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.

INTRODUCTION

Neurofibromatosis type 1 (NF1) is an autosomal-dominant genetic condition caused by loss-of-function variants in the NF1 gene,^1,2 with a birth incidence of approximately 1 per 2,500.³ NF1 variants result in neurofibromin dysfunction and persistent mitogen-activated protein kinase (MAPK) pathway activation.⁴ Plexiform neurofibromas (PNs) are nonmalignant nerve sheath tumors that develop in 30%-50% of patients with NF1^5-7 and can often cause pain, organ displacement/compression, impaired physical function, and disfigurement and substantially deteriorate the health-related quality of life (HRQOL) of patients and caregivers.^8,9 They are also associated with a risk of transformation into malignant peripheral nerve sheath tumors.^10,11

CONTEXT

• Key Objective

• To report the clinical efficacy, patient- and parent proxy-reported outcome measures of pain and health-related quality of life (HRQOL), and safety of the MEK1/2 inhibitor, mirdametinib, for the treatment of adults and children with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) in the pivotal, phase IIb ReNeu trial.

• Knowledge Generated

• Adults and children with NF1-PN treated with mirdametinib had a significant objective response rate by blinded independent central review and deep and durable reductions in target plexiform neurofibroma (PN) volume, and mirdametinib was well tolerated. Patients and parent proxies reported early, sustained, and clinically meaningful improvements in worst tumor pain severity, pain interference, and HRQOL.

• Relevance (J.P.S. Knisely)

• This is a quantum leap forward for this disease; studies evaluating mirdametinib's ability to prevent the development of new plexiform neurofibromas in NF1 patients and identifying optimal chronic dosing regimens are needed.*

• *Relevance section written by JCO Associate Editor Jonathan P.S. Knisely, MD.

Patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) have limited treatment options. Historically, surgery was the primary treatment^9,12; however, it is associated with life-altering morbidities and tumor regrowth.^13,14 Inhibition of MAPK kinase (MEK) is a validated treatment strategy.¹² The MEK inhibitor selumetinib is approved in the United States for patients age 2 to 17 years with symptomatic, inoperable NF1-PN^15,16 but is only available as capsules, limiting its use in young children or those with difficulty in swallowing.^15,16 No therapies are currently approved for adults with NF1-PN.⁹

Mirdametinib is an investigational, highly selective, potent, allosteric, central nervous system (CNS)–penetrant, small-molecule MEK1/2 inhibitor^17-20 that is orally administered as a capsule or tablet for oral suspension, with no fasting requirement. In a phase II trial in 19 adults and adolescents with inoperable NF1-PN, eight (42%) patients achieved a partial response to mirdametinib by cycle 12 (28-day cycles).¹⁹

This article reports efficacy, patient- and parent proxy-reported outcomes, and safety of mirdametinib from the pivotal, phase IIb ReNeu trial of adults and children with symptomatic NF1-PN.

METHODS

Trial Design and Patients

ReNeu is a multicenter, open-label, single-arm, phase IIb trial of mirdametinib in adults and children with NF1²¹ with inoperable, radiologically measurable PN causing significant morbidity. Adults (≥18 years of age) and children (2 to 17 years of age) were enrolled in separate cohorts.

Mirdametinib was administered as a capsule or tablet for oral suspension, at a dose of 2 mg/m² (maximum dose, 4 mg) orally twice daily in 28-day cycles, on an intermittent dosing schedule of 3 weeks on, 1 week off, with no fasting requirement. The trial comprised a 24-cycle treatment phase, an optional long-term follow-up (LTFU) treatment phase, and a 30-day safety follow-up period after treatment discontinuation. Patients could continue receiving mirdametinib until any of the following occurred: centrally confirmed radiographic disease progression, intolerable adverse events (AEs), inability to adhere to the protocol, or patient- or investigator-determined discontinuation. Detailed trial design is described in the Data Supplement (Sections A-C, online only). Efficacy and safety data are reported as of the data cutoff (DCO) date (September 20, 2023).

Trial Oversight

The trial was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines of the International Council for Harmonisation, and all applicable laws, regulations, and scientific guidelines. The protocol was approved by the institutional review board or ethics committee for each site. An independent Data Monitoring Committee monitored safety and efficacy during the study. All patients or their legal guardians provided written informed consent before study enrollment (Data Supplement, Section C). The authors attest to data completeness and accuracy and to the fidelity of the trial to the protocol.

