Targeted agents recommended by the CNS TAP tool compared to those selected by a tumor board in a molecularly-driven clinical trial in children and young adults with DIPG.

Abstract

2048 Background: Genetic sequencing of diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) biopsy specimens has revealed genomic heterogeneity, fueling an interest in individualized, targeted treatment options. The Pacific Pediatric Neuro-Oncology Consortium recently completed a feasibility study PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), in which a multidisciplinary tumor board recommended targeted agents based on the molecular and genetic profiling of each patient’s tumor. Separately, our group developed a numeric scoring tool of targeted anticancer agents, the Central Nervous System Targeted Agent Prediction (CNS TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to generate a numeric score for each agent to objectively evaluate these targeted therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within the CNS-TAP tool would overlap, at least in part, with the agents recommended by the molecular tumor board in PNOC003. Methods: For each study participant (n=28), a retrospective analysis was completed, utilizing the genomic report to identify actionable genetic alterations and to input patient-specific data into CNS TAP to identify the highest scoring agents. We compared high-scoring agents within the CNS TAP tool with recommendations from the PNOC003 tumor board for each of the enrolled 28 patients. Results: Overall, 93% (26/28) of patients had at least one agent recommended by both the tumor board and CNS TAP. Additionally, 39% (37/95) of all agents recommended by the tumor board were also selected by CNS TAP, with additional analysis ongoing. Conclusions: There was significant overlap between the highest-scoring and selected agents via CNS TAP compared with those chose by the molecular tumor board. Through this work, we also identified factors that likely contributed to the discordance in choice of targeted therapies. Without clinician input, the CNS TAP tool is unable to account for drug-drug interactions, includes only designated anticancer agents, and cannot easily be updated in real time, requiring extensive manual literature review for each included agent. However, CNS TAP provides an objective evaluation of targeted therapies, in contrast to inherently subjective recommendations of a tumor board. Given the discordance identified between these methods and the strengths of each, a prospective study incorporating both CNS TAP and a molecular tumor board for targeted therapy selection in patients with high grade glioma is warranted.