Abstract
In non‐small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS). Tumor mutational burden (TMB) has emerged as a predictive biomarker for patients treated with ICIs. Here, we evaluated the predictive power of TMB measured by the Oncomine™ Tumor Mutational Load targeted sequencing assay in 76 NSCLC patients treated with ICIs. TMB was assessed retrospectively in 76 NSCLC patients receiving ICI therapy. Clinical data (RECIST 1.1) were collected and patients were classified as having either durable clinical benefit (DCB) or no durable benefit (NDB). Additionally, genetic alterations and PD‐L1 expression were assessed and compared with TMB and response rate. TMB was significantly higher in patients with DCB than in patients with NDB (median TMB = 8.5 versus 6.0 mutations/Mb, Mann–Whitney p = 0.0244). 64% of patients with high TMB (cut‐off = third tertile, TMB ≥ 9) were responders (DCB) compared to 33% and 29% of patients with intermediate and low TMB, respectively (cut‐off = second and first tertile, TMB = 5–9 and TMB ≤ 4, respectively). TMB‐high patients showed significantly longer progression‐free survival (PFS) and OS (log‐rank test p = 0.0014 for PFS and 0.0197 for OS). While identifying different subgroups of patients, combining PD‐L1 expression and TMB increased the predictive power (from AUC 0.63 to AUC 0.65). Our results show that the TML panel is an effective tool to stratify patients for ICI treatment. A combination of biomarkers might maximize the predictive precision for patient stratification. Our study supports TMB evaluation through targeted NGS in NSCLC patient samples as a tool to predict response to ICI therapy. We offer recommendations for a reliable and cost‐effective assessment of TMB in a routine diagnostic setting. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
The outcome of metastatic non-small cell lung cancer (NSCLC) patients has been considerably improved by the use of immune checkpoint inhibitors (ICIs) targeting programmed cell death receptor-1 (PD-1) or its ligand (PD-L1) [1,2,3]
We examined the performance of the OncomineTM TML assay by retrospectively assessing tumor mutational burden (TMB) in tumor tissue specimens from advanced NSCLC patients who had been treated with ICI therapy
The OncomineTM TML assay is currently being evaluated as part of one of these initiatives, which directly analyzes the assay reproducibility across multiple centers and compares its performance with FDA-approved diagnostic tests
Summary
The outcome of metastatic non-small cell lung cancer (NSCLC) patients has been considerably improved by the use of immune checkpoint inhibitors (ICIs) targeting programmed cell death receptor-1 (PD-1) or its ligand (PD-L1) [1,2,3]. The clinical utility of TMB in ICI treatment of NSCLC has been supported by few seminal studies in which the mutational load was measured through whole-exome sequencing (WES) [14,15,16] or targeted sequencing [17, 18]. In all of these studies, high mutational load correlated with increased response rate to ICIs and longer progression-free survival (PFS) in NSCLC patients. No correlation was observed between PD-L1 expression and mutational load, suggesting that these biomarkers characterize different patient populations
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