Mirdametinib Provides Long-Awaited Treatment Option in NF1-Associated PN

The FDA approval of mirdametinib (Gomekli) for the treatment of adult and pediatric patients with neurofibromatosis type 1 (NF1)–associated plexiform neurofibromas (PN) marks a significant advancement for a patient population previously lacking approved treatment options, according to Christopher L. Moertel, MD.

On February 11, 2025, the FDA approved mirdametinib for patients 2 years of age and older with NF1-PN that is symptomatic and not amenable to complete surgical resection. This regulatory decision was based on findings from the phase 2b ReNeu trial (NCT03962543), which demonstrated substantial reductions in tumor volume, improved pain control, and enhanced quality of life in this patient population.

Data from ReNeu showed that adult patients (n = 58) who received mirdametinib achieved a confirmed overall response rate (ORR) of 41% (95% CI, 29%-55%); pediatric patients (n = 56) experienced a confirmed ORR of 52% (95% CI, 38%-65%).

“We're grateful for the approval of [mirdametinib. It's going to…provide an alternative for [pediatric patients], and having approval for adult [patients is important. Trying to get insurance approval for off-label medications has been a huge headache in the treating community for many years. [Having] an approved drug [for these adult patients] is going to be great,” Moertel explained.

In the interview, Moertel explained the implications of the FDA approval of mirdametinib for patients with NF1-associated PN and detailed the data that helped support its approval.

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 significance of the FDA approval of mirdametinib for NF1-associated PN?

Moertel: The approval of mirdametinib is significant because this is a highly selective MEK inhibitor that will provide benefit to both adult and [pediatric patients] with NF1 who have PN that are not amenable to surgery and are causing significant quality-of-life or pain issues. Therefore, for this population, this is a big win. Adult patients with NF1 have been without an FDA-approved drug for quite some time. It's good that we're there.

What was the rationale and design of the ReNeu trial?

We saw that mirdametinib was effective in patients with NF1-related PN in phase 1 trials and then it was time to bring it out to phase 2. With the education we'd received from prior trials with mirdametinib and other MEK inhibitors, we learned [several] lessons.

The first lesson was [to use a dosing schedule of] 3 weeks on, 1 week off; that helped patients tolerate the drug for a longer period of time. [Second,] we had patients on [mirdametinib] for a prolonged period of time compared with previous trials because we knew that it takes quite some time to get the optimal response to this therapy that you'd like to see. The main point was to see shrinkage of PN, but the secondary end points were important too, since most adult and many [pediatric patients] with PN present with pain. It was very important for us to assess pain through this trial, and we did that.

Lastly, [we looked at] overall quality-of-life measures. How does shrinking a PN or changing the symptoms [affect] the quality of life for these patients, especially adults?

What were the key findings from the study?

We were able to show that PN shrank, and having our patients on the drug for a prolonged period of time by controlling adverse effects [AEs] through scheduling and other means was important. We showed pain relief in both adults and children, and we showed improved quality of life. Therefore, all the [objectives] we set out to achieve were accomplished. For investigators like me who take care of a lot of patients with [NF1-associated PN,] it was a gratifying outcome.

What safety findings were reported in the study?

The safety profile of all MEK inhibitors [is] similar. [The primary AE in skin irritation,] and young [pediatric patients] tend to have a more eczematoid rash; older [pediatric patients] and adults tend to have an acneiform rash. Providing anticipatory guidance for skin care was important in maintaining [patients] on this drug.

The second toxicity that we see very often with MEK inhibitors is gastrointestinal toxicity, specifically nausea, sometimes vomiting, and diarrhea. We provided thorough counseling about diet and management, and in an anticipatory way, we were ready to treat any nausea or [gastrointestinal symptoms] that got in the way of taking this medicine.

Finally, [there are some] more minor things, but they are certainly significant [AEs to note]. Decreases in cardiac ejection fraction are seen with MEK inhibitors and was again seen on this trial; however, none of those reductions were serious. The next is eye toxicity. One adult patient, [who was on] birth control pills and who had a recent COVID-19 vaccine, [experienced] a vascular problem that affected the eye, but at our last check with this patient, that was resolving. Additionally, elevations of creatine kinase are seen with all MEK inhibitors. Again, we saw that on this trial, and we observed it and managed it appropriately. Very few patients had any serious elevations or symptomatic problems with creatine kinase elevation

Given these data and the FDA approval, how do you see mirdametinib being integrated into clinical practice?

I'm grateful that this drug is approved and ready to go for adults with NF1-associated PN. This is a population that hasn't had an FDA-approved drug.

Maintaining people on the drug is important. Providing anticipatory guidance for diet, and [having patients] avoid a lot of fatty foods, fast food, and things like that will help. [Patients and clinicians must also be] serious about skincare by using appropriate lotions, and we started everybody on an antibiotic—usually doxycycline, unless they have a sensitivity to that. We'll start that right at the beginning [of treatment] to prevent that acneiform rash and use appropriate lotions.

[We need to] pay attention to their overall care [by] making sure that they understand [the risk for] muscle enzyme elevations, cardiac toxicity, and eye toxicity. The eye toxicity problem is important to consider in older adults.

Paying attention to all of those safety guidelines and providing appropriate guidance will be important on the pediatric side, as well. A lot of this [awareness] is going to [fall on] the parents, and for very young children, the most important thing we saw in this trial was that we were able to use a dispersible tablet to provide this in a liquid preparation. That helped us give the medicine to younger patients with inexperience swallowing tablets or the inability to swallow tablets.

[Additionally], the 1 week off [treatment during each cycle] is helpful in maintaining people on this regimen for a prolonged period of time. [Regarding] skincare in [pediatric patients], we actually encourage bleach baths to keep the skin clean and to use appropriate lotions to maintain skin integrity.

Reference

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