Addressing the need for a non-invasive test for response to atezolizumab (anti-PD-L1 antibody), Gandara et al. evaluated a targeted sequencing capture assay that measures tumor mutation burden (TMB) from circulating free DNA in a baseline blood sample (bTMB). Correlation was high between TMB in tissue and blood samples. Analysis of bTMB from the randomized NSCLC POPLAR study selected a bTMB cut-point of >16 as associated with atezolizumab efficacy and meaningful clinical outcomes. Analysis of the OAK study validated bTMB as a predictive biomarker of improved progression-free survival, independent of the biomarker of high PD-L1.
Although programmed death-ligand 1-programmed death 1 (PD-L1-PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer (NSCLC). However, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging. Thus, an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy. Here, we describe a novel, technically robust, blood-based assay to measure TMB in plasma (bTMB) that is distinct from tissue-based approaches. Using a retrospective analysis of two large randomized trials as test and validation studies, we show that bTMB reproducibly identifies patients who derive clinically significant improvements in progression-free survival from atezolizumab (an anti-PD-L1) in second-line and higher NSCLC. Collectively, our data show that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC.