Blood tumor mutational burden predicts immunotherapy outcomes in NSCLC
For patients with non–small cell lung cancer (NSCLC), a blood test of tumor mutational burden (TMB) could predict clinical responses to checkpoint inhibitors, according to investigators.
The blood panel, which included 150 genes, showed high correlation with whole-exome sequencing, but it had greater efficiency and cost-effectiveness, which should make it more suitable for clinical use, reported lead author Zhijie Wang, MD, of the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing and his colleagues.
Recent research has shown that whole-exome sequencing or next-generation sequencing can be used to determine TMB, which has been correlated with clinical outcomes of patients with several types of cancer. Blood-based testing that uses circulating tumor DNA (ctDNA) is a logical step forward in this line of biomarker research, and some evidence supports the concept; however, more studies are needed.
“In this study, we aimed to explore the optimal gene panel size and algorithm to design a [cancer gene panel] for TMB estimation, evaluate the panel reliability, and further validate the feasibility of [blood] TMB as a clinically actionable biomarker for immunotherapy,” the investigators wrote in JAMA Oncology.
First, the investigators used whole-exome sequencing data from The Cancer Genome Atlas (TCGA) to design and virtually validate the panel. This process showed that a minimum of 150 genes were needed, with synonymous mutations incorporated to improve correlation with whole-exome sequencing. The investigators then compared the panel’s TMB findings with several established gene panels and used a public NSCLC cohort to stratify checkpoint therapy survival outcomes.
To compare the panel with existing technology, 48 patients with advanced NSCLC underwent TMB testing via the blood-based experimental panel and tissue-based whole-exome sequencing. The tests were well correlated, with a Spearman correlation coefficient of 0.62.
Next, the investigators tested the blood-based panel in 50 NSCLC patients receiving anti–programmed cell death 1 (anti–PD-1) or anti–programmed cell death ligand 1 (anti–PD-L1) therapy. Results showed that the test could predict clinical outcomes. Patients with blood TMB levels of at least 6 had better progression-free survival rates than did those with lower blood TMB levels (hazard ratio, 0.39; P = .01). Similarly, objective response rates were better in patients with higher blood TMB levels (39.3% vs. 9.1%; P = .02).
“The findings suggest that a ctDNA-based [blood] TMB measured by the [experimental] panel could be used as a potential biomarker for anti–PD-1 and anti–PD-L1 treatment in patients with NSCLC,” the investigators concluded.
The study was funded by the National Natural Sciences Foundation Key Program, the National Key R&D Program of China, the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS), and others. Sixteen of the investigators are employed by 3D Medicines.
SOURCE: Wang et al. JAMA Onc. 2019 Feb 28. doi:10.1001/jamaoncol.2018.7098.
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