Effective Toxicity Management is Key to Maximizing Benefit With MEK Inhibitors in NF1-Associated PN

Christopher L. Moertel, MD

With the rise of MEK inhibitors as a key treatment option for patients with neurofibromatosis type 1 (NF1)–associated plexiform neurofibromas (PN), it is essential for oncologists to be well-versed in managing associated toxicities, according to Christopher L. Moertel, MD, who added that understanding these adverse effects (AEs) and carefully implementing strategies to mitigate them could ensure that patients stay on therapy long enough to derive full benefit.

“For the general oncologist, my main message is [that if they] know the toxicity of these agents and the standard practice for ameliorating those toxicities well, then they'll have success,” Moertel stated in an interview with OncLive®. “They'll be able to keep these patients on therapy and enable patients to get the most benefit out of it that they can.”

In the interview, Moertel discussed the evolution of NF1-associated PN management, noting the shift away from debulking surgery toward MEK inhibition, highlighting the FDA approval of mirdametinib (Gomekli) for the treatment of adult and pediatric patients with NF1-associated PN as a particularly significant advancement for a previously underserved patient population. This agent was approved on February 11, 2025, based on results from the phase 2b ReNeu trial (NCT03962543), which showed significant reductions in tumor volume, improved pain control, and enhanced quality of life.

Moertel also explained the rationale behind utilizing MEK inhibitors in this space, discussed the possibility of combining MEK inhibitors with other targeted therapies, and emphasized the importance of knowing and effectively managing toxicities associated with long-term MEK inhibitor use

Moertel serves as a pediatric neuro-oncologist and professor at the University of Minnesota School of Medicine in Minneapolis, where he directs the Pediatric Neuro-Oncology Fellowship Program and co-leads the Pediatric Neuro-Oncology and Neurofibromatosis Programs.

OncLive: What is the current standard of care in NF1-associated PN, and how has the approach to treatment evolved, especially given the symptomatic and variable nature of this malignancy?

Moertel: The standard of care in NF1-associated PN has evolved quite quickly over the last 10 years. In the [past], the NF1-associated PN treatment schema was very difficult and usually fell to surgery, which was not very successful most of the time because of the potential of these tumors to regrow. Patients would undergo so-called debulking operations, and the tumor would grow right back again. Over a decade ago, a series of clinical trials were started [in NF1-associated PN]; [these were] mostly headquartered or facilitated by the National Institutes of Health. Quite a lot of work was put into various clinical trials with varying, but mostly middling, success. Then we sat down as a group facilitated by the Children's Tumor Foundation to look at potential drugs [for this patient population], and we came upon MEK inhibitors. MEK inhibitors, at that time, had been [assessed] in some animal models, but we then [investigated this approach] with greater gusto and did some very thorough testing.

Now, the MEK inhibitor landscape has exploded, not just for the treatment of adult malignancies such as melanoma, but also for brain tumors, and now PN. The first to be approved by the FDA was selumetinib [Koselugo]. Most recently, mirdametinib [gained FDA approval]. We’re gratified now to have these drugs available for children and adults with NF1-associated PN. Through both clinical trials and everyday use, [we’ve seen that] they're quite effective in improving the quality of life of these patients,

Why was MEK inhibition specifically investigated as a potential therapeutic strategy for this patient population?

Since the discovery of the NF1gene, we discovered that this gene turned on the MAPK pathway. The individual components of that pathway include RAF or BRAF—which is inhibited in a lot of different cancers. After the activation of MEK, we see activation of ERK. By targeting MEK, we don't have to be super specific, [meaning] we can be selective in MEK inhibition. We found [MEK inhibition] to be tolerable [and effective] at preventing the end result of ERK activation, which causes cell proliferation. We knew that chemical pathway and chose these MEK inhibitors because of their potential.

How does the approval of mirdametinib for both pediatric and adult populations with NF1-associated PN impact treatment accessibility?

First, mirdametinib is available as a pill, but [is] also [available as] a dispersible pill that can become a liquid, which is flavored and palatable. We do have a large subset of patients with oral aversion. There's also a certain segment of patients with NF1-associated PN who have autism spectrum disorder and have more prominent [oral] aversions. For children and people with difficulty with pills, having that orally dispersible liquid formulation is a great thing.

