Top-line results from the ongoing phase 3 CheckMate-227 trial have shown that treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) led to statistically significant progression-free survival (PFS) benefit (the study’s co-primary end point) compared with chemotherapy in the first-line treatment of patients with advanced non–small-cell lung cancer (NSCLC) and high tumor mutation burden (TMB), regardless of programmed death-ligand 1 (PD-L1) expression. These results highlight the potential of TMB as a biomarker to identify patients who will respond to immune checkpoint inhibitors.
“TMB has emerged as an important biomarker for the activity of immunotherapy. For the first time, this phase 3 study shows superior PFS with first-line combination immunotherapy in a predefined population of NSCLC patients with high TMB,” said Matthew D. Hellmann, MD, a CheckMate-227 investigator and medical oncologist at Memorial Sloan Kettering Cancer Center, New York, NY. “CheckMate-227 showed that TMB is an important, independent predictive biomarker that can identify a population of first-line NSCLC patients who may benefit from the nivolumab plus ipilimumab combination,” he said.
In tumor cells, high TMB corresponds with high levels of neoantigens, peptides that could aid the immune system in recognizing tumors and spur an increase in T-cells and overall antitumor response. In the CheckMate-227 trial, high TMB was defined as ≥10 mutations/megabase, and was measured using FoundationOne CDx, an analytically validated assay from Foundation Medicine. Of patients evaluated for TMB, approximately 45% were classified as having high TMB.
The safety profile of the regimen was consistent with that of previous results in first-line NSCLC for the combination dosing schedule of nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks.
The results come from an analysis of patients from Part 1 of the open-label trial, which consists of Part 1a (which evaluated nivolumab plus ipilimumab and nivolumab monotherapy vs chemotherapy in PD-L1–positive patients with NSCLC) and Part 1b (which evaluated nivolumab plus ipilimumab and nivolumab plus chemotherapy vs chemotherapy in patients whose tumors do not express PD-L1). In addition to PFS, the co-primary end point of the trial is overall survival (OS) in PD-L1–positive patients.
Part 2 of the trial is assessing nivolumab plus chemotherapy versus chemotherapy across a broad population, with OS as the primary end point. The Data Monitoring Committee recommended that the study continue, based on an interim analysis for OS.
Overall, CheckMate-227 has randomized >2500 patients with squamous and nonsquamous advanced NSCLC to evaluate nivolumab-based regimens compared with platinum-doublet chemotherapy as first-line treatments. Results of the study will be presented at a future medical congress.
Pivotal phase 3 CheckMate-227 study demonstrates superior progression-free survival (PFS) with the Opdivo plus Yervoy combination versus chemotherapy in first-line non-small cell lung cancer (NSCLC) patients with high tumor mutation burden (TMB). February 5, 2018. https://news.bms.com/press-release/bms/pivotal-phase-3-checkmate-227-study-demonstrates-superior-progression-free-surviva. Accessed February 22, 2018.