End Points and Assessments

End points were analyzed separately for adults and children. The primary end point was confirmed objective response rate (ORR), defined as the proportion of patients with a ≥20% reduction on magnetic resonance imaging (MRI) of the target PN volume from baseline to cycle 24 (treatment phase) assessed by blinded independent central review (BICR) on ≥2 consecutive scans within 2-6 months (Data Supplement, Section D). Secondary efficacy end points included duration of response (DoR) and change from baseline to prespecified cycle 13 for patient-reported outcome (PRO) or parent proxy-reported outcome measures of worst tumor pain severity (Numeric Rating Scale-11 [NRS-11]),²² pain interference (Pain Interference Index [PII]),²³ and HRQOL (Pediatric Quality of Life Inventory, version 4.0 [PedsQL 4.0]).^24-26 These PROs or parent proxy-reported outcomes have been evaluated in patients with NF1-PN¹⁵ and were used per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) recommendations.^27,28 Progression-free survival (PFS), change from baseline in target PN volume over time, patient-reported change in overall status (Patient Global Impression of Change [PGIC] scores)²⁹ throughout the treatment phase, and acceptability of the tablet for oral suspension (Pediatric Oral Medicines Acceptability Questionnaire [P-OMAQ] scores)³⁰ were key exploratory end points (Data Supplement, Sections D and E).

AEs that emerged or worsened after the first dose through 30 days after the last dose were reported and coded according to the Medical Dictionary for Regulatory Activities, version 24.0. The severity of AEs was graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, version 5.0 (Data Supplement, Section F). Investigators determined whether AEs were related to study treatment.

Historical Control Comparison

To assess the effect of mirdametinib on the natural history of PN, yearly change from baseline in PN volume and PFS were compared between children from the ReNeu trial and the NCI NF1 natural history study (ClinicalTrials.gov identifier: NCT00924196).³¹ Age, lesion type, and prior MEK inhibitor treatment were considered as prognostic factors for 1:1 propensity score matching across cohorts. In addition, mirdametinib-treated children with progressive disease at baseline were compared with those from the placebo arm of the NCI tipifarnib trial in progressive PN (ClinicalTrials.gov identifier: NCT00021541), with 1:1 propensity score matching by age.³² A similar comparison could not be performed for the ReNeu adult cohort because of the lack of comparability of available adult natural history data.

Statistical Analysis

Sample size calculations were based on ORRs from previous studies of MEK inhibitors in PN (Data Supplement, Section G).^15,19 Confirmed ORR was compared with the null hypothesis (minimum clinically relevant response rate of 23% for adults and 20% for children in one-sample two-sided binomial tests at the 5% significance level). PFS and DoR were assessed using the Kaplan-Meier method. Statistical methods for secondary end points, post hoc analyses of clinically meaningful improvement in PROs or parent proxy-reported outcomes, and historical control comparisons in children are described in the Data Supplement, Sections H-J, respectively. All patients who received ≥1 dose of mirdametinib were included in the analyses. A sensitivity analysis was performed for the per-protocol set, defined as patients who received ≥1 dose of mirdametinib, completed ≥1 postbaseline disease evaluation, and had no major protocol deviations (Data Supplement, Table S1).

RESULTS

Baseline Patient Characteristics

Between October 2019 and December 2021, 114 patients (58 adults, 56 children) were enrolled and received ≥1 dose of mirdametinib (Data Supplement, Fig S1). Baseline patient characteristics are shown in Table 1. The median (range) age was 34 years (18-69) for adults and 10 years (2-17) for children. The median (range) target PN volume was 196 mL (1-3,457) in adults and 99 mL (5-3,630) in children. Thirty-one adults (53%) and 35 children (62%) had investigator-determined progressive PN at baseline. The most common NF1-PN–related morbidities in both cohorts were pain (adults, 90%; children, 70%) and disfigurement or major deformity (adults, 52%; children, 50%).

TABLE 1.

Patient Baseline Characteristics (N = 114)

