Tumour mutational burden predicts irAEs with immunotherapy

By Michael Woodhead

4 Sep 2019

A high Tumour Mutational Burden  (TMB) may be a useful biomarker for assessing patients’ risk of immune-related adverse events (irAEs) during anti-PD1 immunotherapy, a study shows.

A retrospective review of irAEs reported for 3661 patients treated with the anti–PD-1 agents nivolumab or pembrolizumab found a significant positive relationship with TMB (defined as the median number of coding somatic mutations per megabase of DNA) across 19 cancer types.

The findings, published by Swiss researchers in JAMA Oncology, are based on adverse event reports submitted to the US Food and Drug Administration Adverse Event Reporting System (FAERS) from July 1, 2014, to March 31, 2019. The irAEs were reported by 22.3% of 16,397 patients treated with anti–PD-1 monotherapy.

The risk of a patient developing any irAE was estimated as reporting odds ratios (RORs) based on comparisons with a control group comprising 16.4 million adverse event reports from 5.2 million patients treated with other drugs. The median TMB in tumour tissue was obtained from previously published comprehensive genomic profiling.

The analysis showed there was a significant positive correlation between the reporting odds ratio for an irAE during anti-PD-1 therapy and the corresponding TMB across all 19 cancer types.

A higher odds of irAEs – as seen with cancers such as melanoma and lung cancer –  was associated with a higher median number of coding somatic mutations per megabase of DNA .

According to the study investigators, the Pearson correlation coefficient (0.704) suggested that 50% of the differences in the irAE risk across cancer types may be attributed to the TMB.

“Our analysis indicates that cancers with a high TMB, such as melanoma and non–small cell lung cancer, are associated with a higher irAE ROR during anti–PD-1 therapy, strongly suggesting that these cancers are associated with a higher risk of irAEs than cancers with a low TMB,” they wrote.

The differences in irAE rates might be explained by the different neoantigenic load across cancer types, or reflect the fact that T cells that react against a neoantigen can crossreact against the corresponding wild-type protein.

Another contributing mechanism could be antigen spreading, where tumour cell death releases antigens, including neoantigens, that prime lymphocytes against the wild-type antigens in healthy tissue.

And the association between irAEs and improved response to anti-PD-1 treatment may be linked via an underlying neoantigenic potential that stems from a high TMB, they added.

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