RNA interference–based spherical nucleic acid nanoconjugates are a potentially safe and brain-penetrant approach for glioblastoma treatment.

Purpose: ANG1005, a novel taxane derivative, consists of 3 paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood-brain and blood-cerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown. Experimental Design: A multi-center, open-label phase 2 study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis (LC) was conducted (n=72 BCBM; n=28 LC subset). ANG1005 was administered IV at 600 mg/m² q3w. Tumor assessment was based on CNS RECIST 1.1 for intracranial, and RECIST 1.1 for extracranial response. The primary endpoint was determination of intracranial objective response rate (iORR). Results: Median age was 47.5 years. Safety profile was similar to that of paclitaxel with myelosuppression as the predominating toxicity. Average number of prior CNS directed therapies was 2.6 and 94% of the patients had prior taxane treatment. Patient benefit (stable disease or better) was seen in 77% (intracranial) and 86% (extracranial) of the evaluable patients, with iORR of 15% (investigator) or 8% (independent radiology review). In the LC subset, 79% of the patients had intracranial disease control and estimated median overall survival of 8.0 months (95% CI 5.4 - 9.4). Conclusions: Even though the study pre-set rule for iORR per IRF was not met in this heavily pretreated population, a notable CNS and systemic treatment effect was seen in all patients, particularly in LC patients, including symptom improvement and prolonged overall survival compared to historical control.

Brain metastases occur commonly in patients with advanced solid malignancies. Yet, less is known about brain metastases than cancer-related entities of similar incidence. Advances in oncologic care have heightened the importance of intracranial management. Here, in this consensus review supported by the Society for Neuro-Oncology (SNO), we review the landscape of brain metastases with particular attention to management approaches and ongoing efforts with potential to shape future paradigms of care. Each coauthor carried an area of expertise within the field of brain metastases and initially composed, edited, or reviewed their specific subsection of interest. After each subsection was accordingly written, multiple drafts of the manuscript were circulated to the entire list of authors for group discussion and feedback. The hope is that the these consensus guidelines will accelerate progress in the understanding and management of patients with brain metastases, and highlight key areas in need of further exploration that will lead to dedicated trials and other research investigations designed to advance the field.

Leptomeningeal metastases (LM) are increasingly becoming recognized as a treatable, yet generally incurable, complication of advanced cancer. As modern cancer therapeutics have prolonged the lives of patients with metastatic cancer, specifically in patients with parenchymal brain metastases, treatment options, and clinical research protocols for patients with LM from solid tumors have similarly evolved to improve survival within specific populations. Recent expansions in clinical investigation, early diagnosis, and drug development have given rise to new unanswered questions. These include leptomeningeal metastasis biology and preferred animal modeling, epidemiology in the modern cancer population, ensuring validation and accessibility of newer leptomeningeal metastasis diagnostics, best clinical practices with multimodality treatment options, clinical trial design and standardization of response assessments, and avenues worthy of further research. An international group of multi-disciplinary experts in the research and management of LM, supported by the Society for Neuro-Oncology and American Society of Clinical Oncology, were assembled to reach a consensus opinion on these pressing topics and provide a roadmap for future directions. Our hope is that these recommendations will accelerate collaboration and progress in the field of LM and serve as a platform for further discussion and patient advocacy.

PURPOSE: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDH^wt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDH^wt GBM have a median age of diagnosis at 68–70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM. The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship. Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve. Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDH^wt GBM patient outcomes.