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

• Type of Material: Article
• Authors: Neal Ready, Duke University; Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Mark M. Awad, Dana Farber Cancer Institute; Gregory A. Otterson, Ohio State University; Martin Gutierrez, Hackensack University; Justin F. Gainor, Massachusetts General Hospital; Hossein Borghaei, Fox Chase Cancer Center; Jacques Jolivet, St Jerome Medical Research Inc.; Leora Horn, Vanderbilt Ingram Cancer Center; Mihaela Mates, Kingston Health Sciences Center; Julie Brahmer, Johns Hopkins University; Ian Rabinowitz, University of New Mexico; Pavan S. Reddy, Cancer Center Kansas; Jason Chesney, University of Louisville; James Orcutt, Charleston Hematol Oncol Associates; David R. Spigel, Sarah Cannon Research Institute/Tennessee Oncology PLLC; Martin Reck, LungenClinic Grosshansdorf; Kenneth John O'Byrne, Princess Alexandra Hospital; Luis Paz-Ares, Universidad Complutense; Wenhua Hu, Bristol Myers Squibb; Kim Zerba, Bristol Myers Squibb; Xuemel Li, Bristol Myers Squibb; Brian Lestini, Bristol Myers Squibb; William J. Geese, Bristol Myers Squibb; Joseph D. Szustakowski, Bristol Myers Squibb; George Green, Bristol Myers Squibb; Han Chang, Bristol Myers Squibb; Suresh Ramalingam, Emory University
• Language: English
• Date: 2019-04-20
• Publisher: American Society of Clinical Oncology
• Publication Version: Final Published Version
• Copyright Statement: © 2019 by American Society of Clinical Oncology.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1200/JCO.18.01042
• Title of Journal or Parent Work: Journal of Clinical Oncology
• Volume: 37
• Issue: 12
• Start Page: 992
• End Page: +
• Grant/Funding Information: Funded by Bristol-Myers Squibb, (Princeton, NJ) and ONO Pharmaceutical (Osaka, Japan).
• Keywords: PD-1; Open label; Science & Technology; Docetaxel; Oncology; Multicenter; Blockade; Landscape; Life Sciences & Biomedicine; Stage IV
• Research Categories: Health Sciences, Oncology; Engineering, Biomedical; Biology, Cell

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.