ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children With Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma

Abstract

Purpose: Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration-approved for adults.

Methods: ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m² twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging.

Results: Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was -41% (-90 to 13) in adults and -42% (-91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children.

Conclusion: In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

Trial registration: ClinicalTrials.gov NCT03962543.

FIG 1.

(A and B) Best change from baseline in tumor volume and (C and D) duration of treatment and best confirmed overall responses. (A and B) Waterfall plots of the best percent change from baseline in target PN volume per patient, assessed by blinded independent central review. Horizontal dotted lines indicate PR (≥20% reduction in target PN volume from baseline) and PD (≥20% increase in target PN volume from baseline). (C and D) Swimmer plots of duration of treatment (days) and response status for each cohort. Colors indicate the best overall confirmed response. Duration of treatment was defined as the time from the date of first exposure to mirdametinib to the date of mirdametinib discontinuation. Confirmed responses were defined as partial or complete responses on ≥2 consecutive scans within 2-6 months during the treatment phase. The vertical line corresponds to the per-protocol date of the end-of-treatment phase on cycle 24, day 21. PD, progressive disease; PN, plexiform neurofibroma; PR, partial response.

FIG 2.

Examples of tumor response (MRI and/or digital photographs). (A and B) A head/neck plexiform neurofibroma in an 8-year-old male that had a volume of 221 mL at baseline, which had reduced to 39 mL (–82%) at cycle 24. (D and E) A head/neck plexiform neurofibroma in a 7-year-old female that had a volume of 95 mL at baseline, which had reduced to 48 mL (–49%) at cycle 21. (G and H) A head/neck plexiform neurofibroma in a 40-year-old male that had a volume of 281 mL at baseline, which had reduced to 60 mL (–79%) at cycle 36. Contours of the tumor edge are indicated in cyan. (C, F, and I) Tumor volume change from baseline (average of Readers A and B) over time for each patient. Permission for use of patient images was obtained through the institutional informed consent process. MRI, magnetic resonance imaging; PN, plexiform neurofibroma.

FIG 3.

Change from baseline in patient- and parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and HRQOL. Shown is LS mean change from cycle 1, day 1 (baseline) over time in patient- and parent proxy-reported outcomes estimated from mixed models for repeated-measures analysis through all cycles, with only results up to cycle 24 displayed; error bars indicate 95% CI. (A and B) NRS-11 scores range from 0 (no pain) to 10 (worst pain imaginable); higher scores indicate worse pain. (C and D) PII scores range from 0 (not at all) to 6 (completely); higher scores indicate greater pain interference. (E and F) PedsQL items are assessed on a Likert scale from 0 (never a problem) to 4 (almost always a problem); these are reverse scored and linearly transformed to a 0 to 100 scale (0 = 100; 1 = 75; 2 = 50; 3 = 25; 4 = 0). PedsQL Total Score is the mean of all item scores; higher scores indicate better HRQOL. *P < .05 for a statistically significant change from baseline. HRQOL, health-related quality of life; LS, least-square; NRS-11, Numeric Rating Scale-11; PedsQL, Pediatric Quality of Life Inventory; PII, Pain Interference Index.

FIG 4.

PFS of target plexiform neurofibroma in mirdametinib-treated children as compared with historical controls (1:1 propensity score matching without replacement). (A) Median PFS was not reached in mirdametinib-treated patients and was 21.8 months (95% CI, 16.4 to 32.3) in propensity score–matched historical controls from the NCI NF1 natural history cohort (hazard ratio, 0.24 [95% CI, 0.110 to 0.508]; log-rank P < .001). (B) Median PFS was not reached in mirdametinib-treated children with progressive disease at baseline and was 12.8 months (95% CI, 8.5 to 18.8) in age-matched historical controls from the tipifarnib phase II trial placebo cohort (hazard ratio, 0.14 [95% CI, 0.049 to 0.392]; log-rank P < .001). NCI, National Cancer Institute; NF1, neurofibromatosis type 1; PFS, progression-free survival.