Limited evidence of tumour mutational burden as a biomarker of response to immunotherapy

Cancer immunotherapy by checkpoint blockade (ICB) is effective for various cancer types, yet its clinical use is encumbered by a high variability of patient response. Several studies have reported that the number of non-synonymous mutations (Tumor Mutational Burden, TMB), can predict patient response to ICB. This belief has become widespread and led to the FDA approval of immunotherapy patient prioritization based on TMB levels. The notion that TMB is predictive of response to immunotherapy is rooted in the neoantigen theory. It stipulates that cancer-specific mutations can form neoantigens recognized by the immune system; the more mutations a tumor has, the more likely the immune response is triggered. Here we revisit the data underlying the reported association of TMB with response, and the neoantigen theory. First we assembled the largest pan-cancer dataset of immunotherapy patients with sequencing and clinical data. Surprisingly, we find little evidence that TMB is predictive of response to ICB. We demonstrate that associations similar to the ones reported previously can be observed in shuffled data, suggesting that previous studies suffered from a lack of correction for multiple hypotheses testing and confounding disease subtypes. Second, we develop a model that expands the neoantigen theory and can be consistent with both immunogenicity of neoantigens and the lack of association between TMB and response. Our analysis shows that the use of TMB in clinical practice is not supported by available data and can deprive patients of treatment to which they are likely to respond.