Characteristic	Adults (n = 58)	Children (n = 56)
Median age at enrollment, years (range)	34 (18-69)	10 (2-17)
Sex, No. (%)
Female	37 (64)	30 (54)
Male	21 (36)	26 (46)
Median volume of target PN, mL (range)	196 (1-3,457)	99 (5-3,630)
Progression status of target PN at trial entry, No. (%)
Progressive	31 (53)	35 (62)
Nonprogressive	27 (47)	21 (38)
Location of the target PN, No. (%)
Head and neck	28 (48)	28 (50)
Lower extremities	15 (26)	4 (7)
Paraspinal	5 (9)	4 (7)
Chest wall	4 (7)	2 (4)
Mesentery and pelvis	1 (2)	5 (9)
Upper extremities	2 (3)	4 (7)
Abdominal wall	0 (0)	1 (2)
Other	3 (5)	8 (14)
Type of PN-related morbidity, No. (%)
Pain	52 (90)	39 (70)
Disfigurement or major deformity	30 (52)	28 (50)
Motor dysfunction/weakness	23 (40)	15 (27)
Lower extremity	15 (26)	10 (18)
Upper extremity	8 (14)	5 (9)
Airway dysfunction	3 (5)	7 (12)
Othera	10 (17)	12 (21)
Optic glioma	11 (19)	16 (29)
Previous PN treatment, No. (%)
Surgery	40 (69)	20 (36)
Targeted medications/therapiesb	11 (19)	8 (14)
Radiotherapy	1 (2)	0 (0)

Abbreviations: MEK, MAPK kinase; PN, plexiform neurofibroma.

^a Other category excluded optic glioma (reported separately).

^b The exclusion criteria were modified in Protocol Amendment 2 to disallow previous MEK inhibitors. Ten patients overall (four adults and six children) with previous MEK inhibitor therapy were enrolled before the protocol amendment.

Adults

Efficacy

Twenty-four adults (41%; 95% CI, 29 to 55) achieved a confirmed objective response by BICR during the treatment phase, which was significantly higher (P < .001) than the predefined minimum clinically relevant response rate of 23% for adults (Full Analysis Set; Per-Protocol Set results are reported in the Data Supplement, Table S1). Two additional adults achieved a confirmed response in the LTFU (onset of response occurred at cycle 28 and cycle 32, respectively). Twenty-three (96%) of the 24 confirmed objective responses remained durable at DCO, with 18 (75%) having met or exceeded 12 months in response. One (4%) patient progressed within 12 months of response onset. The median time to onset of confirmed response was 7.8 months (range, 4.0-19.0). The median duration of treatment was 21.8 months (range, 0.4-45.6; Fig 1), and the median DoR has not been reached (Data Supplement, Table S2). The median best percentage change in target PN volume was –41% (range, –90 to 13), and results were consistent between BICR readers (Data Supplement, Fig S2). Sixty-two percent of adults (15 of 24) with a confirmed objective response achieved a maximum reduction from baseline of >50%. The median time to best volumetric percentage change from baseline was 15.2 months (range, 4.0-40.0). Eighty-four percent of adults who completed the treatment phase chose to enter the LTFU. An example of tumor response is shown in Figure 2. Pearson correlation analysis demonstrated little correlation between baseline target PN volume and best percentage change from baseline in target PN volume in adults (r = 0.016 per Reader A; r = 0.089 per Reader B; Data Supplement, Fig S3). There was little correlation between age at consent and best percentage change from baseline in target PN volume in the combined population of adults and children (r = –0.078 per Reader A; r = –0.009 per Reader B).

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.

From baseline to cycle 13, mirdametinib demonstrated significant improvements (reductions) in PROs of worst tumor pain severity (NRS-11: least-squares [LS] mean change –1.3; SE, 0.2; P < .001) and pain interference (PII: LS mean change, –0.7; SE, 0.2; P < .001) and a significant improvement (increase) in HRQOL (PedsQL Total Score: LS mean change, 3.9; SE, 1.6; P = .02; prespecified secondary end points; Data Supplement, Table S3). The improvements from baseline in NRS-11 and PII were durable and significant, began early (at cycle 3, the first postbaseline assessment), and were sustained throughout the study (P < .05 across cycles; Fig 3). Pain was the most common PN-related morbidity, and adults with moderate-to-severe pain (NRS-11 ≥ 4) at baseline had early and sustained improvements in pain (Data Supplement, Fig S4). Among adults who could achieve a clinically meaningful improvement (defined in the Data Supplement, Section I), 59% (17 of 29), 50% (13 of 26), and 42% (17 of 40) achieved a clinically meaningful improvement in NRS-11, PII, and PedsQL Total Score at cycle 5 from baseline, respectively. At cycle 13, 79% (11 of 14), 58% (7 of 12), and 37% (10 of 27) of adults achieved a clinically meaningful improvement in NRS-11, PII, and PedsQL Total Score from baseline, respectively (Data Supplement, Fig S5). The majority (71%) of adults at cycle 13 reported an improvement (very much/moderately/a little better) in overall status with mirdametinib (PGIC score exploratory end point; Data Supplement, Fig S6).

