Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

Abstract

Immunotherapy induces durable responses in a subset of patients with cancer. High TMB may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free and overall survival (PFS, OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥ 20 mutations/mb) vs. low to intermediate TMB was 22/38 (58%) vs. 23/113 (20%) (P = 0.0001); median PFS, 12.8 vs. 3.3 months (P = <0.0001); median OS, not reached vs. 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders vs. non-responders treated with anti-PD-1/PD-L1 monotherapy was 18.0 vs. 5.0 mutations/mb (P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations vs. anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%) (P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB.

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

“…In a recent report showing that high TMB predicts immunotherapy response in diverse cancers, where TMB was defined as the rate of nonsynonymous mut/Mb, the TMB categories were assigned as low (1–5 mut/Mb), intermediate (6–19 mut/Mb) and high (≥ 20 mut/Mb), and corresponded to approximately 50%, 40% and 10% of the sampled population, respectively. 8 Accordingly, this study would have assigned 83% of the TMB-Hi breast tumors (as defined by our TMB cutpoint) to their low TMB category, and only 7 breast tumors in the entire TCGA cohort would have qualified for their definition of high TMB. To better understand this, we used our TMB computation method to compare the TMB distribution of BRCA to that of other TCGA cancer types and immunotherapy-treated cancers, in particular (eFigure 3 in Supplement 1).…”

“…6,7 TMB is associated with clinical benefit to immune checkpoint blockade in patients with melanoma, lung, and colon cancer. 8–11 The role of TMB in tumor immunogenicity is less clear in breast cancer. While TMB is higher in estrogen receptor (ER)-negative tumors compared with ER-positive tumors, consistent evidence that mutational burden itself significantly correlates with TIL levels is lacking.…”

Diagnostics for Targeted NSCLC Therapy

“…Although there is still a limited number of therapy relevant mutations including point mutations, copy number variations, translocations and fusions, insertions and deletions [7,8], several studies test for virtually all mutations known to be associated with cancers. This includes for example the tumor mutational burden (TMB), which was shown to be associated with a better outcome of immunotherapies, although the biological mechanism is not yet known [9]. As long as the underlying biological significance of the TMB is not assessed, it is rather a parameter for statistical correlations than a diagnostic biomarker.…”

Somatic mutation-associated T follicular helper cell elevation in lung adenocarcinoma

“…Increased neoantigen loads have been associated with improved responses to checkpoint blockade in cancers, and neoantigen specific T cells have been isolated in patients responding to immune checkpoint inhibitors. 11 The role of neoantigen-specific CD4 + T cells in guiding anti-tumour immunity has been demonstrated, but due to the extensive ex vivo T cell expansion required to identify these cells, the original phenotypes of the CD4 + T cells are lost. The role that CD4+ Tfh cells play in orchestrating the neoantigen-specific antitumour immune response has yet to be investigated.…”