Utility of Tumor Mutational Burden as a Biomarker for Response to Immune Checkpoint Inhibition in the VA Population

Immune checkpoint inhibitors (ICIs) are used for an increasing number of indications across various tumor types, as well as several tumor-agnostic indications in patients with advanced cancer. Although many patients benefit from ICI therapy, others do not, highlighting a need for better predictive biomarkers. Tumor mutational burden (TMB) reflects the global number of mutations within a tumor and has been widely explored as a predictive biomarker of ICI response. The current tumor type-agnostic US Food and Drug Administration approval of pembrolizumab for metastatic solid tumors defines high TMB (TMB-H) as ≥10 mut/Mb as measured by FoundationOne CDx. This fixed cutoff may not be the ideal value across all solid tumors.

We performed a retrospective analysis of the association of survival outcomes with TMB in patients treated with ICI for five major cancer types, using real-world data from the VA. Survival was measured from initiation of ICI, and Kaplan-Meier survival curves were compared by log-rank test.

Overall survival (OS) was significantly longer for patients with TMB-H versus TMB low tumors in non-small-cell lung cancer (NSCLC; n = 1,593), head and neck (H&N) cancer (n = 222), and urothelial cancer (n = 332). OS was not significantly different based on TMB status in melanoma (n = 207) or esophageal/gastric cancer (n = 248).

Consistent with previous studies, a predictive value of TMB ≥10 mut/Mb for ICI response was found in NSCLC and H&N, but not in esophageal/gastric cancer. Although inconclusive in the literature, significant association was found in urothelial cancer. The predictive value of TMB in melanoma was inconclusive. Our analysis does not support the use of a fixed threshold for TMB as a standalone predictive biomarker for ICI across all solid tumors.