, Julie 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 journalArticle

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

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Tumor Burden
Lung Neoplasms
Drug Therapy
Disease-Free Survival
Non-Small Cell Lung Carcinoma
Ligands
Confidence Intervals
ipilimumab
nivolumab
Biomarkers
Patient Selection
Disease Progression
Neoplasms
Survival Rate

ASJC Scopus subject areas

  • Medicine(all)

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Hellmann, M. D., Ciuleanu, T. E., Pluzanski, A., Lee, J. S., Otterson, G. A., Audigier-Valette, C., ... Paz-Ares, L. (2018). Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. New England Journal of Medicine, 378(22), 2093-2104. https://doi.org/10.1056/NEJMoa1801946

Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. / Hellmann, M. D.; Ciuleanu, T. E.; Pluzanski, A.; Lee, J. S.; Otterson, G. A.; Audigier-Valette, C.; Minenza, E.; Linardou, H.; Burgers, S.; Salman, P.; Borghaei, H.; Ramalingam, S. S.; Brahmer, Julie; Reck, M.; O'Byrne, K. J.; Geese, W. J.; Green, G.; Chang, H.; Szustakowski, J.; Bhagavatheeswaran, P.; Healey, D.; Fu, Y.; Nathan, F.; Paz-Ares, L.

In: New England Journal of Medicine, Vol. 378, No. 22, 31.05.2018, p. 2093-2104.

Research output: Contribution to journalArticle

Hellmann, MD, Ciuleanu, TE, Pluzanski, A, Lee, JS, Otterson, GA, Audigier-Valette, C, Minenza, E, Linardou, H, Burgers, S, Salman, P, Borghaei, H, Ramalingam, SS, Brahmer, J, Reck, M, O'Byrne, KJ, Geese, WJ, Green, G, Chang, H, Szustakowski, J, Bhagavatheeswaran, P, Healey, D, Fu, Y, Nathan, F & Paz-Ares, L 2018, 'Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden', New England Journal of Medicine, vol. 378, no. 22, pp. 2093-2104. https://doi.org/10.1056/NEJMoa1801946
Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. New England Journal of Medicine. 2018 May 31;378(22):2093-2104. https://doi.org/10.1056/NEJMoa1801946
Hellmann, M. D. ; Ciuleanu, T. E. ; Pluzanski, A. ; Lee, J. S. ; Otterson, G. A. ; Audigier-Valette, C. ; Minenza, E. ; Linardou, H. ; Burgers, S. ; Salman, P. ; Borghaei, H. ; Ramalingam, S. S. ; Brahmer, Julie ; Reck, M. ; O'Byrne, K. J. ; Geese, W. J. ; Green, G. ; Chang, H. ; Szustakowski, J. ; Bhagavatheeswaran, P. ; Healey, D. ; Fu, Y. ; Nathan, F. ; Paz-Ares, L. / Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. In: New England Journal of Medicine. 2018 ; Vol. 378, No. 22. pp. 2093-2104.
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title = "Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden",
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.",
author = "Hellmann, {M. D.} and Ciuleanu, {T. E.} and A. Pluzanski and Lee, {J. S.} and Otterson, {G. A.} and C. Audigier-Valette and E. Minenza and H. Linardou and S. Burgers and P. Salman and H. Borghaei and Ramalingam, {S. S.} and Julie Brahmer and M. Reck and O'Byrne, {K. J.} and Geese, {W. J.} and G. Green and H. Chang and J. Szustakowski and P. Bhagavatheeswaran and D. Healey and Y. Fu and F. Nathan and L. Paz-Ares",
year = "2018",
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language = "English (US)",
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TY - JOUR

T1 - Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden

AU - Hellmann, M. D.

AU - Ciuleanu, T. E.

AU - Pluzanski, A.

AU - Lee, J. S.

AU - Otterson, G. A.

AU - Audigier-Valette, C.

AU - Minenza, E.

AU - Linardou, H.

AU - Burgers, S.

AU - Salman, P.

AU - Borghaei, H.

AU - Ramalingam, S. S.

AU - Brahmer, Julie

AU - Reck, M.

AU - O'Byrne, K. J.

AU - Geese, W. J.

AU - Green, G.

AU - Chang, H.

AU - Szustakowski, J.

AU - Bhagavatheeswaran, P.

AU - Healey, D.

AU - Fu, Y.

AU - Nathan, F.

AU - Paz-Ares, L.

PY - 2018/5/31

Y1 - 2018/5/31

N2 - 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.

AB - 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.

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