Investigational Drug May Treat Neural Tumors from Rare Genetic Disease

A new investigational drug, selumetinib, shows the ability to shrink neural tumors in children with neurofibromatosis type 1 (NF1), according to a recent study published by the New England Journal of Medicine.

Plexiform neurofibromas develop in up to half of patients with NF1, and can result in severe pain, disability, and disfigurement. These tumors are typically diagnosed early in life, and tend to develop rapidly before adolescence.

Total resection of plexiform neurofibromas is rarely viable, and tumors that are not fully resected will regrow, making the procedure unnecessary. A novel treatment option is needed for children with this genetic disorder.

Included in the study were 24 patients with NF1 who developed plexiform neurofibromas as a result of the disease. The investigators used techniques developed by lead researcher Brigitte C. Widemann, MD, that determine the specific measurements of the neural tumors to accurately assess the efficacy of the drug.

In the study, patients were given 2 doses of selumetinib per day for 30 month-long treatment cycles. The central goal of this phase 1 clinical trial was to assess the safety and tolerability of selumetinib in patients who have inoperable tumors. The researchers reported limited, mild toxic effects of selumetinib.

Currently, there are no drug treatments that are effective for patients with NF1 who have developed plexiform neurofibromas. However, approximately 70% of patients included in the study achieved partial response, or at least a 20% reduction in tumor size, according to the study.

A response was observed in tumors that were increasing at more than 20% per year, as well as in tumors that did not progress. Tumor response was maintained for approximately 2 years, and thus far, no disease progression has been seen in any patients, the researchers noted.

A majority of patients are continuing treatment with selumetinib, and have not experienced any developmental or health-related adverse events. The researchers even discovered that patients experienced a decrease in tumor-related pain and disfigurement, as well as improved motor function.

“Some may say that a 20 percent volume reduction is too small to be meaningful, but to me, just stopping the growth of these devastating tumors is an important achievement,” Dr Widemann said. “The difference we see in these patients is truly unprecedented.”

The gene that causes NF1 was first discovered in 1990 by researchers who uncovered that deregulation of the RAS signaling pathway most likely caused the disease, according to the study. However, numerous RAS inhibitors have been tested in patients with NF1, but previous results were insignificant.

Selemetinib is a MEK inhibitor, which is a part of the RAS signaling pathways. This investigational drug, created by AstraZeneca, has shown promise for treating multiple types of cancers that are influenced by this pathway.

Previous studies involving mice models with similar tumors confirmed the use of MEK inhibitors in tumors. In these studies, MEK inhibition was diminished as early as 2 hours after treatment, and the mice received treatment interruptions, but still experienced tumor shrinkage, according to the study.

Those previous findings suggest that limited treatment with MEK inhibitors may result in tumor shrinkage in patients with NF1.

A loss of response to the selumetinib and regrowth of tumors was discovered among certain patients, typically after dose reductions.

Additional studies are needed to characterize tumors that stop responding to the drug, according to the study. There is an ongoing phase 2 clinical trial assessing selumetinib in adult patients with NF1. In this study, tissue samples are being collected, which could uncover new information about the mechanisms that cause selumetinib resistance.

Another large phase 2 clinical trial is enrolling pediatric patients, and will help determine the efficacy of the drug. The researchers will also evaluate how selumetinib impacts pain, quality of life, motor function, and disfigurement.

If this treatment proves effective, children with NF1 who have developed plexiform neurofibromas may have a viable drug therapy that will improve their outcomes.

“In the future, we may wish to look at intermittent dosing in patients to minimize toxicity and retain maximal outcomes,” Dr Widemann concluded.