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The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.

RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1-related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non-NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.

Simple Summary: People with neurofibromatosis type 1 (NF1) may develop tumors called plexiform neurofibromas (PNs). Selumetinib was the first oral medication to gain FDA approval to treat PNs in children, and the drug also has activity in adults. Clinical observations suggest that people must continue taking selumetinib to maintain its effects. Therefore, it is important to research how well people take selumetinib as prescribed over a long period of time. We used electronic pill caps that record when the bottle is opened, pill counts, and self-report diaries to measure adherence over eighteen 28-day treatment cycles. We found that using the caps is feasible but presents some challenges. We also found evidence that depression and stress were related to lower adherence in our small sample. We also interviewed patients, who talked about things that make adherence easier (consistency, reminders, and social support) and more difficult (forgetting and dose timing). Background: Oral therapeutic options for plexiform neurofibromas (PNs) in individuals with neurofibromatosis type 1 (NF1) are receiving attention in clinical research. The MEK inhibitor (MEKi) Selumetinib is FDA-approved in children ages 2+ years with inoperable PNs, and shows activity in adults. Prolonged therapy with selumetinib is necessary to maintain tumor reduction. Therefore, investigating long-term adherence is vital to understand patterns of adherence over time and its impact on clinical outcomes. Mixed methods research offers rich information about adherence that can inform future intervention trials, and can assist practitioners in addressing medication adherence concerns. Methods: This mixed-method pilot study is the first examination of the feasibility of a technology-based adherence assessment method, the medication events monitoring system (MEMSTM), among individuals with NF1-PN. Adherence was monitored in a small sample of patients (N = 12; mean age = 34.36 years; 58% male) with NF1 and PN across eighteen 28-day treatment cycles. Qualitative data were obtained from individual interviews using inductive and deductive techniques for thematic analysis. Results: The predetermined criterion was met, suggesting that using MEMSTM is feasible despite some challenges with the caps. Depression and overall stress were significantly related to reduced adherence, although these results should be considered hypothesis-generating. Barriers to medication adherence included forgetting and the timing of doses related to eating. Facilitators included consistency, reminders, and social support. Conclusions: This study highlights patient characteristics that may be related to increased risk for nonadherence, as well as challenges with electronic pill caps that should be considered in future clinical trials for NF1-related PN. Results can inform future adherence interventions for adults with NF1 and PNs. Future research with larger samples is needed to fully explore factors related to long-term medication adherence among individuals with NF1. [ABSTRACT FROM AUTHOR]

Rare cancers and other rare nonmalignant tumors comprise 25% of all cancer diagnoses and account for 25% of all cancer deaths. They are difficult to study due to many factors, including infrequent occurrence, lack of a universal infrastructure for data and/or tissue collection, and a paucity of disease models to test potential treatments. For each individual rare cancer, the limited number of diagnosed cases makes it difficult to recruit sufficient patients for clinical studies, and rare cancer research studies are often siloed. As a result, progress has been slow for many of these cancers. While rare cancer research efforts have increased over time, the breadth of the research landscape is not known. A recent literature search revealed a sharp increase in rare tumor, and rare cancer publications began in the early 2000s. To identify rare cancer research efforts being conducted in the US and globally, we conducted an online search of rare tumor/rare cancer research programs and identified 76 programs. To gain a deeper understanding of these programs, we composed and conducted a survey to ask programs for details about their research efforts. Of the 42 programs contacted to complete the survey, 23 programs responded. Survey results show most programs are collecting clinical data, molecular data, and biospecimens, and many are conducting molecular analyses. This landscape analysis demonstrates that multiple rare cancer research efforts are ongoing, and the rare cancer community may benefit from collaboration among stakeholders to accelerate research and improve patient outcomes. [ABSTRACT FROM AUTHOR]