Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas

Abstract

Background: Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling.

Methods: We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma.

Results: A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed.

Conclusions: Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).

Figure 1. Mean Plasma Concentration–Time Profiles of Selumetinib and Median Pharmacokinetic Results for Selumetinib for the Three Dose Levels Evaluated

The pharmacokinetics of selumetinib in plasma were evaluated during cycle 1. Blood samples were obtained as follows: on day 1 before the first dose was administered and 0.5, 1, 2, 3, 5, 8, 10 to 12, 24, and 30 to 36 hours after administration of that dose; in addition, a blood sample was obtained on day 27 before the first dose was administered (data not shown). The mean plasma concentration–time profiles of selumetinib and the pharmacokinetic results for the 18 patients for whom consent was provided showed limited variability. Selumetinib was rapidly absorbed. I bars indicate standard deviations. AUC_0–inf denotes the area under the plasma concentration–time curve from time 0 to infinity, C_max the observed maximum plasma concentration after drug administration, and T_max the time from drug administration to C_max.

Figure 2. Best Response to Selumetinib According to Dose Level and According to Dose Reduction Status

Panel A shows the best response to selumetinib as assessed by the percent change from baseline in plexiform neurofibroma tumor volume, according to dose level. Panels B and C show the change in plexiform neurofibroma volumes before (when available) and after initiation of treatment with selumetinib among patients who did not have dose reductions (Panel B) and among those who had dose reductions (Panel C) during the trial. Separate graphs are presented for the three dose levels (20, 25, and 30 mg per square meter of bodysurface area). The time periods during which a patient had no dose reductions are depicted with solid lines, and periods during which a patient had a dose reduction are depicted with dashed lines. Patient 5 had a plexiform neurofibroma with a large nodular component that did not respond to treatment with selumetinib. Patient 7, who remains in the trial, had a prolonged interruption in selumetinib dosing as a result of a toxic effect. Patients 9 and 10, who also remain in the trial, are the only patients who did not have a dose reduction of selumetinib but had a slow increase in plexiform neurofibroma volume after maximal response had been observed. For Patients 3 and 20 (who remain in the trial) and Patients 8 and 6 (who permanently discontinued trial treatment), an increase in plexiform neurofibroma volume was observed after at least one selumetinib dose reduction as a result of a toxic effect (details are provided in Table S3 in the Supplementary Appendix). PT denotes patient number.

Figure 3. Examples of Response to Selumetinib

Panels A and B show data from Patient 20 (25-mg group). In Panel A, results from the volumetric magnetic resonance imaging (MRI) analysis of plexiform neurofibroma growth show the tumor volume before treatment (gray symbols), tumor shrinkage during treatment with selumetinib (black symbols), and the increase in plexiform neurofibroma volume after dose reduction (blue open symbol). In Panel B, the visible reduction in plexiform neurofibroma burden is depicted in the MRI results and photographs before treatment as compared with those at the end of cycles 5 and 10 during treatment. Panel C shows an example of the need for prolonged administration of selumetinib to elicit a sustained response. Patient 7 (30-mg group) had progressive plexiform neurofibroma growth during six treatment regimens directed at his plexiform neurofibroma before treatment with selumetinib (gray symbols). He had a partial response at the evaluation visit after cycle 5 (black symbols), but selumetinib was stopped because of a decrease in the left ventricular ejection fraction (LVEF) (broken line). When selumetinib was restarted at a reduced dose after recovery of the LVEF, the plexiform neurofibroma volume had increased by 44% from the best response value and by 9.6% from baseline. Subsequent disease evaluations (blue open symbols) show responsive disease with a tumor volume reduction of 25% since the time of reinitiation of selumetinib at a reduced dose.