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.

Safety

All adults (n = 58) reported ≥1 AE, and 98% experienced an AE that was deemed by investigators to be related to study treatment, with the majority being grade 1 or 2 (Table 2 and Data Supplement, Table S4). Treatment-related adverse events (TRAEs) reported in ≥20% of adults were dermatitis acneiform (78%), diarrhea (48%), nausea (36%), vomiting (28%), and fatigue (21%). Eighteen adults (31%) experienced a dose interruption, 10 (17%) underwent dose reduction, and 13 (22%) discontinued treatment because of AEs (Data Supplement, Table S5). No adult had a symptomatic ejection fraction decrease (Data Supplement, Section K). One serious TRAE occurred: a grade 3 retinal vein occlusion that resulted in treatment discontinuation in a 26-year-old female approximately 4 months after initiating hormonal contraception and 9 days after COVID-19 vaccination. At the last follow-up, her visual acuity was 20/30 (–2) compared with a baseline of 20/20 (–1). A second patient, a 38-year-old male with hyperlipidemia, reported two events of grade 1 asymptomatic retinal vein occlusions identified on protocol-specified eye examinations. Both events resolved without dose modification. There was one non–treatment-related death because of COVID-19 disease. There were no transformations of PN to malignant peripheral nerve sheath tumors on study.

TABLE 2.

Most Common (≥5% of patients in either cohort) TRAEs in Adults (n = 58) and Children (n = 56)

TRAEs	Adults (n = 58)		Children (n = 56)
	All Grades	Grade ≥3a	All Grades	Grade ≥3b
No. of patients reporting any TRAE,c No. (%)	57 (98)	9 (16)	53 (95)	14 (25)
Most common TRAEs (≥5% of patients in either cohort),d No. (%)
Dermatitis acneiform	45 (78)	5 (9)	24 (43)	1 (2)
Diarrhea	28 (48)	0 (0)	21 (38)	1 (2)
Nausea	21 (36)	0 (0)	12 (21)	0 (0)
Vomiting	16 (28)	0 (0)	8 (14)	0 (0)
Fatigue	12 (21)	1 (2)	5 (9)	0 (0)
Dry skin	8 (14)	0 (0)	8 (14)	0 (0)
Alopecia	7 (12)	0 (0)	7 (12)	0 (0)
Ejection fraction decreased	7 (12)	0 (0)	11 (20)	1 (2)
Blood creatinine phosphokinase increased	6 (10)	1 (2)	11 (20)	4 (7)
Dizziness	5 (9)	0 (0)	2 (4)	0 (0)
Pruritus	5 (9)	0 (0)	3 (5)	0 (0)
Constipation	4 (7)	0 (0)	3 (5)	0 (0)
Rash	4 (7)	0 (0)	7 (12)	1 (2)
Abdominal pain	3 (5)	0 (0)	8 (14)	2 (4)
Acne	3 (5)	0 (0)	0 (0)	0 (0)
Dry mouth	3 (5)	0 (0)	0 (0)	0 (0)
Peripheral edema	3 (5)	0 (0)	2 (4)	0 (0)
Pain of skin	3 (5)	0 (0)	0 (0)	0 (0)
Urticaria	3 (5)	0 (0)	3 (5)	0 (0)
Vision blurred	3 (5)	0 (0)	1 (2)	0 (0)
Abdominal pain upper	2 (3)	0 (0)	6 (11)	1 (2)
Eczema	2 (3)	0 (0)	6 (11)	0 (0)
Stomatitis	2 (3)	0 (0)	5 (9)	0 (0)
Weight increased	2 (3)	0 (0)	8 (14)	2 (4)
Hair color changes	1 (2)	0 (0)	6 (11)	0 (0)
Hair texture abnormal	1 (2)	0 (0)	3 (5)	0 (0)
Pain in extremity	1 (2)	0 (0)	3 (5)	1 (2)
Paronychia	1 (2)	0 (0)	17 (30)	0 (0)
Headache	0 (0)	0 (0)	6 (11)	0 (0)
Hypertriglyceridemia	0 (0)	0 (0)	4 (7)	0 (0)
Hypocalcemia	0 (0)	0 (0)	3 (5)	0 (0)
Neutrophil count decreased	0 (0)	0 (0)	5 (9)	5 (9)
Rash pustular	0 (0)	0 (0)	4 (7)	0 (0)
WBC count decreased	0 (0)	0 (0)	3 (5)	0 (0)
Serious TRAEse, No. (%)	1 (2)		0 (0)

Abbreviations: AEs, adverse events; TRAEs, treatment-related adverse events.

