First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568)

Outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers

Neal Ready, Matthew D. Hellmann, Mark M. Awad, Gregory A. Otterson, Martin Gutierrez, Justin F. Gainor, Hossein Borghaei, Jacques Jolivet, Leora Horn, Mihaela Mates, Julie Brahmer, Ian Rabinowitz, Pavan S. Reddy, Jason Chesney, James Orcutt, David R. Spigel, Martin Reck, Kenneth John O'Byrne, Luis Paz-Ares, Wenhua, Phd Hu & 8 others Kim Zerba, Xuemei Li, Brian Lestini, William J. Geese, Joseph D. Szustakowski, George Green, Han Chang, Suresh S. Ramalingam

Research output: Contribution to journalArticle

Abstract

PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB 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 TMB as a biomarker for first-line nivolumab plus ipilimumab.

Original languageEnglish (US)
Pages (from-to)992-1000
Number of pages9
JournalJournal of Clinical Oncology
Volume37
Issue number12
DOIs
StatePublished - Jan 1 2019

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Tumor Burden
Non-Small Cell Lung Carcinoma
Biomarkers
Ligands
Mutation
Disease-Free Survival
Neoplasms
ipilimumab
nivolumab
Therapeutics
Safety

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568) : Outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. / Ready, Neal; Hellmann, Matthew D.; Awad, Mark M.; Otterson, Gregory A.; Gutierrez, Martin; Gainor, Justin F.; Borghaei, Hossein; Jolivet, Jacques; Horn, Leora; Mates, Mihaela; Brahmer, Julie; Rabinowitz, Ian; Reddy, Pavan S.; Chesney, Jason; Orcutt, James; Spigel, David R.; Reck, Martin; O'Byrne, Kenneth John; Paz-Ares, Luis; Hu, Wenhua, Phd; Zerba, Kim; Li, Xuemei; Lestini, Brian; Geese, William J.; Szustakowski, Joseph D.; Green, George; Chang, Han; Ramalingam, Suresh S.

In: Journal of Clinical Oncology, Vol. 37, No. 12, 01.01.2019, p. 992-1000.

Research output: Contribution to journalArticle

Ready, N, Hellmann, MD, Awad, MM, Otterson, GA, Gutierrez, M, Gainor, JF, Borghaei, H, Jolivet, J, Horn, L, Mates, M, Brahmer, J, Rabinowitz, I, Reddy, PS, Chesney, J, Orcutt, J, Spigel, DR, Reck, M, O'Byrne, KJ, Paz-Ares, L, Hu, WP, Zerba, K, Li, X, Lestini, B, Geese, WJ, Szustakowski, JD, Green, G, Chang, H & Ramalingam, SS 2019, 'First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): Outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers', Journal of Clinical Oncology, vol. 37, no. 12, pp. 992-1000. https://doi.org/10.1200/JCO.18.01042
Ready, Neal ; Hellmann, Matthew D. ; Awad, Mark M. ; Otterson, Gregory A. ; Gutierrez, Martin ; Gainor, Justin F. ; Borghaei, Hossein ; Jolivet, Jacques ; Horn, Leora ; Mates, Mihaela ; Brahmer, Julie ; Rabinowitz, Ian ; Reddy, Pavan S. ; Chesney, Jason ; Orcutt, James ; Spigel, David R. ; Reck, Martin ; O'Byrne, Kenneth John ; Paz-Ares, Luis ; Hu, Wenhua, Phd ; Zerba, Kim ; Li, Xuemei ; Lestini, Brian ; Geese, William J. ; Szustakowski, Joseph D. ; Green, George ; Chang, Han ; Ramalingam, Suresh S. / First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568) : Outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. In: Journal of Clinical Oncology. 2019 ; Vol. 37, No. 12. pp. 992-1000.
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abstract = "PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1{\%} or more and less than 1{\%} tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88{\%}) of 288 were evaluable for PD-L1 expression and 98 patients (82{\%}) of 120 for TMB. ORR was 30{\%} overall and 41{\%} and 15{\%} in patients with 1{\%} or greater and less than 1{\%} tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1{\%}, 48{\%}; PD-L1, < 1{\%}, 47{\%}) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1{\%}, 18{\%}; PD-L1, < 1{\%}, 5{\%}), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29{\%} of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB 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 TMB as a biomarker for first-line nivolumab plus ipilimumab.",
author = "Neal Ready and Hellmann, {Matthew D.} and Awad, {Mark M.} and Otterson, {Gregory A.} and Martin Gutierrez and Gainor, {Justin F.} and Hossein Borghaei and Jacques Jolivet and Leora Horn and Mihaela Mates and Julie Brahmer and Ian Rabinowitz and Reddy, {Pavan S.} and Jason Chesney and James Orcutt and Spigel, {David R.} and Martin Reck and O'Byrne, {Kenneth John} and Luis Paz-Ares and Hu, {Wenhua, Phd} and Kim Zerba and Xuemei Li and Brian Lestini and Geese, {William J.} and Szustakowski, {Joseph D.} and George Green and Han Chang and Ramalingam, {Suresh S.}",
year = "2019",
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language = "English (US)",
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TY - JOUR

T1 - First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568)

T2 - Outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers

AU - Ready, Neal

AU - Hellmann, Matthew D.

AU - Awad, Mark M.

AU - Otterson, Gregory A.

AU - Gutierrez, Martin

AU - Gainor, Justin F.

AU - Borghaei, Hossein

AU - Jolivet, Jacques

AU - Horn, Leora

AU - Mates, Mihaela

AU - Brahmer, Julie

AU - Rabinowitz, Ian

AU - Reddy, Pavan S.

AU - Chesney, Jason

AU - Orcutt, James

AU - Spigel, David R.

AU - Reck, Martin

AU - O'Byrne, Kenneth John

AU - Paz-Ares, Luis

AU - Hu, Wenhua, Phd

AU - Zerba, Kim

AU - Li, Xuemei

AU - Lestini, Brian

AU - Geese, William J.

AU - Szustakowski, Joseph D.

AU - Green, George

AU - Chang, Han

AU - Ramalingam, Suresh S.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB 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 TMB as a biomarker for first-line nivolumab plus ipilimumab.

AB - PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB 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 TMB as a biomarker for first-line nivolumab plus ipilimumab.

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U2 - 10.1200/JCO.18.01042

DO - 10.1200/JCO.18.01042

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