Novel Treatment Approved for NF1-Associated Symptomatic Plexiform Neurofibromas

The Food and Drug Administration (FDA) has approved Gomekli (mirdametinib; SpringWorks Therapeutics, Stamford, CN) for the treatment of neurofibromatosis type 1 (NF1)–associated symptomatic plexiform neurofibromas (PNs) not amenable to complete resection in adults and pediatric patients aged ≥2 years. PNs are tumors that form on the peripheral nerve sheath in an infiltrative pattern, which are difficult to remove in ~85% of cases and can become malignant with potentially fatal outcomes. Gomekli is an oral, highly selective mitogen-activated protein kinase (MEK) inhibitor expected to be available in the United States in the first quarter of 2025 as a 1 mg or 2 mg capsule and a 1 mg tablet for oral suspension.

The approval is based on data reported from the phase 2b, multicenter, open-label ReNeu clinical study (NCT03962543), which included 114 adult (n=58) and pediatric (n=56) participants with documented PNs associated with NF1 causing significant morbidity and unable to be completely removed surgically. All participants received Gomekli 2 mg/m2 twice daily by mouth with a maximum dose of 4 mg. The primary endpoint of the study was confirmed objective response rate (ORR) as defined as a ≥20% reduction in target tumor volume, per blinded independent central review (BICR) of MRI.

• 41% percent of adult participants (n=24) and 52% of pediatric participants (n=20) demonstrated an ORR, meeting the primary endpoint.
• There was a -41% and -42% median best percentage change in target PN volume for adult (range, -90% to 13%) and pediatric participants (range, -91% to 48%), respectively.
• A ≥12-month duration of confirmed response was achieved by 88% of adult participants and 90% of pediatric participants.
• A ≥24-month duration of confirmed response was achieved by 50% of adult participants and 48% of pediatric participants.
• Both pediatric and adult participants showed early and sustained improvements in quality of life and pain from baseline.

In terms of safety and tolerability:

• The most common adverse events (AEs) in adults were nausea, vomiting, diarrhea, musculoskeletal pain, rash, and fatigue.
• The most common AEs in pediatric participants were abdominal pain, diarrhea, nausea, vomiting, musculoskeletal pain, headache, left ventricular dysfunction, and paronychia.
• Serious AEs occurred in 17% of adult and 14% of pediatric participants.

“It was very encouraging in the ReNeu trial to see that GOMEKLI provided deep and durable responses, with a manageable safety profile that enabled patients to stay on therapy,” said Christopher Moertel, MD of the University of Minnesota and lead study investigator. “This approval represents an important advance, especially for adults who previously did not have an approved treatment.”

Gomekli was approved under Priority Review and previously received Orphan Drug designation and Fast Track designation. The FDA granted SpringWorks Therapeutics a rare pediatric disease priority review voucher (PRV), enabling the company to expedite the review process of a future drug application.