Abstract
Tumor mutational burden (TMB) has emerged as an important potential biomarker for prediction of response to immune-checkpoint inhibitors (ICIs), notably in non-small cell lung cancer (NSCLC). However, its in-house assessment in routine clinical practice is currently challenging and validation is urgently needed. We have analyzed sixty NSCLC and thirty-six melanoma patients with ICI treatment, using the FoundationOne test (FO) in addition to in-house testing using the Oncomine TML (OTML) panel and evaluated the durable clinical benefit (DCB), defined by >6 months without progressive disease. Comparison of TMB values obtained by both tests demonstrated a high correlation in NSCLC (R2 = 0.73) and melanoma (R2 = 0.94). The association of TMB with DCB was comparable between OTML (area-under the curve (AUC) = 0.67) and FO (AUC = 0.71) in NSCLC. Median TMB was higher in the DCB cohort and progression-free survival (PFS) was prolonged in patients with high TMB (OTML HR = 0.35; FO HR = 0.45). In contrast, we detected no differences in PFS and median TMB in our melanoma cohort. Combining TMB with PD-L1 and CD8-expression by immunohistochemistry improved the predictive value. We conclude that in our cohort both approaches are equally able to assess TMB and to predict DCB in NSCLC.
Highlights
Immune checkpoint inhibition (ICI) has dramatically revolutionized treatment in various cancers [1], notably in non-small cell lung cancer (NSCLC) and melanoma [2,3]
Mutations detected by FoundationOne test (FO) for the 30 most mutated genes are shown in Figures S2 and S3
The median turn-around time (TAT) for samples sent to Foundation Medicine was 15 business days for NSCLC samples and 13 business days for melanoma samples (Figure S4)
Summary
Immune checkpoint inhibition (ICI) has dramatically revolutionized treatment in various cancers [1], notably in non-small cell lung cancer (NSCLC) and melanoma [2,3]. The expression of Programmed Death-Ligand 1 (PD-L1) as assessed by immunohistochemistry (IHC) in tumor cells has been the only FDA-approved biomarker for the selection of patients undergoing ICI in NSCLC [4]. PD-L1 IHC has limitations in the prediction of durable clinical benefit (DCB) in patients treated by ICI [5,6]. PD-L1 expression in tumor-infiltrating immune cells as well as the tumor infiltration of CD8+ -lymphocytes has been studied as potential biomarkers in ICI [7,8,9,10]. TMB was evaluated using whole exome sequencing (WES) [12,18,19], but for implementation in routine clinical practice, specific targeted sequencing panels have been developed [14,20,21]. The data obtained from these targeted sequencing panels showed significant correlations with WES datasets and predictive power across several solid tumor types [19,22,23]
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