Glioblastoma is the most lethal primary central nervous system (CNS) tumor with a median survival of< 2 years. Despite therapeutic advances, glioblastomas present relapse almost without exception. Currently, there is no proven therapeutic strategy at recurrence. Bevacizumab, a monoclonal antibody targeted at vascular endothelial growth factor (VEGF), serves as an option for salvage treatment. Immunotherapy has yielded remarkable clinical benefits in several advanced non-CNS malignancies, and recent breakthroughs on CNS immune system herald an era of immunotherapy in brain cancers. Several trials using immune checkpoint inhibitors (ICIs) for glioblastomas are ongoing. Unfortunately, the first phase 3 clinical trial for recurrent glioblastomas using antiprogrammed cell death-1 (anti-PD-1) therapy failed to demonstrate improvement in survival over bevacizumab. 1 The unsatisfactory result using ICI monotherapy has led to an interest in using anti-PD-1 plus anti-VEGF concurrent therapy for recurrent glioblastomas. Herein, we report to our knowledge the first case of a patient with multiple intracranial metastases of an IDH wild-type, MGMT (O6-methylguanine DNA methyltransferase)-unmethylated glioblastoma who was successfully treated with this therapeutic regimen. A 57-yearold male received total resection of the right temporal glioblastoma, fractionated radiotherapy (60 Gy) with concurrent and adjuvant (8 cycles) temozolomide (Figure 1A). The follow-up magnetic resonance imaging (MRI) revealed a newly developed contrast-enhanced lesion near the left foreman of Monro suspected as a metastasis. Chemotherapy with carboplatin, etoposide, and methotrexate was then conducted (for only one cycle) but was immediately ceased due to severe lymphopenia and pulmonary infection. Subsequent MRI revealed disease progression, and fractionated radiotherapy (30 Gy) was performed on the metastasis. After radiation, however, the lesion continued growing and new linear enhancements emerged at several other sites, including the surgical site, leptomeninges of the brain stem, and walls of the ventricles. Next-generation sequencing using a 520-gene panel on the primary specimen revealed an extremely high tumor mutation burden (TMB) of 515.9 per million base pairs and a non-synonymous, somatic mutation in exon 14 of polymerase epsilon gene (POLE). This was considered a driver mutation (c. 1381T> C [p. Ser461Pro]), the same as that reported in the children with mismatch repair deficiency glioblastoma who responded to nivolumab. 2 Since anti-PD-1 therapy has clinical benefits in hypermutated glioblastomas and highgrade gliomas harboring POLE mutations tend to have favorable prognosis, 2–5 concurrent therapy using pembrolizumab (100 mg, per month) plus bevacizumab (200 mg, 3 mg/kg, every 2 weeks) was started. No steroids were administered during treatment. The metastasis shrank by> 90% after the first cycle of treatment, and other intracranial linear enhancements and the lesion disappeared after the second cycle. Complete response as defined by RANO (Response Assessment in Neuro-Oncology) criteria was achieved since no neoplasms were monitored and the T2-plain images maintained stable. Seven months have passed since the start of the concurrent therapy. Karnofsky Performance Scale score increased from 40 to 80, and no treatment-related events were recorded. Biweekly routine treatment and follow-up are ongoing.

Anti-PD-1 therapy activates CNS immunosurveillance and induces lymphocyte infiltration in the glioblastoma lesions. 5 Bevacizumab therapy inhibits tumor angiogenesis and relieves …