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FDA Approves Selumetinib for Children with Inoperable Plexiform Neurofibromas

Article In Brief

In a phase 2 trial, selumetinib reduced pain and decreased tumor size in children with inoperable plexiform neurofibromas. The US Food and Drug Administration approved the drug for children 2 years old and older.


Panels D–F relate to a 10-year-old boy with a plexiform neurofibroma in the right neck. The tumor shrank 36.2 percent after 12 cycles of treatment (Panel F) with a visible decrease in the disfigurement caused by the neurofibroma.

The US Food and Drug Administration approved selumetinib on April 10 for children, 2 years of age and older with neurofibromatosis type 1 (NF1), based on a phase 2 trial reported in the March 18 issue of the New England Journal of Medicine.

Selumetinib, a drug that inhibits the RAS pathway in patients with NFI and inoperable plexiform neurofibromas, successfully decreased tumor size, reduced pain, and improved quality of life in a sample of children participating in the trial.

For patients with NF1, loss of the tumor suppressor neurofibromin results in high levels of activated RAS and subsequent development of tumors, explained Verena Staedtke, MD, associate professor of neurology and neuro-oncology at Johns Hopkins School of Medicine, who was not involved with the study.

“Plexiform neurofibromas, which occur in approximately 60 percent of these patients, are the hallmarks of this condition and cause a significant level of morbidity due to pain, neurologic dysfunction, location of the tumor, and large size, even in young children.”

Dr. Staedtke added that these tumors associated with NF11 are often inoperable and difficult to manage given the lack of effective therapies. “Often, merely surveillance and expectant symptom management for pain and neurologic deficits are recommended.”

“One of the most surprising findings of the phase 2 trial was the impact the treatment had on pain, in addition to shrinking tumors,” the first author on the report, Andrea M. Gross, MD, assistant research physician at the Pediatric Oncology Branch of the National Cancer Institute, told Neurology Today. She noted that the phase 1 trial showed tumor shrinkage and anecdotal clinical benefit such as a decrease in pain and improved mobility, but did not systematically assess for changes in function, pain, or quality of life.

“Given that these are not malignant tumors, we felt that in order to truly demonstrate clinical benefit we had to show not only tumor shrinkage but also improvements in pain and/or function.”

While some of the children in the phase 2 trial experienced medication side-effects, experts regard the drug as generally well-tolerated by those who take it.

How the Study Was Conducted

Researchers from the NCI, Children's Hospital of Philadelphia, Cincinnati Children's Hospital, and Children's National Hospital recruited 50 children with NF1 and inoperable plexiform neurofibromas between August 2015 and August 2016.

Children received two daily doses of selumetinib for a maximum of two years or until there was partial response, defined as target neurofibroma volume decrease from baseline of at least 20 percent. A confirmed partial response was defined as a partial response on consecutive examinations at least three months apart, and a durable partial response was defined as a partial response lasting for at least a year. The most frequent symptoms related to neurofibroma were those of disfigurement (44 patients), motor dysfunction (33 patients), and pain (26 patients).

After a year of treatment with selumetinib, researchers noted a substantial decrease in child-reported tumor pain intensity. These changes were noted as soon as two months after initiation of treatment. There was also a significant decrease in child and parent-reported pain interference (95% CI, −1.02 to −0.21) and for parents, this change was −0.81 points (95% CI, −1.32 to−0.31), with a decrease occurring as early as two months after initiation of treatment for pain intensity and four months for pain interference.

According to the report, 37 of 50 patients (74 percent) had a partial response in terms of tumor volume reduction, 35 (70 percent) had a confirmed partial response, and 28 (56 percent) had a durable response.

The median time to initial response was eight months, and the median time to best response was 16 months. The median change in tumor volume at best response was −30 percent. Five patients discontinued the medication due to side-effects, which mostly included nausea, vomiting, diarrhea, and rash. Six patients ended treatment due to disease progression.

