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BACKGROUND: Oncogenic fusions involving neurotrophic tyrosine receptor kinase (NTRK) have been identified across cancer types and represent potential therapeutic targets given availability of TRK inhibitors. Gliomas harboring NTRK fusions have been described most commonly in infants with high-grade histology and hemispheric tumor location, though there is emerging evidence suggesting clinical, histopathologic, and molecular heterogeneity. Herein, we present two cases of NTRK-rearranged suprasellar/ optic pathway gliomas. CASE DESCRIPTIONS: The first patient was diagnosed at 6 months old with an extensive suprasellar/ optic pathway tumor, treated with carboplatin/ vincristine, which initially responded but subsequently progressed. A biopsy was then performed, with pathology consistent with infiltrating piloid astrocytoma with anaplastic features (elevated mitoses and Ki-67 index); a BCAN-NTRK1 fusion was identified by RT-PCR and confirmed by Sanger sequencing. After further disease progression on vinblastine monotherapy, this patient began treatment with entrectinib (NCT02650401), with favorable clinical and radiographic responses thus far. The second patient was diagnosed with a large suprasellar/ optic pathway tumor at 3 years old, and underwent upfront partial resection, revealing similar infiltrating piloid/pilocytic astrocytoma with anaplastic features (elevated mitoses and Ki-67 index). A diagnosis of “midline” infantile high-grade glioma (HGG) was also considered, as with the former case. Sequencing demonstrated a SOX10-NTRK3 rearrangement, resulting in an integrated diagnosis of NTRK-fused infantile HGG, for which the patient recently started treatment with larotrectinib (NCT04655404). Both patients’ fusions retain the entire kinase domain of respective NTRK partners, supporting oncogenicity, and neither tumor harbored additional somatic pathogenic variants (both lacked BRAF alterations). Methylation profiling did not confidently classify either tumor. CONCLUSIONS: NTRK-rearranged gliomas may present with primary suprasellar/ optic pathway involvement in infants. Given the potential to offer targeted therapy, testing for the presence of NTRK fusions should be strongly considered for infantile gliomas in any location, including midline, and across the histologic spectrum.

BACKGROUND: The B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) protein, implicated in self-renewal and DNA-damage signaling, is highly expressed in DIPG and HGG. Preclinically, BMI-1 modulation by unesbulin (PTC596 [which mediates hyperphosphorylation and subsequent degradation of BMI-1]) leads to DIPG/HGG cell proliferation blockade, mitotic abnormalities, and tumor cell sensitization to radiation-induced DNA damage. METHODS: This phase Ib study sought to determine the maximally tolerated dose/ recommended phase 2 dose (RP2D) of unesbulin administered concurrently with radiotherapy and adjuvantly in children with newly diagnosed DIPG or HGG. Patients were enrolled according to a Rolling-6 design and received oral unesbulin twice weekly during radiotherapy and as maintenance therapy. RESULTS: Twenty-seven patients enrolled (median age: 8.5 years [range: 2-18]), including 18 patients with DIPG and nine patients with HGG. Unesbulin was administered in capsule formulation in the first nine patients, then tablet formulation for subsequent patients. Within the capsule formulation group, three dose-limiting toxicities (DLTs) were observed in two patients on dose level 2 (grade 4 neutropenia). Within the tablet formulation group, four DLTs were experienced by three patients on dose level 2 (grade 3 ALT elevation, grade 3 dehydration/vomiting, grade 3 decreased ejection fraction, grade 4 neutropenia). Dose level 1 was declared the RP2D, and six additional patients enrolled in the expansion cohort at this dose without DLTs. Most common drug-related grade 3/4 toxicities were neutropenia (48%), leucopenia (35%), and elevated ALT (26%). Similar pharmacokinetic profiles were observed for capsule and tablet formulations, consistent with adult data. Survival outcomes and genomics results will be shared at time of presentation. CONCLUSIONS: The RP2D of unesbulin in children newly diagnosed with DIPG or HGG is 200mg/m2 twice weekly, concurrent with and following radiotherapy. The recently opened surgical cohort will assess intratumoral pharmacokinetics and inhibition of tumor BMI-1 signaling, with results forthcoming.