High TMB, Adverse Events May Predict Immunotherapy Response in mUC


Patients with metastatic urothelial carcinoma with higher tumor mutational burden and who experienced immune-related adverse events tended to have higher response rates to immune checkpoint inhibitor.

Patients with metastatic urothelial carcinoma (mUC) who had a higher tumor mutational burden (TMB) tended to have more immune-related adverse events (irAEs) than those with low TMB. Additionally, high TMB and irAEs rates were associated with better response rates with immunotherapy, according to recent research presented at the 2021 Genitourinary Cancers Symposium.

“It has been shown previously in the literature that TMB serves as a candidate biomarker of clinical outcomes from immune checkpoint inhibitors in urothelial carcinoma. In addition, the immune-related adverse events have been associated with a better [immune checkpoint inhibition] efficacy in multiple cancers,” said study author Elie W. Akl, MD, of the Dana-Farber Cancer Institute.

“So, we hypothesized that the immune response against new antigens is partly responsible for [irAEs] and investigated the association between [irAEs] and TMB and response to [immune checkpoint inhibition].”

The study involved 101 patients with mUC who were being treated with immune checkpoint inhibition (either single-agent or combination) at the Dana-Farber Cancer Institute.

About a third of patients (32%) reported irAEs. Six patients had grade 1 irAEs, 20 patients had grade 2, and 6 patients had grade 3. Those who experienced irAEs had a higher average TMB (15.4/mb) than those without irAEs (9.8/mb). Notably, the cutoff for TMB-high was 10/mb (non-synonymous exonic mutations per megabase).

Ninety-four patients had radiological data available at the time of the study. Among them, 50% of patients with irAEs responded, to therapy, compared to only 16% of patients without irAEs (P < .001).

“However, when both adverse events and response were included in the multivariable regression, the association between adverse events and TMB was not significant,” Akl explained.

Patients who experienced an irAE and had a high TMB had an overall response rate of 56%, about double the rate of patients who had an irAE but low TMB, at 28.6%. That finding was statistically significant. A total of 21.2% of patients with high TMB but no irAE responded, and 10.3% of patients with low TMB and no irAE responded.

The researchers did not find any correlation between TMB and grading of irAE.

Looking ahead, Akl said the further research is warranted to better understand the associations between TMB, irAEs, and immunotherapy response.

“Further evaluation in metastatic urothelial carcinoma is needed to confirm this relationship between TMB adverse events and response, a larger cohort and explore specific mutations signature that may be associated with immune-related adverse events,” he said.

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