The results of the study further confirmed findings from an earlier phase I trial demonstrating that selumetinib could shrink tumors. In that trial, the researchers noted a median tumor reduction of 30 percent and a confirmed partial response in 71 percent of the patients.

The authors noted that limitations of the study included the fact that with the exception of the Pain Interference Index and measurements of visual acuity, the other outcome measures used have not yet been validated for those with neurofibromatosis type 1.

In addition, the researchers observed that they did not find a direct correlation between change in neurofibroma size and patient-reported outcomes or functional responses. “This relationship is probably influenced by multiple factors, including neurofibroma location, growth rate, and the degree of neurofibroma-related pain,” they wrote in the report.

Currently, Dr. Gross and her colleagues at NCI are conducting a clinical trial looking at the use of selumetinib for adults with inoperable plexiform neurofibromas, and preliminary findings show that it may help that population as well. In addition, she said, “we are interested in the possibility of combining MEK inhibitors with other medications to see if we can achieve even more tumor shrinkage and/or clinical benefit.”

Another research goal of the group is to explore the treatment of patients with growing tumors before the tumors start causing problems such as vision loss or airway obstruction, with the goal of preventing those issues from developing.

Dr. Gross noted that other MEK inhibitors are being studied for the treatment of plexiform neurofibromas, such as trametinib, mirdametinib, and binimetinib. “We don't know yet if any of these MEK inhibitors will be better or worse than the others for this indication,” she said.

Expert Commentary

“This is a pivotal study,” Scott Plotkin, MD, professor of neurology at Harvard Medical School and executive director of the Pappas Center for Neuro-Oncology, told Neurology Today. “This team did an outstanding job of documenting the clinical benefit for patients that occurred alongside tumor shrinkage.”

Dr. Plotkin noted that the researchers were unable to correlate changes in tumor size with functional outcomes found in the study. “In small studies like this, it is sometimes difficult to correlate within a given patient how much function improves or how much pain is decreased, or to what degree they feel better,” Dr. Plotkin said.


“One of the most surprising findings of the phase 2 trial was the impact the treatment had on pain, in addition to shrinking tumors.”—DR. ANDREA M. GROSS

MEK inhibitors, which slow overactivation of the RAS pathway, may also be useful for other indications, he said. “There is emerging data with MEK inhibitors in the same types of patients, but with a different tumor called an optic pathway glioma, which are tumors of the optic nerve. These cause children to go blind and have other neurological problems—we are seeing very similar benefit from selumetinib.”

Dr. Plotkin said the idea that MEK inhibitors may have broad activity against a range of tumor types is “super exciting, and not something we see very often.”

“The data are strongest for selumetinib,” he said, “but the data are strong for some of the other MEK inhibitors as well, so I think of this as being a class effect for now. Which is the optimum MEK inhibitor remains to be seen.”

Ultimately, he noted, each MEK inhibitor has a slightly different side-effect profile. “I think we will end up selecting different compounds based on each patient's ability to tolerate the medication,” he said.

“The results of this phase 2 clinical trial are exciting for physicians and patients alike,” Dr. Staedtke agreed. “Selumetinib, showed significant tumor reductions in 70 percent of treated children, essentially confirming earlier results from the phase 1 study published a few years ago, along with meaningful clinical

The results of the phase 2 trial, Dr. Staedtke noted, “are an unprecedented treatment success that will transform the clinical care of these patients, particularly those with inoperable and growing plexiform neurofibromas.”

She said additional research is needed to explore remaining unanswered questions, for example why some tumors cease to respond to selumetinib and began to regrow in the current study, long-term durability of the treatment effects after treatment discontinuation, and dosing schedules that allow long-term use.


Drs. Gross and Staedtke had no disclosures. Dr. Plotkin is co-founder of NF2 Therapeutics and NFlection Therapeutics. He has also been a consultant for Astra Zeneca.

Link Up for More Information

• Gross AM, Wolters PL, Dombi E, et al. Selumetinib in children with inoperable plexiform neurofibromas N Engl J Med 2020; Epub 2020 Mar 18.