Therapeutic Advances in Neurofibromatosis Type 1: A Focus on Selumetinib

Faith Cormier, MD, FRCPC¹; Irene Lara-Corrales, MD, MSc¹; Maxwell Sauder, MD, FRCPC²; Rebecca Levy, MD, FRCPC¹

¹Division of Dermatology, The Hospital for Sick Children, Toronto, ON, Canada
²Division of Dermatology, University of Toronto, Toronto, ON, Canada

Conflicts of interest: Faith Cormier and Maxwell Sauder have no conflicts of interest.
Irene Lara-Corrales and Rebecca Levy are research grant recipients, consultants, and speakers for Alexion.
Funding sources: None.

Abstract: Neurofibromatosis type 1 (NF1) is a genetic condition inherited in an autosomal dominant pattern, but with 50% of cases caused by de novo mutations. Neurofibromin, the gene product in NF1, regulates the RAS/MAPK pathway, and mutation can lead to cell proliferation and the development of tumours. NF1 often presents in childhood with cafe-au-lait macules, skinfold freckling, nervous system tumours, and phenotypically variable findings. Plexiform neurofibromas (PN), a type of peripheral nerve sheath tumour seen in NF1, are typically histologically benign. However, PN can cause significant physical disfigurement, pain, and decreased quality of life, and have historically been difficult to treat. Selumetinib, a MEK inhibitor inhibiting the RAS/MAPK pathway, was Health Canada approved in 2022 for the treatment of symptomatic, inoperable PN in individuals with NF1 aged 2 years and older. Phase 1 and 2 trials have demonstrated reduced tumour size, decreased disfigurement and pain, and increased quality of life.

Keywords: neurofibromatosis type 1, plexiform neurofibromas, RAS/MAPK pathway, MEK inhibitor, selumetinib

Introduction

Neurofibromatosis type 1 (NF1) is a genetic condition caused by mutations in the NF1 gene. It is inherited in an autosomal dominant pattern, but with 50% of cases resulting from de novo mutations. Penetrance is complete, but expressivity is variable, accounting for the wide range of phenotypes seen. NF1 often shows clinical signs in childhood, including the development of cafe-au-lait macules, skinfold freckling, nervous system tumours, and other phenotypically variable findings. The revised diagnostic criteria for NF1 are detailed in Table 1.¹

Table 1.

The RAS/MAPK signaling cascade (Figure 1) is one of the main intracellular pathways regulating normal cellular proliferation. The NF1 gene product, neurofibromin, regulates the RAS/MAPK pathway; reduced production or function of neurofibromin results in cell proliferation and the development of tumours. MEK inhibitors, like selumetinib, have emerged as potential therapeutic agents in NF1 given they inhibit this pathway and lead to reduced cellular proliferation, cell cycle arrest, and apoptosis.²

Figure 1.

Plexiform neurofibromas (PN), a histologically benign type of peripheral nerve sheath tumour, develop in up to 50% of patients with NF1. Despite their ‘benign’ classification, their size, location, and propensity for slow continued growth can cause significant physical disfigurement, pain, and decreased quality of life.

Historically, these tumours have been difficult to treat medically or with surgery.⁴ Selumetinib has emerged as a safe and effective treatment and was approved by Health Canada in August 2022 for patients aged 2 years and above with NF1 who have symptomatic, inoperable PN.⁵

Clinical Trials

Preliminary information on the efficacy and safety of selumetinib was assessed in phase 1 and phase 2 clinical trials.^4,6

Phase 1

The phase 1 trial included 24 NF1 patients with inoperable PN, ranging from 3 to 18 years of age (median age at enrolment was 10.9 years). Selumetinib was given every 12 hours on a continuous dosing schedule, in 28-day cycles. Selumetinib was decreased or stopped if any toxic effects were noted. A dose of 25 mg per square meter of body surface area was determined to be the optimal dose, with an acceptable side effect profile. Evaluation of treatment response was performed using magnetic resonance imaging (MRI) volumetric analysis. Partial response to treatment was defined as a decrease in PN volume of at least 20%, sustained for at least 4 weeks.⁴

