Comprehensive Genomic Profiling (CGP), which can comprehensively evaluate multiple types of variations in multiple genes in tumor samples and effectively assess complex genomic markers (such as Tumor Mutation Burden, TMB), has become a trend in clinical cancer testing. However, previous CGP tests, including FDA-approved CGP products in the United States (such as Foundation Medicine's F1CDx and Memorial Sloan Kettering Cancer Center's MSK-IMPACT), have been highly reliant on specific certified laboratories, making decentralization impossible. On February 24th, pharmaceutical giant Merck & Co., Inc. (MSD)...The Journal of Molecular Diagnostics The magazine was published onlinePerformance Evaluation of TMB Detection and Correlation Study with the Efficacy of Immune Checkpoint Inhibitor Pembrolizumab (Keytruda, Abbreviated as K Drug) Based on a Globally Standardized CGP Kit (Illumina TruSight™ Oncology 500, Abbreviated as TSO 500)。
This study is the first to systematically compare the correlation in TMB detection performance and the effectiveness in predicting drug efficacy between a standard CGP kit product and classic laboratory reference methods (F1CDx and WES), using clinical study samples from drug marketing registration. The research results confirm,Even for complex biomarkers like TMB, CGP kits have been able to achieve the performance level of reference laboratories.This will mean that more clinical laboratories can be empowered to conduct CGP testing on their own, ensuring the accuracy, repeatability, and comparability of test results across different laboratories and operators. A globally unified standard CGP kit will effectively promote the standardization of NGS in clinical applications and increase testing penetration, benefiting more patients.
In this article titled "Evaluation of the TruSight Oncology 500 Assay for Routine Clinical Testing of Tumor Mutational Burden and Clinical Utility for Predicting Response to Pembrolizumab In the study, the team analyzed paraffin-embedded (FFPE) samples from 294 patients with advanced solid tumors enrolled in eight previous single-agent clinical trials of Keytruda (KEYNOTE-001, KEYNOTE-012, KEYNOTE-028, KEYNOTE-055, KEYNOTE-061, KEYNOTE-086, KEYNOTE-100, KEYNOTE-199). Using the TSO500 reagent and its corresponding localized analysis software, tumor mutational burden (TMB) was assessed across various cancer types. Correlation and consistency analyses were conducted with two widely-used reference methods (F1CDx and WES). Among 268 samples with data from all three methodologies, researchers found that when using thresholds of 10 mut/Mb (for F1CDx and TSO 500) or 175 mut/exome for high tumor mutational burden (TMB-H), TSO 500 demonstrated strong correlations with both reference methods (Pearson correlation coefficient: r=0.98, 95% CI [0.98-0.99] compared to F1CDx; r=0.96, 95% CI [0.96, 0.97] compared to WES).Further ROC (receiver-operating characteristic) analysis showed that the TMB status (TMB-H and non-TMB-H) obtained by the TSO 500 assay was highly consistent with the TMB status obtained by the globally recognized F1CDx and WES assays.(Figure 1)
More importantly, the researchers further combined the previous clinical trial data of the samples to conduct a correlation study on the clinical utility of TSO 500 TMB and the efficacy prediction of Keytruda. In these pan-cancer (including major cancer types such as non-small cell lung cancer, head and neck squamous cell carcinoma, gastric cancer, ovarian cancer, prostate cancer, triple-negative breast cancer, etc.) advanced solid tumor patient samples, the TMB values indicated by TSO 500 were significantly correlated with the efficacy of Keytruda.In terms of sensitivity, specificity, positive predictive value, negative predictive value, and objective response rate for predicting the efficacy of K medicine, the TSO 500 detection method is similar to F1CDx and WES.(ORR results are shown in Figure 2)
Figure 2
The patient samples with advanced solid tumors used in this study were previously utilized to establish the TMB-H threshold (10 mu/Mb) for F1CDx in the KEYNOTE-158 (NCT02628067) clinical trial. As a single-arm, open-label, Phase II basket trial, KEYNOTE-158 demonstrated the efficacy of Keytruda in 790 treatment-naïve or previously treated samples across 11 types of solid tumors. (Figure 3)
Figure 3
In addition to Pembrolizumab, Illumina TSO 500 was published in 2020 inLancet Oncology In a Phase II single-arm clinical trial (NCT02760498) of Cemiplimab (produced by Regeneron in the United States), the tumor mutational burden (TMB) status of enrolled patients was also assessed. Researchers from multiple clinical institutions in the United States, Germany, and Australia, including Harvard Medical School, MD Anderson, and Washington University School of Medicine, found that among the 78 enrolled patients with locally advanced cutaneous squamous cell carcinoma, the TSO 500 TMB status was closely related to the clinical efficacy of Cemiplimab. (Figure 4)
Figure 4
The retrospective study conducted by MSD, which was head-to-head with the classic TMB reference method, further demonstrates,CGP standard kits represented by TSO 500 can effectively assess the TMB status of clinical FFPE samples and are closely related to the immunotherapy efficacy of immune checkpoint inhibitors represented by Keytruda.In clinical testing, the CGP standard kit can provide immunotherapy opportunities for a wide range of cancer patients, especially those with solid tumors and TMB≥10mut/Mb.
References:
1.Marabelle A et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21:1353-1365.
2.Migden MR et al. Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. Lancet Oncol 2020; 21: 294–305.
