Kaleb H. Yohay, MD: Recently there have been a number of clinical trials in attempt to find potential treatments for plexiform neurofibromas in neurofibromatosis type 1. One of those drugs, selumetinib, is in the hands of the FDA currently and has received approval for the treatment of plexiform neurofibromas in children with neurofibromatosis type 1.
In the majority of patients treated with selumetinib, there has been a reduction in the overall volume of the plexiform neurofibromas, as well as improvement in symptoms such as pain and functional impairment.
MEK inhibitors are a class of drug that were designed for a variety of different cancers, and our understanding of the cellular pathways involved in neurofibromatosis, the RAS pathway in particular, led researchers to look at MEK inhibitors and their potential role in treating the symptoms of neurofibromatosis.
As you might guess from their name, MEK inhibitors impact and inhibit MEK. MEK is 1 of the downstream effectors of the RAS pathway. When MEK is inhibited, the increased rates of proliferation of tumors can be impacted and can decrease the growth or even reduce the size of tumors. We don’t exactly know all the mechanisms by which MEK inhibitors impact the growth and impact the reduction in the size of plexiform neurofibromas, but it is thought to act primarily along its impact on the RAS pathway.
Our understanding of the reason why patients with neurofibromatosis develop tumors, and specifically plexiform neurofibromas, is that the RAS pathway is hyperactivated in the absence of neurofibromin. Because that is underlying the growth of these tumors, inhibiting the RAS pathway is postulated to impact tumor growth and MEK inhibition as 1 strategy to impact the RAS pathway.
From what we know from previously published clinical trials of selumetinib in plexiform neurofibromas and neurofibromatosis type 1, the majority of patients with plexiform neurofibromas show reduction in the size of their tumors when treated with this drug. Additionally, there are data that suggest that symptoms such as pain or functional limitation can also be improved with treatment with selumetinib. In general, selumetinib is well tolerated. Some of the adverse effects that are commonly seen include rash. For postpubertal patients, an acneiform rash on the face is quite common, and for younger kids a more diffuse follicular rash can be seen. We also have to monitor for liver function tests as well as cardiac function. But in general, most people tolerate the medication quite well.
Clinical trials of selumetinib and other MEK inhibitors in neurofibromatosis have primarily relied on volumetric measurements of plexiform neurofibromas to assess efficacy. However, future studies and ongoing studies are also looking at functional outcomes measuring neurological impairment, cosmetic changes, and quality of life as additional outcome measures for these medications.