NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas

Abstract

Purpose: Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis.

Methods: Inclusion criteria included age ≥ 16 years and a PN that was either progressive or causing significant morbidity. First-dose pharmacokinetics were performed. Patients completed patient-reported outcome measures. Patients received mirdametinib by mouth twice a day at 2 mg/m²/dose (maximum dose = 4 mg twice a day) in a 3-week on/1-week off sequence. Each course was 4 weeks in duration. Evaluations were performed after four courses for the first year and then after every six courses. Patients could receive a maximum of 24 total courses.

Results: Nineteen patients were enrolled, and all 19 received mirdametinib. The median age was 24 years (range, 16-39 years); the median baseline tumor volume was 363.8 mL (range, 3.9-5,161 mL). Eight of the 19 patients (42%) achieved a partial response of the target PN by course 12, and 10 (53%) had stable disease. One patient (5%) developed progressive disease at course 8. Significant and durable decreases were observed in pain ratings.

Conclusion: To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and PNs and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and PNs. 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.

Trial registration: ClinicalTrials.gov NCT02096471.

FIG 1.

Each patient is represented by a single bar. Blue bars did not achieve a partial response (PR). Red bars achieved a PR. (A) Waterfall plot of maximal tumor volume change by patient. Patients are aligned left to right according to maximal tumor volume change from baseline. There was one patient who had progressive disease, 10 with stable disease, and eight with PR. (B) Swimmers plot of duration of exposure, time to PR, and time to maximum response. Patients are aligned top to bottom from largest response to least response. Length of bar represents duration of exposure. Magenta triangles represent the time a PR was first observed, and magenta circles represent the time of maximum tumor volume change from baseline. Green stars represent time of dose reduction. Note the green star indicating a dose reduction at the same time PR first noted in red bar 4th from the top.

FIG 2.

Relationship between the maximum tumor volume change from baseline and the AUC_0-12h estimate in steady state (R² = 0.22; P = .052). The predicted exposure of mirdametinib at tumor size readout (as measured by AUC_0-12h) was compared with maximum tumor volume change from baseline in individual patients using linear regression analysis. Blue triangles represent patients who did not achieve a partial response (PR). Red circles are those patients who did achieve a PR; one patient who achieved a PR did not have pharmacokinetics performed. Filled in shapes represent patients who had a dose reduction, only one of whom achieved a PR (although the dose reduction was after the PR was achieved). The patient near the very top of the graph had a small plexiform neurofibroma that significantly progressed in the first eight courses. AUC_0-12h, area under the concentration-time curve from time 0 to 12 hours.

FIG A1.

Exemplary response to mirdametinib in a single patient. Axial short-TI inversion recovery magnetic resonance imaging (MRI) sequence shows a plexiform neurofibroma in the left anterior thigh. (A) Example of MRI on enrollment with a volume of 593 mL. (B) Example of MRI after course 12 with a volume of 473 mL.