Tumour mutational burden (TMB) is a promising biomarker of a response to immune-checkpoint inhibitors, independent of programmed cell death 1 ligand 1 (PD-L1) status. TMB is usually measured in DNA from tumour tissue samples through whole-exome sequencing (WES) or sequencing of cancer gene panels (CGPs). New data support the use of plasma cell-free DNA to determine the blood TMB (bTMB) as a less invasive and more convenient alternative.

A novel CGP for TMB assessment was developed and validated virtually using The Cancer Genome Atlas WES data from 9,205 specimens of 33 different cancer types. This CGP panel, NCC-GP150, encompasses the entire exonic regions of 150 rationally selected genes and had a correlation with the WES data similar to that of established CGPs (such as MSK-IMPACT and F1CDx). When NCC-GP150 was applied to a published data set comprising 34 patients with non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death 1 (PD-1) antibodies, a greater than median TMB was associated with better progression-free survival (PFS; HR 0.36, 95% CI 0.14–0.93; P = 0.03).

Assessment of matched tumour tissue and plasma samples from 48 patients with advanced-stage NSCLC using WES and NCC-GP150, respectively, resulted in a Spearman correlation coefficient between tissue TMB and bTMB of 0.62. At the median tissue TMB (75), the optimal bTMB threshold was ≥ 6, with a sensitivity and specificity of 0.88 and 0.71, respectively.

In an independent cohort of 50 patients with advanced-stage NSCLC treated with anti-PD-(L)1 antibodies, those with a bTMB ≥6 (n = 28) had superior objective response rates (39.3% versus 9.1%; P = 0.02) and PFS (HR 0.39; 95% CI 0.18–0.84; P = 0.01). These relationships held upon multivariate analysis. In keeping with previous evidence for tissue TMB, bTMB and PD-L1 status were not correlated.

These findings warrant testing of bTMB as a biomarker in prospective trials.