First-line nivolumab (OpdivoⓇ) plus ipilimumab (YervoyⓇ) was associated with a more than tripled 1-year progression-free survival (PFS) rate compared to platinum-based chemotherapy for patients with tumour mutation burden (TMB)-high non-small cell lung cancer (NSCLC) in the Phase III CheckMate 227 trial. The results were presented during the 2018 AACR Annual Meeting with simultaneous online publication in the New England Journal of Medicine (NEJM).

“In this study of TMB-high non–small cell lung cancer, we found that nivolumab plus ipilimumab significantly improved progression-free survival compared to chemotherapy,”

~Matthew D. Hellman, MD, Memorial Sloan Kettering Cancer Center

Study Design

The CheckMate 227 (NCT02477826) initially was a multipart study comparing various immunotherapeutic regimens of programmed death 1 (PD-1) inhibitor nivolumab with chemotherapy (Figure 1). Eligible patients had Stage IV or recurrent NSCLC and not received prior systemic treatment. Participants were stratified as squamous NSCLC and non-squamous NSCLC. Subjects with insufficient tissue available for testing of PD-1 ligand (PD-L1) could not participate in the study.

Upon successful study-registration, participants were divided into a low PD-1 ligand (PD-L1) expression-group [PD-L1<1%] and high PD-L1 expression-group [PD-L1≥1%] and randomised to either nivolumab plus ipilimumab, chemotherapy alone, or nivolumab alone. Patients in the PD-L1<1% group and allocated to the nivolumab-arm received concomitant chemotherapy (Figure 1).

Based on the results of the CheckMate 012 and 032 studies, which showed efficacy of nivolumab plus ipilimumab in TMB-high lung cancer, the study was amended to include the co-primary progression-free survival endpoint comparing the immunooncology combination (IO-IO) with chemotherapy in patients with TMB-high (≥10 mutations per megabase [mut/Mb]).

Figure 1. Study design of the CheckMate 227 study. Platinum-doublet chemotherapy was subject to the histological subtype. Patients with non-squamous NSCLC received pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) or carboplatin (area under the concentration-time curve [AUC] 5 or 6), every 3 weeks (q3w) for up to four cycles. Maintenance therapy with pemetrexed 500 mg/m² after chemotherapy or with nivolumab 360 mg q3w plus pemetrexed 500 mg/m² after nivolumab plus chemotherapy was optional. Patients with squamous NSCLC received gemcitabine (1000 or 1250 mg/m²) plus cisplatin (75 mg/m²), or gemcitabine (1000 mg/m²) plus carboplatin (AUC 5) q3w for up to four cycles.

Progression-Free Survival

In patients with TMB-high NSCLC the 1-year PFS rate was 43% for nivolumab plus ipilimumab compared with 13% for platinum-doublet chemotherapy (Figure 2). The median PFS was 7.2 months (nivolumab plus ipilimumab) versus 5.5 months (chemotherapy), a 42% risk reduction for disease progression or death (hazard ratio [HR]=0.58, P<0.001; 97.5%CI, 0.41-0.81).

Figure 2. Progression-free survival (PFS) for chemotherapy vs ipilimumab plus nivolumab in TMB-high NSCLC, the co-primary endpoint of the CheckMate 227 study (NCT02477826). The combination IO-IO was associated with a 42% reduction of risk for disease progression or death (HR=0.58, P<0.001; 97.5% confidence interval [CI], 0.41-0.81). mPFS: median PFS.