Study Reveals Mirdametinib as Potential Game-Changer in NF1-Associated PNs

3D illustration of brain anatomy: © PIC4U - stock.adobe.com3D illustration of brain anatomy: © PIC4U - stock.adobe.com

On Wednesday, August 28, 2024, the FDA granted priority review to the new drug application of mirdametinib, a novel MEK inhibitor, for the treatment of adult and pediatric patients with neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas (PNs).¹

The phase 2 ReNeu study (NCT03962543) investigated the efficacy and safety of mirdametinib in this patient population and supported this designation. Here, mirdametinib demonstrated a high overall response rate (ORR) with 41% (95% CI, 29%-55%; P <.001 vs null) of adult patients and 52% (95% CI, 38%-65%, P <.001 vs null) of pediatric patients experiencing at least a 20% reduction in PN volume.² Many patients maintained responses for a significant length of time, with the median duration of response not yet reached.

Patients also reported improvements in quality-of-life markers including pain severity and pain interference. While adverse events were observed, most were manageable and did not lead to frequent discontinuation of treatment.

Overall, the ReNeu study suggests that mirdametinib holds promise as a potential treatment option for NF1-associated PNs, offering a new therapeutic approach for patients with this condition.

In an interview with Targeted Oncology^TM, Christopher Moertel, MD, professor of pediatrics at the University of Minnesota and first author of the ReNeu study, discussed several key points regarding the study and its implications for patients with NF1-associated PNs.

Targeted Oncology: What is mirdametinib and its mechanism of action?

Christopher Moertel, MD

Moertel: Mirdametinib is an investigational agent and a MEK1/2 inhibitor. It is highly [central nervous system (CNS)]-penetrant, it is taken orally, and it is useful for patients who have RAS-driven tumors.

What are the unmet needs in this patient population that the study focused on?

Neurofibromatosis type 1 happens in about 1 in 2500 live births, [making it a] relatively common disorder, [though it is still classified as a rare disease]. [Patients] with neurofibromatosis type 1 frequently suffer from a tumor called plexiform neurofibroma. Plexiform neurofibroma can cause pain and disfigurement, and it can impact [patients’] quality-of-life. Our whole purpose in providing medicines for plexiform neurofibroma is to try to improve those 3 things. It can happen in children; it can happen in adults. We are trying, with this study, to affect the lifespan of [patients] with NF1.

What was this study evaluating?

We were evaluating the effect of mirdametinib on plexiform neurofibroma. Our primary goal was to look at the confirmed overall response rate. That is what percent of tumors shrunk by more than 20%. We had secondary goals looking at pain and health-related quality-of-life. Luckily, we achieved all those goals.

What were the efficacy findings?

Specifically, regarding tumor volume, 41% of adult patients had a confirmed overall response rate. That met our goals. A few of those had very deep response. One patient in the adult cohort had their tumors shrink by more than 90%. In the pediatric cohort, 52% of patients achieved our primary goal. One patient had an overall response of greater than 90%.

Looking at pain, we saw that there was a significant change in pain from time of enrollment to our 13th cycle, which is about 1 year, and that improvement in pain happened in both the pediatric cohort and the adult cohort. When looking at health-related quality-of-life, again, we saw an improvement in the adult cohort. In the pediatric cohort, the parent proxy measure of health-related quality-of-life was significant.

Were there any relevant safety signals you identified?

Overall, compared with other MEK inhibitors, our overall safety measures were positive. Specifically, when looking at the typical MEK inhibitor toxicities, overall, the toxicities on this trial were lower than those previously reported. Patients were able to stay on trial and had fewer interruptions compared to previous trials. Overall, it was acceptable. We had 1 patient who did have a grade 3 treatment-related adverse event, and that patient had retinal vein occlusion. In that case, the patient had recently started hormonal contraception and had 2 COVID-19 vaccines, so there were some confounding things going on. Overall, we thought that things went well regarding safety.

What are the implications for clinicians from these findings?

NF1-associated associated plexiform neurofibroma is an important problem for people living with NF1, so having treatment options available to them is important. This is the first study that has provided good data regarding adults with NF1. Currently, there are no approved therapies for adults with NF1. Likewise, having an alternative that may have improved and improved toxicity profile is important to this patient population.

What are the planned next steps from this research?

Our hope would be that the FDA would look upon this trial kindly and would see this as another reason to approve this this drug for use in our patient population. With FDA approval and broader availability, I think it can have a significant impact.

REFERENCES:
1. FDA grants priority review to SpringWorks Therapeutics’ new drug application for mirdametinib for the treatment of adults and children with NF1-PN. News release. SpringWorks Therapeutics, Inc. August 28, 2024. Accessed August 28, 2024. https://tinyurl.com/3bd2r8h8

2. Moertel, CL, Hirbe AC, Shuhaiber HH, et al. ReNeu: A pivotal phase 2b trial of mirdametinib in children and adults with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN). J Clin Oncol. 2024;42(suppl 16):abstr 3016. doi:10.1200/JC).2024.42.16_suppl.3016