HGG-62. Molecularly guided treatment of mismatch repair-deficient pediatric brain tumors

Mismatch repair (MMR)-deficient brain tumors, defined by high tumor mutational burden (TMB) and alterations in MMR or DNA proofreading genes, may harbor therapeutic vulnerabilities to immune checkpoint inhibition (ICI) and resistance to temozolomide. We report a single-institution experience incorporating a personalized genomics approach for pediatric brain tumor patients with high TMB. Tumor and peripheral blood samples were obtained at surgery or autopsy and molecular profiling performed by UWOncoPlex, a multiplexed DNA sequencing panel. Treatment and survival information was obtained by medical records review. Tumor types included high-grade glioma (10, including 1 DIPG), and desmoplastic/nodular medulloblastoma (1). Metachronous tumors were present in three patients and median age at diagnosis was 11.5 years (range 8 – 18). Constitutional predisposition included MMR deficiency (CMMRD), Lynch syndrome, and polymerase proofreading deficiency (PPD). All patients had localized disease, with gross total resection achieved in 6/11 (55%). All received radiation (RT), with concurrent temozolomide delivered in HGG (9). 7/9 patients (78%) with HGG had radiographic progression following RT/temozolomide. Five patients received ICI with pembrolizumab (4), nivolumab/ipilimumab (2), or nivolumab alone (1). Two patients progressed on pembrolizumab then had partial responses to dual nivolumab/ipilimumab. Another patient had a complete response to pembrolizumab and remains disease-free nearly 1 year after discontinuing drug due to reactivated skin GHVD. While not statistically significant in this small cohort, median survival of ICI-treated patients (5) compared to those who received alternative therapies (6) was 40.4 vs. 17.7 months. Patients with durable responses >18 months to ICI (3) included one who underwent surgical debulking following nivolumab, and two patients molecularly classified as CMMRD + somatic PPD. This series highlights the importance of integrating molecular findings and identification of high TMB early in clinical diagnosis and supports the use of ICI to achieve durable responses in children with MMR-deficient brain tumors.