The investigational MEK inhibitor selumetinib showed clinical activity in adult patients with neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas, according to preliminary results from an ongoing phase II study presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (Abstract PR07). The conference is jointly provided by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).

NF1 and Risk of Tumor Development

“Patients with NF1 develop both benign and malignant tumors at an increased frequency throughout their lifetimes,” said Geraldine O’Sullivan Coyne, MD, PhD, a staff clinician in the Developmental Therapeutics Clinic at the National Cancer Institute, in a statement. “Between 20% and 50% 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 Dr. 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 of over 70% in pediatric patients with NF1 and inoperable plexiform neurofibromas, as reported by Gross et al in the Journal of Clinical Oncology.

Study Methods

Based on the results of these studies, Dr. 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.

Results

Preliminary results showed that 71% 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 Dr. O’Sullivan Coyne. 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 noncompliance. A total of 21 of the 26 enrolled patients remain on the study.

“We are pleased that patients appear to be benefiting without significant toxicity to date,” said Dr. 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.”

Disclosure: This study was funded by the National Institutes of Health. For full disclosures of the study authors, visit eventpilotadmin.com/AACR19MT.