“Patients with neurofibromatosis type 1
(NF1) develop both benign and malignant tumors at an increased frequency throughout their lifetimes,” said Geraldine O’Sullivan Coyne, MD, PhD
, staff clinician of the Developmental Therapeutics Clinic at the National Cancer Institute. “Twenty to 50 percent of patients with NF1 develop plexiform neurofibromas, which are tumors that form in peripheral nerves. While these are not cancerous, they are at risk for developing into aggressive cancers.”
In addition to the increased risk for cancer, patients with NF1-associated plexiform neurofibromas commonly experience pain and disfigurement, and 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, explained O’Sullivan Coyne. There are currently no approved therapeutics available for NF1-associated plexiform neurofibromas.
Previous studies using mouse models of NF1 have shown increased activity of the cellular MAPK pathway, which controls cellular proliferation. Inhibition of MEK, a protein involved in this pathway, led to tumor regression in mice. In addition, the MEK inhibitor selumetinib yielded response rates over 70 percent
in pediatric patients with NF1 and inoperable plexiform neurofibromas.
Based on the results of these studies, O’Sullivan Coyne and colleagues tested the efficacy of selumetinib in adult patients with NF1-associated inoperable plexiform neurofibromas. As of August 2019, the study had enrolled 26 patients between the ages of 18 and 60 years.
Patients were evaluated for shrinkage of plexiform neurofibromas and for improvement in pain and other symptoms using patient-reported outcomes. 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 have significantly improved, according to O’Sullivan Coyne. To date, no patients have stopped treatment due to an increase in plexiform neurofibroma volume, added O’Sullivan Coyne.
Grade 3 or higher drug-related toxicities included transaminitis (high levels of a family of liver enzymes), 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.
“We are pleased that patients appear to be benefiting without significant toxicity to date,” said O’Sullivan Coyne. “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, noted O’Sullivan Coyne.
This study was funded by the National Institutes of Health. O’Sullivan Coyne declares no conflicts of interest.
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