In Reply We thank Fabrizio and colleagues for their comments on our Invited Commentary on the role of tumor mutational burden in selecting patients with lung cancer for first-line immunotherapy.1 The Checkmate 227 study was amended to add a co–primary end point of progression-free survival (PFS) by tissue TMB, with the TMB cutoff prespecified as 10 mutations per megabase (mut/Mb), based on data from the phase 2 CheckMate 568 study (NCT02659059).2 The relationship between plasma TMB and outcome in the MYSTIC study was an exploratory end point only, with the optimal blood TMB cutoff of 20 mut/Mb being retrospectively determined, rather than prospectively defined as in CheckMate 227.2,3 Both studies used the FoundationOne CDx assay for tumor TMB testing on archival/fresh tumor tissue collected prior to study enrollment, with valid TMB data available for only 57.7% and 41.1% of randomized patients from the CheckMate 227 and MYSTIC studies, respectively.