Patients received a median of 30 cycles (approximately 2.5 years) of treatment with selumetinib. Maximum response was reached at a median of 20 cycles (approximately 1.5 years) of treatment. A decrease in the volume of PN was observed in all patients. Seventy-one percent of patients met criteria for a partial response (defined as a decrease in PN volume of at least 20%, sustained for at least 4 weeks). These partial responses were durable and were sustained for a median of 23 cycles. At the time of trial publication, no patients had progression of the tumours from their baseline and 15 of 17 patients maintained their response to selumetinib. Some patients did have slow regrowth of tumours, in the context of selumetinib dose reductions or treatment interruptions due to side effects. Importantly, with selumetinib treatment, patients noted improvements in their pain, decreases in disfigurement, and better motor function.⁴

Grading of side effects was done using the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.7 A few grade 3 reactions (severe or medically significant but not immediately life-threatening) were noted, including cellulitis (1 patient), urticaria (1 patient), and significant creatine kinase (CK) elevation (1 patient). One patient experienced a grade 3 asymptomatic decrease in their left ventricular ejection fraction.⁴

Most early side effects from selumetinib were mild (grade 1) and these included gastrointestinal (GI) upset and CK elevation (asymptomatic in all patients except 1 who developed temporary arm pain). Of note, the CK was of skeletal muscle origin (not cardiac muscle origin).

Post-pubertal patients experienced acneiform eruptions: 9 patients (38%) in the first 3 cycles of treatment and 7 patients (29%) after 4 or more cycles of treatment. A higher selumetinib dose was associated with a higher CTCAE grade of acneiform eruption. Pre-pubertal patients more commonly experienced maculopapular eruptions: 5 patients (21%) in the first 3 cycles of treatment and 8 patients (33%) after 4 or more cycles of treatment.⁴

Later in treatment, side effects included ALT elevation and decreased neutrophil count. One patient developed an asymptomatic cataract. No effect on height or weight was observed. At or after 4 cycles of treatment, mucositis developed in 11 patients (46%) and paronychia developed in 6 patients (25%).⁴

Phase 2

The phase 2 trial included 50 patients with NF1, ranging from 3 to 17 years of age (median age at enrolment of 10.2 years). Selumetinib was given every 12 hours on a continuous dosing schedule, in 28-day cycles, at a dose of 25 mg per square meter of body surface area. Up to two dose reductions of selumetinib were allowed if toxic side effects occurred. Evaluation of treatment response was performed using MRI volumetric analysis. Partial response to treatment was defined as a decrease in PN volume of at least 20%, sustained for at least 4 weeks. A durable partial response was defined as a partial response lasting at least 12 cycles.⁶

This trial aimed to better determine, prospectively, the effect of selumetinib on functional limitations, pain, and quality of life. In addition, the study compared trial patients to patients in a study looking at the natural history of NF1.⁶

The average number of treatment cycles was 36 (3 years). 74% of patients had a partial response. The median time to initial response was 8 cycles (approximately 8 months), and the median time to best response was 16 cycles (approximately 15 months). At the cutoff time for data submission, 46% of patients continued to have partial response, 12% had stable disease, and 42% discontinued treatment (for reasons discussed below).⁶

Regarding functional measurements, 68% of patients had at least some improvement, including decreases in pain intensity and the interference of pain on activity, and improvements in health-related quality of life, strength, and range of motion. One tracheostomy patient was able to be decannulated due to tumour shrinkage.⁶

The patients with tumour shrinkage in this trial contrast significantly with the patients in the NF1 natural history study, where most patients experienced disease progression, and none showed shrinkage of the tumour of at least 20%.⁶

Reasons for discontinuation of treatment were varied but included progressive disease, stable disease, toxic side effects, investigator decision, patient declining further treatment, non-adherence to treatment, and transformation to malignant tumour. Of the 6 patients who had progressive disease, 5 of them had previous dose reductions of selumetinib. There were no ophthalmologic or cardiovascular problems observed in any of the patients.⁶