^a All events in adults were grade 3, except for one grade 4 AE of blood creatinine phosphokinase increased.

^b All events in children were grade 3, except for one grade 4 event of blood creatinine phosphokinase increased. There were no grade 5 AEs.

^c Five (9%) adults and 8 (14%) children experienced a TRAE leading to dose interruption, 10 (17%) adults and 7 (12%) children experienced a TRAE leading to dose reduction, and 12 (21%) adults and 5 (9%) children experienced a TRAE leading to treatment discontinuation.

^d TRAEs occurring in 5% or more patients in either cohort by order of decreasing incidence in the adult cohort.

^e There was one serious TRAE in the adult cohort: grade 3 retinal vein occlusion with confounding factors (hormonal contraception and COVID-19 vaccination). There were no serious TRAEs or retinal vein occlusion reported in children.

Children

Efficacy

Twenty-nine children (52%; 95% CI, 38 to 65) achieved a confirmed objective response by BICR during the treatment phase, which was significantly higher (P < .001) than the minimum clinically relevant response rate of 20% for children (Full Analysis Set; Per-Protocol Set results are reported in the Data Supplement, Table S1). One additional child achieved a confirmed response (onset occurred at cycle 32) in the LTFU. All (100%) the 29 confirmed objective responses remained durable at DCO, with 22 (76%) having met or exceeded 12 months in response. The median time to onset of confirmed response was 7.9 months (range, 4.1-18.8). The median duration of treatment was 22.0 months (range, 1.6-40.0; Fig 1), and the median DoR has not been reached (Data Supplement, Table S2). The median best percentage change in target PN volume was –42% (range, –91 to 48), and results were consistent between readers (Data Supplement, Fig S2). Fifty-two percent of children (15 of 29) with a confirmed objective response achieved a maximum reduction from baseline of >50%. The median time to best volumetric percentage change from baseline was 13.4 months (range, 4.0-32.7). Eighty-five percent of children who completed the treatment phase chose to enter the LTFU. Examples of tumor response are shown in Figure 2. Pearson correlation analysis demonstrated little correlation between baseline target PN volume and best percentage change in target PN volume in children (r = –0.082 per Reader A; r = –0.05 per Reader B; Data Supplement, Fig S3).

From baseline to cycle 13, mirdametinib demonstrated significant improvements (reductions) in patient-reported worst tumor pain severity (NRS-11: LS mean change, –0.8; SE, 0.2; P = .003), patient-reported pain interference (PII: LS mean change, –0.5; SE, 0.2; P = .02), and parent proxy-reported pain interference (PII: LS mean change, –0.3; SE, 0.1; P = .03) and a significant improvement (increase) in parent proxy-reported HRQOL (PedsQL Total Score: LS mean change, 5.6; SE, 1.9; P = .005; prespecified secondary end points; Data Supplement, Table S3). The improvements from baseline in patient-reported NRS-11 and patient- and parent proxy-reported PII were durable and significant, began early (at cycle 3 or 5), and were sustained through most cycles (P < .05 for all, except PII by patient report at cycles 3 and 24; Fig 3). Among children who could achieve a clinically meaningful improvement (defined in the Data Supplement, Section I), the percentage who achieved a clinically meaningful improvement from baseline at cycle 5 was 57% (8 of 14) for patient-reported NRS-11, 33% (4 of 12) for patient-reported PII, 45% (5 of 11) for parent proxy-reported PII, 39% (14 of 36) for patient-reported PedsQL Total Score, and 41% (17 of 41) for parent proxy-reported PedsQL Total Score. At cycle 13, a clinically meaningful improvement from baseline was achieved by 73% (8 of 11) for NRS-11, 50% (5 of 10) for patient-reported PII, 60% (6 of 10) for parent proxy-reported PII, 45% (13 of 29) for patient-reported PedsQL Total Score, and 47% (15 of 32) for parent proxy-reported PedsQL Total Score (Data Supplement, Fig S5). The majority (79%) of children at cycle 13 reported an improvement (very much/moderately/a little better) in overall status with mirdametinib (PGIC score exploratory end point; Data Supplement, Fig S6).

Children who were administered the tablet for oral suspension reported high median P-OMAQ scores (P-OMAQ patients; n = 13) of 5 (range, 3-5) for willingness to take the suspension and 5 (range, 2-5) for easiness to swallow, of a maximum score of 5 (5 = very willing/very easy). Similarly, P-OMAQ caregiver scores (n = 17) were 5 (range, 4-5) for easiness to swallow and 5 (range, 3-5) for child willingness to continue.

