The findings from the CheckMate 227 study, reported on 16 April at the American Association for Cancer Research (AACR) Annual Meeting 2018 and published simultaneously in the New England Journal of Medicine, show that a progression-free survival (PFS) was significantly longer with first-line combination therapy with nivolumab/ipilimumab than with chemotherapy among patients with advanced non-small cell lung cancer (NSCLC) and a high tumour mutational burden (TMB), irrespective of PD-L1 expression level. These results validate the benefit of combination of these two immune checkpoint inhibitors in first-line setting as well as the role of TMB as a biomarker for patient selection.
The CheckMate 227 study investigators wrote in a study background that nivolumab/ipilimumab combination showed promising efficacy for the treatment of NSCLC in a phase I trial, and TMB has emerged as a potential biomarker.
The CheckMate 227 is an open-label phase III trial evaluating multiple hypotheses regarding the efficacy of nivolumab or nivolumab-based regimens as first-line treatment in biomarker-selected populations of patients with advanced NSCLC. On the basis of the emerging data related to TMB, the CheckMate 227 study protocol was amended to add a coprimary endpoint evaluating PFS with nivolumab/ipilimumab combination versus chemotherapy among patients with a TMB of at least 10 mutations per megabase, irrespective of PD-L1 expression level. The investigators reported the findings for this coprimary endpoint in NEJM.
The trial was designed and data were analyzed jointly by the sponsor (Bristol-Myers Squibb) and a steering committee, with the participation of individual authors. All the investigators collected data. The trial protocol was approved by the institutional review board or independent ethics committee at each centre. The protocol was amended on the basis of external evidence to include TMB–based efficacy analyses in October 2017, after enrolment had been completed but before the database lock and breaking of the coded treatments.
The study enrolled patients with stage IV or recurrent NSCLC who were not previously treated with chemotherapy.
The patients with a level of tumour PD-L1 expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab/ipilimumab combination, nivolumab monotherapy, or chemotherapy.
The patients with a tumour PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab/ipilimumab combination, nivolumab plus chemotherapy, or chemotherapy.
TMB defined as the number of somatic, coding base substitutions and short insertions and deletions (indels) per megabase of genome examined, was determined by the FoundationOne CDx assay.
The 1-year PFS rate was 42.6% with nivolumab/ipilimumab combination versus 13.2% with chemotherapy. The median PFS was 7.2 months versus 5.5 months (hazard ratio for disease progression or death, 0.58; p < 0.001).
The objective response rate was 45.3% with nivolumab/ipilimumab combination and 26.9% with chemotherapy.
The benefit of nivolumab/ipilimumab combination over chemotherapy was broadly consistent within subgroups, irrespective of PD-L1 expression level.
Data on the safety of nivolumab/ipilimumab combination are consistent with previously reported data on first-line treatment of NSCLC. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab/ipilimumab combination and 36.1% with chemotherapy.
The authors commented that important questions remain regarding the role of immunotherapy combinations versus immunotherapy/chemotherapy combinations, the preferred sequencing of therapies, whether TMB can be used to identify patients who may derive benefit from immunotherapy/chemotherapy combinations, and whether a clinically useful cut-off for TMB can be identified for nivolumab monotherapy.
In CheckMate 227 study, the rate of obtaining results for TMB was 58% due to limited availability of tumour samples of sufficient quantity or quality, mainly as a consequence of limited tissue requested for biomarker analysis. The authors commented that in clinical practice, when TMB test is requested early, successful determination can be expected for 80% to 95% of patients undergoing testing. However, whether circulating tumour DNA could provide a non-invasive method for assessing TMB is not yet clear.
The study findings reported are practice changing and establish the nivolumab/ipilimumab combination as a first-line treatment option for patients with advanced NSCLC and high TMB. The study also identified TMB as an important and reliable biomarker that should be tested in patients with newly diagnosed advanced NSCLC. The overall survival data are still not mature and will add further insights into the clinical benefit of combination of these two immune checkpoint inhibitors as a first-line option for patients with advanced NSCLC and high TMB.
Hellmann MD, Ciuleanu T-E, Pluzanski A, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. NEJM; Published Online 16 April, 2018. DOI: 10.1056/NEJMoa1801946