Dr Jordan on Challenges With Drug Development in Adult NF1-Associated PN

"Although these [tumors] are slow growing…creating a therapy that is able to be tolerated for long periods of time with minimal toxicity and controls the growth rate of a tumor [has been a challenge]. We're thankfully now in an era where we can take advantage of the vulnerabilities of this particular tumor and the pathway alterations related to the NF1 mutation."

Justin T. Jordan, MD, MPH, FAAN, an associate professor of neurology, head of the Neuro-Oncology Section, and an associate professor of O'Donnell Brain Institute at UT Southwestern Medical Center, discusses historical challenges with drug development for adult patients with neurofibromatosis type 1 (NF1)–associated plexiform neurofibromas (PN).

Approximately 50% of individuals with NF1 develop associated PNs, which are typically slow-growing tumors that involve multiple nerves and nerve fascicles, often extending into deep tissues or adjacent to critical structures such as large vessels or organs, Jordan began. Historically, the mainstay of management has been surgical debulking, he stated. However, because of the complex anatomy and infiltrative nature of these tumors, complete surgical resection is rarely feasible, and the role of surgery has largely been limited to symptom management or functional compromise, Jordan explained

Jordan noted that the biological behavior of PN—specifically its indolent growth—has posed a longstanding challenge in developing systemic therapies. In oncology, it is often difficult to demonstrate a clear therapeutic effect in tumors with slow progression, Jordan explained, particularly when long-term tolerability and low toxicity are essential. He emphasized that treatment approaches must be sustainable over extended periods to provide meaningful benefit in this population.

This is evidenced by the FDA approval of mirdametinib, which introduced the first treatment option for adults with NF1-PN. 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 supported by findings from the phase 2b ReNeu trial (NCT03962543), which demonstrated significant and durable reductions in tumor volume, as well as clinically meaningful improvements in pain and quality of life.