Baseline characteristics were balanced after propensity score matching of children in ReNeu to historical controls (Data Supplement, Tables S6 and S7). As compared with matched historical controls, mirdametinib-treated children (LS mean difference, –41%; P < .001) and mirdametinib-treated children with progressive disease at baseline (LS mean difference, –44%; P < .001) had a significantly greater decrease from baseline at year 1 in target PN volume. Mirdametinib-treated children had significantly longer PFS (P < .001) and significantly greater (P < .05 for all years assessed) annual percentage tumor volume reduction than historical controls (Fig 4; Data Supplement, Table S8).

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.

Safety

All children (n = 56) reported ≥1 AE, and 95% experienced an AE that was determined by an investigator to be related to study treatment, with the majority being grade 1 or 2 (Table 2; Data Supplement, Table S9). TRAEs occurring in ≥20% of children were dermatitis acneiform (43%), diarrhea (38%), paronychia (30%), nausea (21%), ejection fraction decreased (20%), and increased blood creatinine phosphokinase (20%). Seventeen children (30%) had a dose interruption, seven (12%) underwent a dose reduction, and five (9%) discontinued treatment because of AEs (Data Supplement, Table S5). No child had a symptomatic ejection fraction decrease (Data Supplement, Section K), a retinal vein occlusion, or a serious TRAE. There were no transformations of PN to malignant peripheral nerve sheath tumors on study.

DISCUSSION

There remains an unmet need for highly effective and better tolerated NF1-PN pharmacologic therapies with a formulation option for young children or those with difficulty in swallowing. Mirdametinib (capsule and tablet for oral suspension) was studied in adults and children with NF1-PN in the ReNeu trial and led to deep tumor volume reductions (median best change in tumor volume >40% reduction) and durable responses on therapy. In children, including those with progressive disease at baseline, mirdametinib treatment resulted in significantly longer PFS and greater annual reductions in target PN volume than historical controls. In addition, mirdametinib treatment was associated with significant and clinically meaningful improvement in patient-/parent proxy-reported outcomes from baseline to cycle 13, including measures of worst tumor pain severity, pain interference, and key HRQOL measures in adults and children. Improvement in most patient-/parent proxy-reported outcomes began at cycle 3 (the first post-treatment timepoint evaluated) and was generally sustained throughout the trial. AEs with mirdametinib were manageable and mostly grade 1 or 2.

ReNeu is the largest multicenter NF1-PN trial reported to date and prospectively used BICR for assessing target tumor response. The confirmed ORRs were 41% in adults and 52% in children within the treatment phase and increased to 45% and 54%, respectively, when additional objective responses observed during the LTFU phase were included. For reference, BICR analysis was applied retrospectively in the pediatric SPRINT study of selumetinib,¹⁵ with a reported confirmed ORR of 44%.¹⁶

Mirdametinib treatment led to deep responses (maximum PN volume reduction from baseline of >50%) in 62% of adults and 52% of children among those who achieved a confirmed response in ReNeu. Confirmed ORR with mirdametinib was numerically higher in children than it was in adults; however, median tumor volume reduction was very similar across age groups, and a numerically higher percentage of adults than children achieved a deep response. The tumor volume responses observed in the ReNeu trial are consistent with available preclinical data. In an NF1^flox/flox;DhhCre genetic mouse model, clinically relevant doses of mirdametinib resulted in sustained suppression of pERK in mouse tissue samples and substantial PN volume reduction.^17,33 Preclinical and clinical data suggest that mirdametinib's high potency for inhibiting ERK phosphorylation^17,34 and half-life,¹⁸ together with hypotheses including alterations in the tumor microenvironment, blood-tumor barrier penetration, and effects on collagen and vasculature within the PN, could be plausible explanations for mirdametinib's deep responses in ReNeu.

The tablet formulation for oral suspension of mirdametinib demonstrated high acceptability by patients and caregivers, providing a dosing option for patients with swallowing difficulties, such as children and adults with tumors in the head and neck region. In addition, mirdametinib can be given without regard to food, providing dosing flexibility.

