Brief Report: Correlation cannot be used to compare sequencing panels used for the assessment of tumor mutational burden in non-small cell lung cancer.

Introduction Tumor mutational burden (TMB) has been proposed as a novel predictive biomarker for the stratification of patients undergoing immune-checkpoint inhibitor (ICI) treatment in non-small cell lung cancer (NSCLC) patients. The assessment of TMB has recently been established using large targeted sequencing panels and numerous studies are ongoing to harmonize the TMB assessment. However, usually "correlation" has been used to evaluate the association between the respective panels and we hypothesized that correlation might overestimate the comparability especially in lower TMB values, thus limiting the joint analysis of targeted sequencing panels for the assessment of TMB. Methods Thirty NSCLC samples from patients undergoing ICI treatment were consecutively sequenced using three large targeted sequencing panels: FoundationOne, Oncomine TML and QiaSeq TMB, respectively. TMB values were compared in the whole patient population and in a subset of patients where the TMB assessed by FoundationOne was between 5-25 mutations/Mb. Prediction of durable clinical benefit (DCB; >6 months no progression) was assessed using receiver operator characteristics and optimal cut-off values were calculated using Youden9s J. Results Correlation between the targeted sequencing panels was strong in the whole patient population between the three panels (R2 > 0.79) but was dramatically reduced in the subset of patients with TMB 5-25 mutations/Mb. All panels were able to predict DCB in the TMB high population. Conclusions Assessment of TMB using the three targeted sequencing panels was possible and predictive of response to ICI treatment but "correlation" was an inappropriate measurement to assess the association between the respective panels.