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J Clin Oncol. 2019 Feb 20:JCO1801042. doi: 10.1200/JCO.18.01042. [Epub ahead of print]

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.

Author information

1
1 Duke University Medical Center, Durham, NC.
2
2 Memorial Sloan Kettering Cancer Center, New York, NY.
3
3 Dana-Farber Cancer Institute, Boston, MA.
4
4 The Ohio State University, Columbus, OH.
5
5 John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ.
6
6 Massachusetts General Hospital, Boston, MA.
7
7 Fox Chase Cancer Center, Philadelphia, PA.
8
8 St Jerome Medical Research Inc., Saint-Jérôme, Quebec, Canada.
9
9 Vanderbilt-Ingram Cancer Center, Nashville, TN.
10
10 Kingston Health Sciences Centre, Kingston, Ontario, Canada.
11
11 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.
12
12 University of New Mexico Comprehensive Cancer Center, Albuquerque, NM.
13
13 Cancer Center of Kansas, Wichita, KS.
14
14 James Graham Brown Cancer Center, University of Louisville, Louisville, KY.
15
15 Charleston Hematology Oncology Associates, Charleston, SC.
16
16 Sarah Cannon Research Institute/Tennessee Oncology PLLC, Nashville, TN.
17
17 LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.
18
18 Princess Alexandra Hospital, Brisbane, QLD, Australia.
19
19 Hospital Universitario Doce de Octubre, Centro Nacional de Investigaciones Oncológicas, Universidad Complutense, CiberOnc, Madrid, Spain.
20
20 Bristol-Myers Squibb, Princeton, NJ.
21
21 Winship Cancer Institute, Emory University, Atlanta, GA.

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.

PMID:
30785829
DOI:
10.1200/JCO.18.01042

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