Cancer Res Treat.  2022 Apr;54(2):424-433. 10.4143/crt.2021.583.

Comparison of the Predictive Power of a Combination versus Individual Biomarker Testing in Non–Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors

• Kim H
• Kwon HJ
• Kim ES
• Kwon S
• Suh KJ
• Kim SH
• Kim YJ
• Lee JS
• Chung JH

• KMID: 2528212
• DOI: http://doi.org/10.4143/crt.2021.583

Abstract

Purpose
Since tumor mutational burden (TMB) and gene expression profiling (GEP) have complementary effects, they may have improved predictive power when used in combination. Here, we investigated the ability of TMB and GEP to predict the immunotherapy response in patients with non–small cell lung cancer (NSCLC) and assessed if this combination can improve predictive power compared to that when used individually.
Materials and Methods
This retrospective cohort study included 30 patients with NSCLC who received immune checkpoint inhibitors (ICI) therapy at the Seoul National University Bundang Hospital. programmed cell death-ligand-1 (PD-L1) protein expression was assessed using immunohistochemistry, and TMB was measured by targeted deep sequencing. Gene expression was determined using NanoString nCounter analysis for the PanCancer IO360 panel, and enrichment analysis were performed.
Results
Eleven patients (36.7%) showed a durable clinical benefit (DCB), whereas 19 (63.3%) showed no durable benefit (NDB). TMB and enrichment scores (ES) showed significant differences between the DCB and NDB groups (p=0.044 and p=0.017, respectively); however, no significant correlations were observed among TMB, ES, and PD-L1. ES was the best single biomarker for predicting DCB (area under the curve [AUC], 0.794), followed by TMB (AUC, 0.679) and PD-L1 (AUC, 0.622). TMB and ES showed the highest AUC (0.837) among other combinations (AUC [TMB and PD-L1], 0.777; AUC [PD-L1 and ES], 0.763) and was similar to that of all biomarkers used together (0.832).
Conclusion
The combination of TMB and ES may be an effective predictive tool to identify patients with NSCLC patients who would possibly benefit from ICI therapies.

Keyword

Tumor mutational burden; Gene expression profiling; Predictive biomarker; Immune checkpoint inhibitors; Non/small cell lung cancer

Figure

• 

  Fig. 1 Summary of the clinical and molecular features associated with response to anti–PD-1/PD-L1 therapy in non-small cell lung cancer patients. Individual patients are represented in each column and sorted according to treatment response (DCB vs. NDB). Tumor histology and smoking status are characterized. PD-L1 expression is stratified as < 1%, 1%–49%, and ≥ 50%. The frequency of a selected gene mutation and tumor mutational burden (mutations/megabase) are sequentially displayed on the histogram. DCB, durable clinical benefit; NDB, no durable benefit; PD-1, programmed death-1; PD-L1, programmed cell death-ligand-1; TMB, tumor mutational burden; VUS, variant of uncertain significance.

• 

  Fig. 2 Tumor mutational burden (TMB) according to response to anti–PD-1/PD-L1 therapy. TMB was greater in patients with DCB than in those with NDB and was significantly different among those with CR/PR vs. SD vs. progressive disease. Box plots represent medians and interquartile ranges. Vertical lines extend to the 95th percentiles. CR, complete response; DCB, durable clinical benefit; NDB, no durable benefit; PD, progressive disease; PD-1, programmed death-1; PD-L1, programmed cell death-ligand-1; PR, partial response; SD, stable disease; TMB, tumor mutational burden. *p < 0.05.

• 

  Fig. 3 (A) Top ten pathways with gene ontology molecular function, as identified by singular enrichment analysis. (B) Representative differentially expressed genes in the DCB and NDB groups. (C) Gene set enrichment analysis showed that the DCB group was significantly enriched in the GSE37605 (Treg and Tconv Cells) and GSE20366 (TregLP vs. TconvLP up). DCB, durable clinical benefit; NDB, no durable benefit.

• 

  Fig. 4 Receiver operating characteristic curve of sensitivity vs. 1-specificity of durable clinical benefit for TMB, ES, PD-L1, and the combination of two or more biomarkers. ES, enrichment score; PD-L1, programmed cell death-ligand-1; TMB, tumor mutational burden.

• 

  Fig. 5 Kaplan-Meier survival curves showing progression-free survival according to TMB (A) and ES (B). ES, enrichment score; TMB, tumor mutational burden.

Reference

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