Changing a pivotal trial’s primary endpoint analysis after the study is under way is usually not a good sign. So when Bristol-Myers Squibb Co. revealed top-line results from the CheckMate -227 trial in a biomarker-defined population that differed from the one it started with, some analysts and media were dubious.
Changing the population in which the endpoint was measured, however, appears to have been the only reasonable move BMS could have made. Emerging science suggests the new biomarker could identify responders who are missed by existing assays.
CheckMate -227 is an open-label Phase III trial in first-line non-small cell lung cancer (NSCLC). The first part is testing Opdivo nivolumab plus Yervoy ipilimumab or Opdivo monotherapy vs. chemotherapy doublet. The second part is comparing Opdivo plus chemotherapy doublet vs. chemotherapy doublet alone.
Part 1 began in August 2015, and stratified patients by PD-L1 status. The Part 1a subgroup included patients with expression ≥1% as assessed with the PD-L1 IHC 28-8 pharmDx assay. All others were put in the Part 1b subgroup, which also included an Opdivo plus chemotherapy doublet instead of the Opdivo monotherapy arm in the Part 1a portion of the trial.
“It seemed to us that TMB was our strongest hypothesis and therefore we had to ask the question.”
The protocol specified different primary endpoints for these subgroups: overall survival (OS) for patients in Part