What is the Burden of Proof for Tumor Mutational Burden in gliomas?

The treatment of patients with a variety of solid tumors has benefitted from immune checkpoint inhibition targeting the anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis. The US Food and Drug Administration (FDA) granted accelerated approval of PD-1 inhibitor pembrolizumab for the treatment of adult and pediatric patients with TMB-high (TMB-H), solid tumors that have progressed following prior treatment and who have no other treatment options, including the extension to tumors of the Central Nervous System (CNS). In general, pan-cancer approvals are viewed positively to empower patients and clinicians. There are subsets (eg, BRAF, NTRK) for which this pathway for approval is appropriate. However, the pan-cancer FDA approval of pembrolizumab raises several concerns regarding the generalizability of the evidence to other tumor types, including managing patients with gliomas and other CNS tumors. The cut off for TMB-H is not well defined. There are intrinsic immunological differences between gliomas and other cancers types, including the immunosuppressive glioma microenvironment, the tumor's effects on systemic immune function, and the transformation of the T cell populations to an exhausted phenotype in glioma. Here we address the caveats with pan-cancer approvals concerning gliomas, complexities of the unique CNS immune environment, and discuss potential predictive biomarkers, including TMB, and explain why the recent approval should be applied with caution in CNS tumors.