Pathogenic mutation of DNA polymerase epsilon catalytic subunit (POLE) is associated with high tumor mutation burden (TMB) and response to immune checkpoint inhibitor (ICI) in several cancers. Owing to its rarity, clinical trial to evaluate the ICI efficacy in POLE-mutated glioblastoma is very challenging. Here, we report a case of recurrent POLE-mutated glioblastoma with response to pembrolizumab and bevacizumab. With growing real-world evidence, we propose that ICI may be considered among the treatment options for recurrent hypermutated glioblastoma with POLE mutation.

A 65-year-old man presented with naming difficulty and confusion in October 2016, and brain MRI revealed left parietal enhancing tumor. He underwent awake craniotomy with gross total resection of tumor in November 2016. Pathology confirmed glioblastoma (WHO grade IV), IDH wild type. Standard radiotherapy with concurrent temozolomide followed by adjuvant temozolomide was administered. MRI after 3 cycles of temozolomide demonstrated progression that prompted a repeat resection with pathology confirming recurrent glioblastoma. Tumor multigene panel (FoundationOne) revealed microsatellite stable, high TMB of 32 mutations/Mb. Genomic alterations were identified with mutations of NF1 E524, PIK3CA G118D, PTEN D24Y, E299, CBL splice site 1096-1 G> T, CHD2 E1542, CSF1R F971fs* 7, PIK3R1 R348, POLE P286R, SETD2 E463, E581 and TP53 P151S, and R213. These mutations were determined as clonal events. The pathogenic POLE P286R is the most common somatic mutations involving the proofreading domain leading to hypermutation with neoantigen abundance and T-cell infiltration rendering response to ICI in several cancers. 1, 2 One month after resection, tumor progression was noted. Therefore, pembrolizumab 200 mg with bevacizumab 10 mg/kg were given every 3 weeks with neurologic improvement and without significant side effects. Our reason to combine bevacizumab was for symptom control from edema requiring corticosteroids (Figure 1A and D). As corticosteroids