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.

Trial registration: ClinicalTrials.gov NCT02659059.

FIG 1.

Receiver operating characteristic curves of objective response rate by (A) tumor programmed death ligand 1 (PD-L1) expression and (B) tumor mutational burden (TMB). AUC, area under the curve.

FIG 2.

Progression-free survival (PFS) by (A) tumor programmed death ligand 1 (PD-L1) expression and (B) tumor mutational burden (TMB) cutoff. mut/Mb, mutations per megabase.

FIG A1.

Study design. (*) Efficacy analyses by blinded independent central review. (†) Programmed death ligand 1 (PD-L1) status determined by Dako PD-L1 IHC 28-8 pharmDx immunohistochemical test. Database lock: August 24, 2017; minimum follow-up: 6 months; median follow-up: 8.8 months. ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC, non–small-cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TMB, tumor mutational burden.

FIG A2.

Biomarker assessment flow diagram. PD-L1, programmed death ligand 1; TMB, tumor mutational burden.

FIG A3.

Regression analysis of tumor mutational burden (TMB) and tumor programmed death ligand 1 (PD-L1) expression. mut/Mb, mutations per megabase.

FIG A4.

Tumor mutational burden (TMB) distribution across first-line non–small-cell lung cancer data sets. (*) In CheckMate 026, TMB was evaluated by whole-exome sequencing and values were converted to mutations per megabase (mut/Mb) using TMB bridging analysis.

FIG A5.

Progression-free survival (PFS) in all treated patients.

FIG A6.

Progression-free survival (PFS) in patients with 50% or greater tumor programmed death ligand 1 (PD-L1) expression. NA, not available.

FIG A7.

Tumor responses by tumor programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) category. (A) Receiver operating characteristic (ROC) curve for TMB and objective response rate (ORR) by tumor PD-L1 expression. (B) ORRs per blinded independent central review. (*)Complete responses were 4% for both TMB less than 10 mutations per megabase (mut/Mb) and TMB 10 or more mut/Mb. (†) Complete responses were 0% for TMB less than 10 mut/Mb and 16% for TMB 10 or more mut/Mb. AUC, area under the curve.