As a result of the 2018 Cutaneous Neurofibroma Initiative, several working groups were formed to produce papers addressing key challenges identified. Those papers are summarized below with links to the full papers provided. This information is provided here to the public to advance knowledge of NF1 across all scientific communities and spur accelerated development of therapies that will improve patients quality of life.
The Clinical Definition of cNF
Since characteristics of Cutaneous Neurofibroma (cNF) and other neurofibromas can overlap, there has been uncertainty about how to define and classify cNF. Various classification schemes have been proposed, but the lack of consensus has hindered consistent communication among clinicians and scientists, slowing progress on the development of new therapeutics. In the second paper of the supplement, titled ‘Cutaneous Neurofibromas: Current Clinical and Pathologic Issues,’ these challenges are discussed. The paper presents the existing classification schemes for the various forms of neurofibromas and the learnings from two multidisciplinary meetings. The experts in these meetings reviewed the core features of cNF (including clinical and histological features, and data about effects of cNF on quality of life) and they propose necessary elements for a modern classification scheme for cNF. Taking into consideration the learnings from previous efforts, an initiative is now underway to create a commonly accepted classification scheme validated in a prospective study with blinded review by dermatopathologists, neuropathologists and NF1 clinicians that accurately describes each tumor type by its clinical classification, clinical appearance, pathological, and molecular and histological features. By having such a classification scheme in place, researchers, clinicians, drug makers, and regulators will be able to communicate more consistently, thereby facilitating research and discovery aimed at developing tumor-specific management strategies.
The Biology of cNF
Summit participants agreed that the current limited knowledge of the underlying mechanistic, structural, and genetic factors responsible for the formation of cNF represents a major hurdle to understanding the progress of the disease and ultimately to being able to develop effective treatments. To identify knowledge gaps and define future research priorities, the authors undertook a comprehensive examination of published (and unpublished) results from which five key areas of research priority were identified. As described in the third paper of the supplement, titled ‘The Biology of Cutaneous Neurofibromas,’ these are: (1) identifying the human cells of origin for cNF and understanding how these cells influence and drive cNF initiation and progress, (2) understanding how both nerve and tumor microenvironment contribute to cNF development, (3) identifying and elucidating the specific genetic and molecular factors that underlie cNF initiation and progression, including factors that contribute to tumor size and number, (4) generating preclinical model systems to elucidate disease biology and enable preclinical therapeutic testing and (5) understanding how age and sex hormones influence tumor growth. These research topics provided the basis for a first request for applications (RFA) sponsored by NTAP in 2017, from which nine projects were launched. These coordinated projects are a critical early step towards answering key questions that will facilitate the development of therapeutics for these tumors.
Therapeutic Development
Current clinical management of cNF involves surveillance or some form of procedure-based treatment, but lacks a therapeutic (drug-based) approach. To overcome barriers to new treatment development and focus resources on options most likely to succeed, a working group of experts reviewed existing methods, outcomes, patient characteristics, and drug trials for cNF. Insights into current procedural approaches, endpoints applied to assess biologic effect and clinical benefit, and specific factors to consider when developing a drug-based therapy are described in the fourth paper of the supplement, titled ‘Considerations for Development of Therapies for Cutaneous Neurofibromas.’ A key finding is that, while multiple procedures are available for the removal of cNF and each provides treatment options for patients, there were several limitations to the trials that evaluated these approaches. These included a lack of detailed enrollment criteria, distinction among the different types of cNF evaluated, comparisons of treated versus untreated areas, duration of follow-up, and standardized endpoints. Additional, unaddressed challenges include scarring, pain, risk of infection, and the cost and availability of the interventions. As such, no single approach has been identified as optimal, owing to a lack of prospective data about short- and long-term adverse events or the efficacy of treatments. Beyond procedure-based techniques, there have been a few interventional drug trials for cNF, but outcomes were highly variable. As cNF is a disease of a nonfatal nature with relatively limited patient numbers, it was concluded that for any product to have a higher likelihood of acceptance, it will have to demonstrate an effect that is clinically meaningful, have a safety profile conducive to long-term dosing, and have a low manufacturing cost. In consideration of these factors, four specific elements were identified as being critical to incorporate into a cNF drug development path : (1) safety, (2) anatomic distribution of cNF, (3) numbers of tumors to be treated, and (4) route of administration. As the number, size, and distribution of tumors is so variable among patients, different groups of patients will require different drug development paths and thus provide opportunities for multiple therapeutic approaches.
Clinical Trial Design
The fifth and final paper of the supplement, titled ‘_Clinical Trial Design for Cutaneous Neurofibromas describes recommendations to consider for cNF clinical trials. The priority areas presented include: (1) assessment of existing methods for the measurement and quantification of cNF, (2) advances in technological methods and outcome tools utilized in other skin diseases that may be applicable to cNF studies, and (3) consideration of clinical factors that may influence or confound clinical trial outcomes, including sex and age. To guide clinical trial design, a sound understanding of the natural history of cNF is required. The authors report that two ongoing studies of this kind have led to some important insights, but go on to identify six areas that should be addressed in future prospective studies: (1) the rate of appearance and development of cNF in children and young adults, (2) the growth rates of new versus mature tumors, (3) the influence of hormones and other growth factors on tumors, (4) the rate of spontaneous tumor shrinkage, (5) the identification of biomarkers, and (6) an evaluation of tools used to count and measure tumors. The group agreed that all cNF clinical trials should monitor tumor size, tumor number and patient-reported outcomes to assess efficacy but it emphasized that consensus must first be reached on best methods for monitoring each type of outcome. To this end, the authors detail the tools available, including several developed for other skin diseases. In addition to studying the utility of each technology as applied to cNF, they recommend the creation of a global assessment scale to consistently capture therapeutic effects on patients’ quality of life.