How Tumour Mutation Burden Affects Immunotherapy Response

Tumour mutation burden (TMB) is a genomic biomarker that measures how many mutations are present in a tumour's DNA. Like PD-L1 expression and MSI-H status, high TMB is associated with a better chance of responding to pembrolizumab. Understanding it adds another dimension to how eligibility for immunotherapy is assessed.

What TMB measures and why it matters

Every cancer accumulates mutations - changes in the DNA sequence of tumour cells - as it develops. These mutations can produce abnormal proteins (neoantigens) that the immune system may recognise as foreign. Tumours with a high number of mutations - high TMB - present more of these potential targets to immune cells. When pembrolizumab releases the PD-1 brake, T cells have more to recognise and attack in high-TMB tumours.

TMB is measured by sequencing the DNA of the tumour and counting the number of somatic mutations per megabase of coding sequence. High TMB is typically defined as 10 mutations per megabase or higher, though thresholds vary by assay and clinical context.

The KEYNOTE-158 TMB-H approval

KEYNOTE-158 was a basket trial that enrolled patients with multiple tumour types who had progressed on standard therapy. Analysis of TMB data from this trial demonstrated that patients with TMB-high tumours had higher response rates to pembrolizumab than those with lower TMB, across multiple cancer types. This led to the first tumour-agnostic approval for TMB-high solid tumours - meaning pembrolizumab is approved for any cancer with TMB 10 mutations per megabase or higher that has progressed after prior treatment, regardless of cancer type.

TMB vs PD-L1: are they interchangeable?

No. TMB and PD-L1 expression measure different things and are not strongly correlated. A tumour can have high TMB and low PD-L1, or vice versa. Some patients who are PD-L1 negative or low may still benefit from pembrolizumab if their TMB is high. In practice, both biomarkers provide complementary information, and oncologists may use both when evaluating immunotherapy suitability.

TMB testing requires a next-generation sequencing (NGS) panel rather than standard immunohistochemistry, and is not available at all centres. If you have had genomic profiling of your tumour and received a TMB result, include this in your eligibility check information.