Side effects of selumetinib included GI upset, asymptomatic CK elevation, acneiform eruption, and paronychia. Acneiform eruptions occurred in 17 patients (34%) within cycles 1-6, 9 patients (19%) within cycles 7-12, and in 12 patients (27%) in cycles 13 and above. Paronychia occurred in 8 patients (16%) within cycles 1-6, 9 patients (19%) within cycles 7-12, and in 21 patients (47%) in cycles 13 and above.⁶

Discussion

NF1 is a genetic condition which can result in multi-system disease, including inoperable PN that may be disfiguring, painful, or functionally impairing. While historically difficult to treat, selumetinib is a promising new treatment option for pediatric patients with problematic PN, with recent clinical trials demonstrating significant reductions in tumour volume and a largely tolerable safety profile.

A recent review demonstrated further long-term efficacy and safety of selumetinib for NF1 patients with PN.⁸ Seventy-four children treated in phase 1 and 2 clinical trials were enrolled and followed for up to 5 years. The median age of the patients was 10.3 years, with an age range of 3 to 18.5 years. The mean duration of treatment for these patients was 57.5 cycles (just under 4.5 years). Across both trials, the median time to initial response was approximately 8 cycles (approximately 8 months) and time to best response was 18 cycles (approximately 17 months).⁸

Some patients in the review completed quality of life measures after over 4 years of treatment. Many of these patients continued to have decreased pain intensity and decreased pain interference with daily activities. Selumetinib causes PN shrinkage in most children and significantly slows growth of these tumours.⁸

Side effects during this longer period of observation included asymptomatic CK elevation, GI upset, mucositis, fatigue, paronychia, and acneiform rash. Importantly, these side effects could occur even after years of treatment, which underlies the need for continuous side effect monitoring in these patients. MEK inhibitors as a class have the potential for serious ocular and cardiac complications. During this extended period of treatment, only one patient developed an ocular complication, central serous retinopathy. Sixteen patients developed an asymptomatic decrease in their left ventricular ejection fraction.⁸

During this 5-year observation period, no new safety concerns were identified. As noted above, patients continued to have previously known side effects, even years into treatment.⁸ At this time, longer term safety information is not available.

A reduction in tumour volume of 20% was utilized as the primary outcome measure. Plexiform neurofibromas are typically inoperable and progressive, so even small reductions in tumour volume may represent a significant clinical benefit, particularly via symptom improvement (decreased pain, improved function, reduced disfigurement). This volume reduction, confirmed via imaging (e.g. MRI), provides an objective and quantifiable endpoint that demonstrates the biological activity and potential efficacy of selumetinib. This threshold is a pragmatic choice for capturing measurable change while avoiding overly stringent criteria that might exclude meaningful responses. Limitations of this outcome measure include that the 20% threshold does not fully capture functional outcomes (mobility, quality of life), which are critical for pediatric patients. Tumour growth control or stabilization, rather than reduction, may be equally valuable in preventing
complications over time.

Cutaneous toxicities with selumetinib are common. These toxicities include acneiform eruptions (primarily occurring in post-pubertal patients), maculopapular eruptions (primarily occurring in pre-pubertal patients) and paronychia. When present, these toxicities can be challenging to treat, particularly for practitioners with little experience in this area. This underlies the need for dermatology involvement, where available, early in the treatment course with selumetinib. There should be clear and consistent counselling
around preventative skin care measures, and use of evidence-based directed management strategies for skin toxicities when needed.⁹ Acneiform eruptions to MEK inhibitors can be treated similarly to acneiform eruptions to EGFR inhibitors, with topical steroids and/or calcineurin inhibitors as well as oral antibiotics.¹⁰ The use of topical retinoids should be avoided.

Conclusion

Selumetinib, an oral MEK inhibitor, is an effective treatment option for inoperable PN in pediatric patients with NF1 and the first of its kind approved by Health Canada for this indication, providing new opportunities for pain reduction, functional improvement, and overall improved quality of life. Close monitoring for toxicities, including cutaneous, remains a critical component of its use.