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NF1 Call to Action
Call to Action: What to Know About Caring for Adult and Pediatric Patients With Inoperable Neurofibromatosis Type 1-Associated Tumors

Released: October 09, 2023

Jaishri Blakeley
Jaishri Blakeley, MD
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Key Takeaways
  • Neurofibromatosis type 1 (NF1) is a genetic condition that predisposes to the development of both benign and malignant nervous system tumors.
  • These tumors can develop in both children and adults. The most common tumors on NF1 involve the nervous system (central nervous system for gliomas and peripheral nervous system for neurofibromas).
  • Key considerations for management of NF1-associated manifestation are dependent on the age of the individual, the tumor type and location and the risk of neurologic injury. For example, optic pathway gliomas (OPGs) are of greatest concern in very young children and may be associated with vision loss early in life. OPGs are extremely unlikely to progress or cause vision loss in adolescents and adults. In contrast, plexiform neurofibromas can cause neurologic morbidity in both children and adults with NF1 and are more likely to progress towards malignancy in late adolescence or early adulthood.
  • The MEK inhibitor selumetinib is currently the only approved agent for systemic treatment of pediatric patients with inoperable, symptomatic plexiform neurofibromas related to NF1. Selumetinib is being investigated in adults with NF1-associated plexiform neurofibromas and for children with OPGs. Other MEK inhibitors as well as multi-target tyrosine kinase inhibitors are also being studied for plexiform neurofibromas in both adults and children with NF1.

Key points both adult and pediatric neuro-oncologists should be aware of related to the care of people with NF1-associated tumors include:

NF1 Epidemiology
Neurofibromatosis type 1 (NF1) is one of the most common single gene, autosomal dominant tumor predisposition conditions. It affects roughly 1 in 2600 people worldwide and can involve a range of manifestations and symptoms across the lifespan. The manifestations may include benign and malignant tumors, cognitive processing or attention disorders, vascular lesions (including moya moya), bone anomalies, and skin findings. Focal neurologic deficits such as pain or motor weakness associated with plexiform neurofibromas in people of any age or new vision loss associated with optic pathway gliomas (OPGs) in young children are what often lead patients to a neurologist or ophthalmologist and subsequently to a neuro-oncologist.

Assessing Which NF1-Associated Tumors Need Treatment
There have been recent important treatment advances for NF1-associated tumors in both children and adults. Neuro-oncologists should be comfortable with the factors that guide which NF1-associated tumors need treatment, the timing and goals of treatment, surgical and nonsurgical treatment options, how long to continue treatment, and optimal safety surveillance for both children and adults.

Plexiform Neurofibromas: These peripheral nerve sheath tumors can impact up to 50% of people living with NF1 (both adults and children). The MEK inhibitor selumetinib received FDA approval for symptomatic inoperable plexiform neurofibromas in children in 2020. The studies that demonstrated the safety and efficacy of selumetinib for symptomatic inoperable plexiform neurofibromas in this patient population provide helpful information about the range of tumor-associated symptoms that benefit from treatment with selumetinib and the balance of radiographic response, symptomatic improvement, and treatment-emergent side effects. There are ongoing studies of selumetinib as well as other MEK inhibitors and multi-tyrosine kinase inhibitors such as cabozantinib for both children and adults with NF1-associated plexiform neurofibromas that indicate promising clinical results that neuro-oncologists should be aware of.

OPGs: These are low-grade gliomas that are most frequently isolated to the optic pathway and of greatest clinical concern in very young children who have NF1. Although OPGs can be seen in up to one third of children with NF1, only a minority of OPGs need treatment. Many OPGs will stabilize or spontaneously regress as the child with NF1 ages. Therefore, it is critical that pediatric neuro-oncologists in particular are aware of the features of OPGs that require treatment, the importance of timing of treatment to prevent permanent vision loss, and the clinical factors that indicate surveillance alone is appropriate. When treatment is needed, chemotherapy is first line. Based on compelling phase II efficacy data with selumetinib for NF1-associated OPG, there is an ongoing phase III study evaluating selumetinib vs standard of care carboplatin and vincristine in patients between the ages of 2 and 21 (NCT03871257).

Treatment With MEK Inhibitors
Once a decision has been made that treatment is appropriate for an NF1-associated tumor, the first task is to discuss with the patient and family the benefits and risks of the various treatments available considering the patient’s age, the tumor type, the type and severity of symptoms, and the tempo of symptom progression. Currently, selumetinib is the only systemic agent FDA approved for the treatment of symptomatic, inoperable plexiform neurofibromas in children. The potential benefit of selumetinib treatment was demonstrated in the phase II SPRINT trial in which 68% of pediatric patients achieved a confirmed radiographic partial response (>20% reduction in tumor size by volume), often associated with notable symptom improvement. Indeed, there can be symptom improvement in advance of the radiographic response. Other MEK inhibitors and targeted agents are under investigation for this indication and also show symptom improvement. Cumulatively, these results provide evidence that symptomatic plexiform neurofibromas can regress and their associated symptoms can improve.

As with any drug, potential side effects can occur. The side effects commonly associated with MEK inhibitors in children include fatigue, nausea, change in appetite, laboratory changes, rash and nail changes (ie, paronychia infections), changes in cardiac ejection fraction, and a risk of retina vein occlusion (although this has not been seen in any clinical trial for MEK inhibitor in patients with NF1 to date). Fortunately, in all the studies to date, the side effects have been mild to moderate and reversible. However, these potential side effects do require regular monitoring and management. Prescribers should inform patients and their families of the importance of committing to regular scheduled clinic visits for clinical evaluation, laboratory analysis, ophthalmologic evaluation, and cardiac evaluation. The requirement for ongoing surveillance is one of the factors that should be discussed regarding the benefit vs risk of starting therapy for a child with NF1-associated inoperable, symptomatic plexiform neurofibroma.

Ongoing clinical trials of MEK inhibitors in adults with NF1 indicate that the side effect profile is slightly different in adults, with diffuse rash being the most concerning and prevalent symptom and occurring very early in treatment.  As a result, in these ongoing trials in adults, concurrent oral doxycycline and topical agents are often started concurrently with the MEK inhibitor to manage the rash. Adults with NF1 on experimental treatment with MEK inhibitors have also been reported to have gastrointestinal malaise and changes in cardiac echocardiogram. These symptoms have been reversible with holding or dose reducing the agent in the clinical trials to date.

To Learn More, Join Us for Our Upcoming Symposium
I am very excited to join my colleagues Michael Fisher and Miriam Bornhorst in preparing for the CME-certified symposium, Tumors Associated With Neurofibromatosis Type 1: Precision Medicine Approaches to Improve Patient Outcomes Across All Age Groups, to be presented in conjunction with the 2023 Society for Neuro-Oncology Annual Meeting in Vancouver. I am an adult neuro-oncologist and my colleagues are pediatric neuro-oncologists. We all specialize in NF1 and tumors of the nervous system so we will be able to share our expertise in this disease area from both the pediatric and adult care perspectives. Please register to attend either in person or via live simulcast at: http://www.clinicaloptions.com/NF1Vancouver2023.

Your thoughts?
Have you encountered pediatric or adult patients with inoperable tumors related to NF1 that would benefit from treatment? Do you have any questions for the faculty at the upcoming symposium? Leave a comment below to join the discussion!

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How many patients with an NF1-associated plexiform neurofibroma requiring treatment have you provided care for?

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