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.

The role and therapeutic implications of T cells in cancer of the lung

“…52 In clinical trials, nivolumab and ipilimumab combination therapy achieved an overall response rate of 43% in unselected patients with NSCLC, compared with 23% in the nivolumab monotherapy group; and in the PD-L1 positive subgroup, nivolumab in combination with ipilimumab showed a response rate of 57%, whilst nivolumab alone was 28% (CheckMate 012 study). 54 However, adverse events of grade 3 or above of combination therapy reached 37%, thereby limiting the widespread clinical application. 54 However, adverse events of grade 3 or above of combination therapy reached 37%, thereby limiting the widespread clinical application.…”

Nivolumab plus Ipilimumab in Non–Small-Cell Lung Cancer

“…Results of the Phase II CheckMate 568 study confirmed that high TMB (determined by the FoundationOne CDx assay), irrespective of PD-L1 status, is associated with improved rates of response to nivolumab plus ipilimumab in patients with advanced NSCLC [79]. ORRs were 9, 15 and 44% for patients with <5, 5 to <10 and ≥10 mutations/Mb, respectively; however, no additional benefit was noted for patients with higher TMB, suggesting that a TMB of ≥10 mutations/Mb is a clinically useful cut-off for the selection of patients most likely to respond to first-line nivolumab plus ipilimumab.…”

“…The study did not find a meaningful correlation between TMB and PD-L1 expression [79]. Although both PD-L1 expression ≥1% and TMB ≥10 mutations/Mb were associated with higher ORR, PD-L1 expression appeared to have little influence on ORR in patients with high TMB (Table 1).…”

“…HR: Hazard ratio; NR: Not reached; NSCLC: Non-small-cell lung cancer; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; TMB: Tumor mutational burden; Q2W: Every 2 weeks; Q6W: Every 6 weeks; Q12W: Every 12 weeks. Data for CheckMate 012, 568 and 227 based on [46,76,78], [79] and [47,80,81], respectively. of patients with a complete or partial response who maintained this response for at least 1 year was 68% with nivolumab plus ipilimumab versus 25% with chemotherapy [47].…”

“…Analyses of patient-reported outcomes in CheckMate 227 found that patients with TMB ≥10 mutations/Mb being treated with nivolumab plus ipilimumab experienced more rapid, durable and clinically meaningful improvements in disease-related symptom burden and health-related quality of life (HRQoL) than those being treated with chemotherapy, despite the potential for immune-related AEs [88,89]. Based on results obtained with the lung [79]. § Based on reference [47].…”