Nivolumab with radiation therapy in a glioblastoma patient with Lynch syndrome

Abstract

Lynch syndrome is an autosomal dominant disorder leading to cancer predisposition caused by mutations in mismatch repair genes. There is minimal published experience treating glioblastoma in patients with Lynch syndrome. We report a patient with Lynch syndrome who was initially diagnosed with a left occipital isocitrate dehydrogenase (IDH) wild-type glioblastoma. After resection, she was treated with chemoradiation, followed by tumour treating fields. Three years after diagnosis, recurrence was resected. After refusing cytotoxic chemotherapy, decision was made to treat with off-label nivolumab concurrently with radiation. She has been maintained on nivolumab without recurrence of her glioblastoma now over 5 years out from her initial diagnosis. This case provides the first report of glioblastoma in a patient with Lynch syndrome responding to nivolumab and concurrent radiation. In patients with Lynch syndrome and glioblastoma, immunotherapy in the form of nivolumab may be an alternative option to standard cytotoxic chemotherapy.

Durable benefit and change in TCR clonality with nivolumab in a Lynch syndrome–associated glioma

“…Interestingly, two of the latter three cases were alive without disease 20 and 60 months after starting anti-PD-1 therapy (Table 2). [17][18][19] Similar to the case reported by Kamiya-Matsuoka et al, 17 our patient did not respond to anti-PD--1 inhibition, but a slowly progressive disease with a 10-month overall survival was achieved, which suggests a true benefit from nivolumab, given the 9.8-month median OS with nivolumab in secondline recurrent unselected GB patients, while our patient received nivolumab as a sixth line of therapy. 11 Therefore, the heavily treated nature of the tumor of our patient may explain the lack of response and limited survival.…”

“…35 In addition, it would have been of interest to study the tumor mutational burden and MSI in our patient's tumor, which, at least in theory, should be TMBhigh and MSI-H as it commonly occurs in LS-associated cancers. 18,19,31 Other heritable syndromes leading to hypermutant cancers that also commonly respond to ICIs are the BMMRDS characterized by the occurrence of gliomas and hematological cancers at early ages, and polymerase deficiency syndrome due to POL-E and POL-D mutations where both colorectal and endometrial cancers but also gliomas are part of the disease spectrum. 13,14,36 A few cases of gliomas treated with anti-PD-1 agents developed within the BMMRDS and germline POLE-mutant syndrome have been reported.…”

“…35 In addition, it would have been of interest to study the tumor mutational burden and MSI in our patient’s tumor, which, at least in theory, should be TMB-high and MSI-H as it commonly occurs in LS-associated cancers. 18,19,31…”

“…Interestingly, two of the latter three cases were alive without disease 20 and 60 months after starting anti-PD-1 therapy (Table 2). 17–19…”

“…1,2 While ICIs against the programmeddeath-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis have not shown efficacy either alone or in combination with bevacizumab or temozolomide in sporadic newly diagnosed or recurrent glioblastoma (GB) (Table 1), a few reported cases of GB associated with germline replication-repair defects (gRRDs) have shown tumor responses to anti-PD-1 agents. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Brilliant responses to these agents have been reported in biallelic mismatchrepair deficiency syndrome (BMMRDS) characterized by the appearance of CNS tumors and hematological cancers at early ages. Benefit from ICIs has also been reported in LS-associated GB (Table 2).…”