Mirdametinib's safety profile was consistent with what has been reported for other MEK inhibitors, and the side effects were mostly manageable.^15,35 TRAEs with a ≥20% difference between age groups included dermatitis acneiform (more common in adults) and paronychia (more common in children; Table 2); these differences are most likely attributed to the age difference between groups and age-related development.^36,37 Adults had a higher rate of treatment discontinuation because of AEs than children (22% v 9%). Rates of acneiform rash, nausea, vomiting, diarrhea, and paronychia were lower in ReNeu than those reported to date in previously published phase II studies of other MEK inhibitors in pediatric patients with NF1-PN.^15,16,38 In addition, AEs leading to dose reduction and interruption in our study were less frequent than those reported in the aforementioned studies.^15,16,38

Our study was not designed to assess off-treatment durability of response or off-treatment–sustained benefits in PROs and parent proxy-reported outcomes. In addition, optimal treatment duration was not evaluated in the trial. As with other MEK inhibitors, potential long-term or late-emerging side effects and the potential benefit of long-term therapy are yet to be fully elucidated.

In ReNeu, mirdametinib demonstrated clinical benefit in adults and children with symptomatic NF1-PN. Mirdametinib demonstrated significantly confirmed ORRs by BICR, with deep and durable target PN volume reductions; significant and clinically meaningful improvements in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and key HRQOL measures from baseline to cycle 13; and a tolerable safety profile. In summary, given these data, along with availability as a tablet for oral suspension, mirdametinib has the potential to be a new treatment option in adults and children with NF1-PN.

APPENDIX

TABLE A1.

List of Investigators

Investigator Name	Clinical Study Site
Ahmed Raslan	Oregon Health & Science University (OHSU), Portland, OR
Alpa Sidhu	University of Iowa Hospital and Clinics, Iowa City, IA
Ana Aguilar-Bonilla	Orlando Health, Inc Arnold Palmer Hospital for Children, Orlando, FL
Andrea T. Franson	University of Michigan, Ann Arbor, MI
Andrew Walter	Nemours Children's Hospital, Delaware, Wilmington, DE
Angela C. Hirbe	Washington University School of Medicine—Siteman Cancer Center, St Louis, MO
Brian Van Tine	Washington University School of Medicine—Siteman Cancer Center, St Louis, MO
Carl Koschmann	University of Michigan, Ann Arbor, MI
Christopher L. Moertel	University of Minnesota/Masonic Children's Hospital, Minneapolis, MN
Cynthia Campen	Lucile Packard Children's Hospital Stanford University, Palo Alto, CA
Daniela A. Bota	University of California Irvine Health, Orange, CA
David Schiff	University of Virginia Health—Emily Couric Clinical Cancer Center, Charlottesville, VA
David Viskochil	The University of Utah, Center for Clinical and Translational Sciences, Salt Lake City, UT
Dusica Babovic-Vuksanovic	Mayo Clinic, Rochester, MN
Fouad M. Hajjar	AdventHealth Orlando, Orlando, FL
Gurcharanjeet Kaur	Nemours Children's Hospital, Delaware, Wilmington, DE
Hans H. Shuhaiber	University of Florida Clinical Research Center, Gainesville, FL
Jamie K. Capal	UNC Neurology Clinical Trials Unit, Chapel Hill, NC
John Slopis	The University of Texas MD Anderson Cancer Center, Houston, TX
Jonathan Gill	The University of Texas MD Anderson Cancer Center, Houston, TX
Julia Meade	UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
Kathryn Nevel	Indiana University (IU) Health Brain Tumor Infusion Clinic, Indianapolis, IN
Kevin Bielamowicz	Arkansas Children's Hospital—University of Arkansas, Little Rock, AR
Laura J. Klesse	Children's Medical Center, Dallas, TX
Laura K. Metrock	University of Alabama at Birmingham—Children's of Alabama, Birmingham, AL
Lauren Weintraub	Albany Medical Center, Albany, NY
Leia Nghiemphu	University of California, Los Angeles Oncology Center, Los Angeles, CA
Lindsay Kilburn	Children's National Medical Center, Washington, DC
Maciej M. Mrugala	Mayo Clinic Hospital, Phoenix, AZ
Mary Lou Schmidt	University of Illinois Hospital and Health Systems (Outpatient Care Center), Chicago, IL
Miriam Bornhorst	Children's National Medical Center, Washington, DC
Nagma Dalvi	Children's Hospital at Montefiore, Bronx, NY
Nathan J. Robison	Children's Hospital Los Angeles, Cancer and Blood Disease Institute, Los Angeles, CA
Nicholas K. Foreman	Children's Hospital Colorado, Aurora, CO
Paul L. Moots	Henry-Joyce Cancer Clinic, Nashville, TN
Prakash Ambady	Oregon Health & Science University (OHSU), Portland, OR
Punita Gupta	Saint Joseph's University Medical Center, Paterson, NJ
Radhika Dhamija	Mayo Clinic Hospital, Phoenix, AZ
Rene Y. McNall-Knapp	University of Oklahoma—Health Sciences Center; Jimmy Everest Center for Cancer and Blood Disorders in Children, Oklahoma City, OK
Rueben Antony	University of California Davis, Comprehensive Cancer Center, Sacramento, CA
Ryan D. Roberts	Nationwide Children's Hospital, Columbus, OH
Ryan Merrell	Henry-Joyce Cancer Clinic, Nashville, TN
Sarah Chagnon	Children's Hospital of the King's Daughters, Norfolk, VA
Stacie Stapleton	Johns Hopkins All Children's Hospital, St Petersburg, FL
Stefania Maraka	University of Illinois Hospital and Health Systems (Outpatient Care Center), Chicago, IL
Timothy R. Gershon	UNC Neurology Clinical Trials Unit, Chapel Hill, NC
Tobias Walbert	Henry Ford Health System, Detroit, MI
Ziad Khatib	Nicklaus Children's Hospital, Miami, FL
Zsila Sadighi	The University of Texas MD Anderson Cancer Center, Houston, TX

