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.

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.

• Authors: 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 Hu, Kim Zerba, Xuemei Li, Brian Lestini, William J Geese, Joseph D Szustakowski, George Green, Han Chang, Suresh S Ramalingam
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 37 Issue 12 Pg. 992-1000 (04 20 2019) ISSN: 1527-7755 [Electronic] United States
• PMID: 30785829 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• B7-H1 Antigen
• Biomarkers, Tumor
• CD274 protein, human
• Ipilimumab
• Nivolumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• B7-H1 Antigen (biosynthesis, immunology)
• Biomarkers, Tumor (biosynthesis, genetics, immunology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, immunology)
• Female
• Humans
• Ipilimumab (administration & dosage)
• Lung Neoplasms (drug therapy, genetics, immunology)
• Male
• Middle Aged
• Mutation
• Neoplasm Recurrence, Local (drug therapy)
• Neoplasm Staging
• Nivolumab (administration & dosage)
• Treatment Outcome