Patients with recurrence of high-grade glioma (HGG) after bevacizumab (BEV) have an extremely poor prognosis. Etirinotecan pegol (EP) is the first long-acting topoisomerase-I inhibitor designed to concentrate in and provide continuous tumor exposure throughout the entire chemotherapy cycle. Here we report results of a Phase 2, single arm, open-label trial evaluating EP in HGG patients who progressed after BEV. Patients age >18 with histologically proven anaplastic astrocytoma or glioblastoma (GB) who previously received standard chemo-radiation and recurred after BEV were eligible. A predicted life expectancy >6 weeks and KPS ≥ 50 were required. The primary endpoint was PFS at 6-weeks. Secondary endpoint was overall survival from first EP infusion. Response was assessed by RANO criteria. Single agent EP was administered IV every 3 weeks at 145 mg/m2. Patients did not receive BEV while on EP. 20 patients (90 % GB) were enrolled with a median age of 50 and median KPS of 70. Three patients with GB (16.7 % of GB) had partial MRI responses. 6-week PFS was 55 %. Median and 6-month PFS were 2.2 months (95 % CI 1.4–3.4 months) and 11.2 % (95 % CI 1.9–28.9 %) respectively. Median overall survival from first EP infusion was 4.5 months (95 % CI 2.4–5.9). Only one patient had grade 3 toxicity (diarrhea with dehydration) attributable to EP. Hematologic toxicity was mild. Three patients had confirmed partial responses according to RANO criteria. These clinical data combined with a favorable safety profile warrant further clinical investigation of this agent in HGG.

2058 Background: Glioblastoma is the most common and aggressive primary brain tumor, with 75-85% of patients historically having recurrence within the original tumor site. We have shown in preclinical studies that inhibition of the SDF1/CXCR4 pathway by the CXCR4 inhibitor Plerixafor increases tumor response to irradiation by inhibition of the recovery of tumor blood vessels. Methods: Newly diagnosed glioblastoma patients were enrolled to the clinical trial using the investigational agent Plerixafor after standard radiation therapy and temozolomide (NCT01977677). To date, 28 patients out of the planned accrual of 29 have been enrolled to this study. Normalized relative cerebral blood volume (rCBV) ratios were calculated by the mean rCBV within the 95% isodose radiation field one month post-radiation as compared to contralateral white matter outside of the radiation field. Our imaging analysis compares patients treated with Plerixafor compared to a control group receiving standard therapy (chemo-RT). Results: There was a significant reduction in rCBV measured by DSC-MRI within the 95% isodose field one month after radiation therapy in patients receiving Plerixafor compared to control (p < 0.02). The rCBV out of the radiation field was similar between patients receiving Plerixafor compared to control patients one-month post radiation therapy. As of February 7, 2017, only 2 of the total of 9 recurrences occurred within the irradiated field. The rate of out of field recurrence (77%) was therefore much higher than expected (20%), with statistical significance (p < 0.03, Fisher’s exact test). Conclusions: We show that Plerixafor has a meaningful impact on local control of glioblastoma. Furthermore, DSC-MRI could be a useful biomarker of its efficacy.

BACKGROUND Up to 65% of anaplastic pleomorphic xanthoastrocytomas (A-PXA) harbor the BRAFV600E oncogene. Trials and case series have demonstrated that BRAF-mutant gliomas, including A-PXAs, can be responsive to the first generation BRAF inhibitors dabrafenib and vemurafenib, with an ORR ranging from 26–43%. The second generation BRAF/MEK inhibitor combination encorafenib/binimetinib improves systemic outcome in melanoma patients, has better tolerability, and may have better intracranial activity compared to first generation drugs. METHOD We review the three patients with BRAFV600E A-PXA treated with encorafenib/binimetinib in our practice. RESULTS Two patients were diagnosed with A-PXA in 2014 and one in 2013. The presence of BRAFV600E was confirmed by molecular testing. All patients have received prior surgery, chemotherapy, and radiation and were at a recurrence when BRAF/MEK inhibition was initiated. One patient had CR after 2 months on treatment and remains in CR at 1-year. One patient, who is also receiving bevacizumab, has a PR, with continued clinical and imaging improvement at 6 months. Our third patient had a PR at 2 months and remains on therapy, currently 3 months post-initiation. All 3 patients report improvement in symptoms. The patient who has been on treatment for 1 year experienced rapid onset bilateral multifocal sub-retinal fluid collections followed by rapid resolution, without intervention, within days of starting treatment. This patient has also had mild decrease in EF over time. We will present continued follow up. CONCLUSIONS Encorafenib/binimetinib appears feasible, with 3 of out 3 patients with BRAFV600E A-PXA demonstrating radiographic response; 2 of these patients have durable responses. We stress the importance of a clear lab, cardiac, ophthalmologic, and dermatologic monitoring regimen as side effects can be rapid and severe. Prospective studies with encorafenib/binimetinib in BRAF-mutant primary CNS tumors are underway, and we eagerly anticipate their RESULTS:

Metastases from extra-CNS sites typically enhance on MR after the administration of gadolinium-based contrast agents due to disruption of the blood-brain barrier. Fibromyxoid sarcoma involving the brain is extremely rare, with only a few reported cases manifesting as well-circumscribed enhancing masses. Here, we report an extremely rare non-enhancing brain metastasis secondary to an already rare sarcoma. A 44-year-old woman with gluteal fibromyxoid sarcoma metastatic to cervical paraspinal muscles and adrenal gland treated with ipilimumab/nivolumab presented with diplopia and was found to have an 8 mm T2-hyperintense midbrain lesion without enhancement or mass effect. An inflammatory etiology associated with checkpoint inhibitor therapy was suspected, and she was treated with IV methylprednisolone 1 g daily for 3 days followed by an oral prednisone taper, IV immunoglobulin, and plasma exchange without improvement. The midbrain lesion steadily grew over 15 months of follow up, eventually involving the bilateral medial thalami and demonstrating diffusion restriction in the midbrain, but never showing gadolinium enhancement. The imaging was reminiscent of peripheral brainstem non-enhancing band-like lesions reported in leptomeningeal lung cancer, however CSF cytology was repeatedly normal, as was extensive infectious and inflammatory testing. Her neurologic disability continued to progress, with development of bilateral oculomotor nerve palsies, dysarthria, and depressed level of alertness, devolving into non-convulsive status epilepticus requiring intubation. She died six months after onset of neurologic symptoms. At autopsy, histologic and immunohistochemical evaluation revealed fibromyxoid sarcoma (MUC-4 positive, TAOK1-FUS fusion) centered on the periventricular aqueduct with accompanying disseminated single-cell infiltration throughout the midbrain. The background midbrain and periventricular parenchyma were notable for voluminous microglial activation and histiocytic infiltrate. In sum, this case represents a radiographically unique sarcoma brain metastasis which on pathologic exam showed robust inflammatory changes far out of proportion to the tumor present.