Second, having approval for adults [is a big deal]. For many years now, we've been treating patients off-label with a number of different MEK inhibitors. One can imagine all the gauntlets we have to run through to get insurance approval for off-label medications, so we're grateful to finally have that label for adults [with mirdametinib].

What are the key challenges and unmet needs in the management of NF1-associated PN with MEK inhibitors, and how do current strategies address the associated toxicities?

Although these MEK inhibitors have been a huge hit in NF1-associated PN, they still have toxicity. All these patients are susceptible to potential ocular toxicity, heart toxicity, skin, gastrointestinal [GI] tract [toxicity], and so on. [A MEK inhibitor] is a chronic medication, and we don’t intend for people to take this for only 3 to 6 months. I'm committing my patients to a minimum course of 18 months. We want to facilitate patients being able to [handle] this medication time.

It's up to us practitioners to provide good, anticipatory guidance regarding symptom management. We also need to realize what those AEs are and how to treat them effectively. Skin AEs, [for example], can be prevented with antibiotics or bleach baths and good emollient lotions; GI toxicity can be handled by attention to diet and things like that. If we can do the best we can to ameliorate these toxicities and enable patients to stay on [treatment] for a long time, we've done a good job. Nevertheless, these drugs aren't making NF1-associated PN disappear, and we still have toxicity to deal with. There's plenty of opportunity for discovery in this space to help these patients.

Are there any other potential treatment strategies under investigation for patients with NF1-associated PN based on recent biological insights?

We are gaining more and more knowledge about the biology of neurofibroma cells. We know [that in] NF1-associated PN, there are a lot of mast cells, neutrophils, and other cells that come into these tumors. There's a large fibroblast population, and then, of course, the Schwann cell population. That Schwann cell population performs a lot of cell signaling to attract cells to the tumor. If we think about the different cell signaling pathways, metabolic pathways, and tissue-specific targets that are available to us, there’s a lot of potential for either combination therapies or other more directed therapies.

What are the potential benefits and challenges of combining MEK inhibitors with agents targeting different pathways, such as mTOR or PI3K inhibitors?

I know from personal experience that we're able to combine [MEK inhibitors] with other medicines that have a different mechanism. For instance, mTOR inhibitors or PI3K pathway inhibitors have been used quite commonly in combination with MEK inhibitors and haven't shown a marked increase in toxicity. We've had some experiences with HDAC inhibitors in combination [with MEK inhibitors], and those 2 have been well tolerated. Right now, if we're not hitting the same target repeatedly and not potentiating the MEK agents, the overall toxicity shouldn’t be much more than [expected]. In my clinical experience, we've had good luck with it.

What are the key considerations for managing long-term MEK inhibitor therapy, and how can providers ensure appropriate dosing and toxicity management?

The current treatment paradigm is surgical removal. If this is a limited tumor, we’re not going to cause any AEs with the removal. [We shouldn’t] attempt debulking unless we find ourselves in a life-or-limb or organ-threatening situation. We're then left with MEK inhibition as the main avenue for treatment for these patients. We know that [pediatric patients as young as] age 2 or 3 can tolerate these medications. We know now that we have preparations that can be swallowed by all age groups and people types, so we're in a good place there.

[We have to] make sure that providers who are going to be prescribing these medications are well-educated about the fact that these are chronic medications meant to have patients on them for years. We're not just blasting melanoma or colon cancer. I've seen lots of instances where these agents have been used in higher doses, and patients have experienced some pretty [terrible] toxicity; [however,] they know they've got a [terrible] disease, so they're willing to make the trade-off. If we've got a patient who's going to potentially live with these tumors for the rest of their life, the blasting approach will never work. We've got to be careful and thorough in our premedication evaluations, thorough in our education, and use the resources that are out there. The people who are marketing these drugs have excellent resources for providers and patients to use.

Reference

FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection. FDA. Feburary 11, 2025. Accessed March 27, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirdametinib-adult-and-pediatric-patients-neurofibromatosis-type-1-who-have-symptomatic