DATA SHARING STATEMENT

SpringWorks Therapeutics is committed to data transparency and sharing data to further research while maintaining the privacy and confidentiality of research participants. Pertinent patient-level data from completed registrational clinical trials will be made available by SpringWorks to qualified researchers upon approval of reasonable requests following deidentification/anonymization pursuant to applicable law. Requests for data must be sent to medinfo@springworkstx.com.

AUTHOR CONTRIBUTIONS

Conception and design: Christopher L. Moertel, Angela C. Hirbe, Hans H. Shuhaiber, Kevin Bielamowicz, Michael D. Weber, L. Mary Smith, Punita Gupta, Nathan J. Robison, Stacie Stapleton, Dusica Babovic-Vuksanovic, Timothy R. Gershon

Provision of study materials or patients: Christopher L. Moertel, Angela C. Hirbe, Hans H. Shuhaiber, Kevin Bielamowicz, Alpa Sidhu, David Viskochil, Michael D. Weber, Fouad M. Hajjar, Rene Y. McNall-Knapp, Reuben Antony, Andrea T. Franson, Julia Meade, David Schiff, Tobias Walbert, Prakash Ambady, Daniela A. Bota, Laura J. Klesse, Stefania Maraka, Cynthia J. Campen, Paul L. Moots, Kathryn Nevel, Miriam Bornhorst, Ana Aguilar-Bonilla, Sarah Chagnon, Punita Gupta, P. Leia Nghiemphu, Ryan D. Roberts, Nathan J. Robison, Dusica Babovic-Vuksanovic

Collection and assembly of data: Christopher L. Moertel, Angela C. Hirbe, Hans H. Shuhaiber, Kevin Bielamowicz, Alpa Sidhu, David Viskochil, Michael D. Weber, L. Mary Smith, Nicholas K. Foreman, Fouad M. Hajjar, Rene Y. McNall-Knapp, Lauren Weintraub, Reuben Antony, Andrea T. Franson, Julia Meade, David Schiff, Tobias Walbert, Daniela A. Bota, Cynthia J. Campen, Gurcharanjeet Kaur, Laura J. Klesse, Stefania Maraka, Paul L. Moots, Kathryn Nevel, Miriam Bornhorst, Ana Aguilar-Bonilla, Sarah Chagnon, Ziad Khatib, Laura K. Metrock, P. Leia Nghiemphu, Ryan D. Roberts, Nathan J. Robison, Zsila Sadighi, Stacie Stapleton, Dusica Babovic-Vuksanovic, Timothy R. Gershon

Data analysis and interpretation: Christopher L. Moertel, Angela C. Hirbe, Hans H. Shuhaiber, Kevin Bielamowicz, Michael D. Weber, Armend Lokku, L. Mary Smith, Reuben Antony, Andrea T. Franson, Julia Meade, David Schiff, Tobias Walbert, Prakash Ambady, Daniela A. Bota, Laura J. Klesse, Stefania Maraka, Paul L. Moots, Kathryn Nevel, Miriam Bornhorst, Sarah Chagnon, Nagma Dalvi, Laura K. Metrock, P. Leia Nghiemphu, Nathan J. Robison, Zsila Sadighi, Dusica Babovic-Vuksanovic, Timothy R. Gershon

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

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