Wang, Nancy

Expanding the US Food and Drug Administration–approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%–12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

Abstract Craniopharyngiomas are surgically challenging brain tumors. Postoperatively, quality of life is often significantly impaired due to neurological and endocrinological complications. Currently, FDA approved systemic treatments are not available for patients in whom craniopharyngiomas recur after surgery and radiation. Papillary craniopharyngiomas are characterized by the presence of BRAFV600E mutations. To date, five case reports have been published on the treatment of BRAFV600E mutant papillary craniopharyngiomas with BRAF and/or MEK inhibitors. In this presentation, authors from all five previously published reports share their collective experience and provide updated follow-up on their patients, thus generating an overview of all currently available information on targeted therapy in patients with BRAFV600E mutant papillary craniopharyngiomas. We have also included information on an additional patient with a papillary craniopharyngioma recently treated with BRAF and MEK inhibitors after tumor biopsy alone, in the absence of recurrence, highlighting the potential for a neo-adjuvant therapeutic approach. All six cases in our series showed dramatic responses to targeted treatment with BRAF (and MEK) inhibitors. Collectively, our cases are highly promising and informative for patient treatment, although uncertainty remains with regards to the optimal timing, the specific agents (single agent or dual therapy) to be used and the duration of treatment. The ongoing multicenter phase II Alliance A071601 trial (NCT03224767) of vemurafenib and cobimetinib for patients with biopsy-proven residual or recurrent papillary craniopharyngiomas should provide additional information to help guide patient management.

Papillary craniopharyngiomas (PCPs) are characterized by the presence of BRAF V600E mutations, which are emerging as a useful guide for diagnosis and treatment decision making. The ongoing multicenter phase 2 Alliance A071601 trial is evaluating the efficacy of BRAF and mitogen‐activated protein kinase kinase (MEK) inhibitors for patients with PCPs. With continued successful responses, it is proposed that BRAF (and MEK) inhibitors be evaluated for the neoadjuvant treatment of patients with PCPs.