1. Fuerst, Mark L.

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BOSTON-An investigational MEK inhibitor, selumetinib, shows clinical benefit in adult patients with neurofibromatosis type 1-associated plexiform neurofibromas, according to preliminary results from an ongoing phase II study.

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Patients with neurofibromatosis type 1 (NF1) develop both benign and malignant tumors, and between 20 percent and 50 percent of these patients develop plexiform neurofibromas, which are locally invasive tumors that can cause debilitating complications, including pain, disfigurement, and functional limitations, said Geraldine O'Sullivan Coyne, MD, PhD, staff clinician of the Developmental Therapeutics Clinic at the National Cancer Institute, at a press conference before the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. "While these are not cancerous, they are at risk for developing into aggressive cancers," she said.


The primary treatment option for plexiform neurofibromas is surgical debulking, which is often challenging. Some patients may also experience motor weakness, decreased vision, or difficulties breathing. Complete surgical resection of NF1-associated plexiform neurofibromas is often not feasible, and even when it is, the tumors often recur, noted O'Sullivan Coyne. Currently, there is no approved therapeutic available for NF1-associated plexiform neurofibromas. "Even though these are not malignant tumors, they are locally invasive on crucial structures and are difficult to treat."


These tumors demonstrate increased activation of the MAP kinase (MEK) pathway, which led researchers to attempt to inhibit MEK as a rational therapeutic strategy. Selumetinib, an oral MEK inhibitor, has recently received breakthrough designation for NF1-related plexiform neurofibromas based on two early phase studies for children with NF1 and inoperable plexiform neurofibromas, showing unprecedented 71 percent and 74 percent response rates.


Study Details

O'Sullivan Coyne reported the initial results of an ongoing phase II study of selumetinib in adults with NF1 and inoperable plexiform neurofibromas, which includes pharmacodynamic evaluation of serial plexiform neurofibromas and cutaneous neurofibroma biopsies, as well as patient-reported outcomes (PROs). A PRO-based analysis will be assessed over time, she said.


A total of 26 adult patients were enrolled in the phase II study, and O'Sullivan Coyne reported the results of the first 21 patients. Preliminary results showed that 71 percent of the 21 evaluable patients had a partial response. The majority of patients experienced a reduction in plexiform neurofibroma volume, and patient-reported tumor pain intensity and pain interference scores significantly improved, said O'Sullivan Coyne.


"Baseline plexiform neurofibroma core biopsies and cutaneous neurofibroma shave biopsies deliver sufficient protein yield and phospho-ERK/phospho-MEK levels for pharmacodynamic target inhibition assessments," she said. To date, no patients have stopped treatment due to an increase in plexiform neurofibroma volume.


Grade 3 or higher drug-related toxicities included transaminitis, rash, and pancreatic enzyme elevation. Four patients required a dose reduction due to toxicity, and two of these patients required a second dose reduction. Five patients withdrew from the study as a result of rash, surgical resection, patient choice, or non-compliance. Twenty-one of the 26 enrolled patients remain on the study.


Toxicity is important because clinicians administer selumetinib in a chronic, continuous fashion, O'Sullivan Coyne noted.


"We are pleased that patients appear to be benefiting without significant toxicity to date," she stated. "We hope the results in adults will parallel those reported in pediatric populations. The results are very exciting, and we hope this will give patients suffering from the effects of plexiform neurofibromas an option for treatment."


It is important to keep in mind that the results are preliminary, as the study is ongoing, O'Sullivan Coyne said. "This novel approach assesses outcomes tailored to plexiform neurofibromas symptoms. The assessment is highly individualized."


In summary, "we found evidence of clinical benefit without excess toxicity. Biopsy is feasible and safe, and is center to determining the pharmacodynamic effects of selumetinib."


Mark L. Fuerst is a contributing writer.