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MAPK/ERK Inhibitor Mirdametinib in Adolescents and Adult Patients With NF1-Related Plexiform Neurofibromas


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In the Neurofibromatosis Clinical Trials Consortium phase II NF106 trial, reported in the Journal of Clinical Oncology, Weiss et al found evidence of activity of the oral MAPK/ERK kinase inhibitor mirdametinib in adolescents and adult patients with neurofibromatosis type 1 (NF1)-related plexiform neurofibromas.

Study Details

A total of 19 patients aged ≥ 16 years with inoperable plexiform neurofibromas that were either progressive or associated with significant morbidity were enrolled at NF Clinical Trials Consortium sites between July 2014 and September 2015. Patients received mirdametinib at 2 mg/m2 twice daily (maximum dose = 4 mg twice a day) in 3-week-on/1-week-off 4-week courses, up to a maximum of 24 courses. The primary outcome measure was response rate based on volumetric magnetic resonance imaging.  

“To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and plexiform neurofibromas and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and plexiform neurofibromas.”
— Weiss et al

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Key Findings

Patients had a median age of 24 years (range = 16–39 years). Median baseline tumor volume was 363.8 mL (range = 3.9–5,161 mL).

Partial response of the target plexiform neurofibromas was observed in 8 patients (42%) by course 12, with an additional 10 patients (53%) having stable disease. The median change in tumor volume vs baseline was −17.1% (range = −28.0% to +48.7%).

Assessment of maximum tumor shrinkage from baseline suggested a positive relationship with mirdametinib exposure at steady state (P = .052). Most responses were observed in patients with steady state area under the concentration time curve at 0 to 12 hours of ≥ 600 ng * h/mL.

The mean patient worst tumor pain rating on the Numerical Rating Scale-11(0–10, moderate to severe = ≥ 4) at baseline was 4.95. Worst tumor pain ratings were numerically reduced in patients both with and without partial response at courses 4, 8, and 12. Significant reductions were observed at course 4 among all patients (P = .0075), including patients with (mean score = 3.3) and without (mean score = 2.9) partial response and at course 12 in patients with partial response (mean score = 2.7; P = .018).   

Among treatment-related adverse events, the most common of any grade were acneiform rash (94.7%), fatigue (57.9%), nausea (52.6%), diarrhea (26.3%), and vomiting (26.3%). No grade 4 or 5 events were observed. Grade 3 events were observed in two patients (10.5%). Dose reductions were required in five patients (26.3%).

The investigators concluded, “To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and plexiform neurofibromas and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and plexiform neurofibromas. Mirdametinib given at 2 mg/m2/dose (maximum dose = 4 mg) twice daily in a 3-week-on/1-week-off sequence resulted in a 42% partial response rate, with preliminary evidence of reduction in pain.”

Brian D. Weiss, MD, of the Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by a Department of Defense award. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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