Herbert B. Newton, MD, FAAN: There has been a drug recently FDA approved for treatment of symptomatic plexiform neurofibromas called selumetinib. It goes by the brand name Koselugo. This was FDA approved in April 2020, and this was published by Andrea Gross in the New England Journal of Medicine. Based on this publication, this drug is now available. The SPRINT trial is a phase 2 open-label, single-arm, multicenter study, coordinated by the National Cancer Institute as well as 3 other sites, to evaluate the efficacy of selumetinib in pediatric patients with NF1 [neurofibromatosis type 1] with symptomatic inoperable plexiform neurofibromas. There were 50 patients in the study. The mean age was 10.2 years, and 60% of them were male. The selumetinib was dosed at 25 mg/m2 orally twice daily, and the target tumor evaluation was measured using volumetric MRI [magnetic resonance imaging] at baseline every 4 cycles on drug for 2 years and then every 6 cycles.
The target plexiform tumor locations included the neck and trunk in 24% of patients, the trunk and extremity in 24%, along with the head, neck, and trunk extremities. The plexiform tumor status was progressive in 42% and nonprogressive in 30%. In terms of the target plexiform tumor-related morbidities, among the most common things seen was disfigurement in 88% of the patients, motor dysfunction in 66%, and pain in 52%, along with airway dysfunction, visual impairment, as well as bowel and bladder dysfunction. The number of plexiform tumor-related morbidities was a median of 3. Again, these were very symptomatic patients from their target tumors. Also, 40% of them had had previous surgeries for their plexiform tumors in the past.
Selumetinib is a MEK inhibitor, and this is a class of drugs that inhibit MEK1 and MEK2, which are single transduction proteins in the RAS/RAF/MEK/ERK pathway that leads from tyrosine kinase receptors at the surface of tumor cells and then activates cell proliferation and promotes survival. After inhibition of MEK, there is reduced phosphorylation of ERK. It begins to reduce promotion of cell proliferation and cell survival. This pathway is known to be activated in NF1 plexiform neurofibroma tumors since the loss of neurofibroma leads to overactive RAS GTP activity and excessive activation of the RAF/MEK/ERK pathway, again leading to excessive cell proliferation and plexiform tumor formation. There’s actually been a study by Eva Dombi, also published in the New England Journal of Medicine in 2016, looking at a mouse model for NF1-related plexiform tumors. In that model, selumetinib was able to inhibit ERK phosphorylation as well as reduce plexiform tumor formation, volume, and proliferation.
In the SPRINT study, inoperable tumors were defined as a plexiform neurofibroma that could not be fully resected with high risk for substantial morbidity because of encasement of or close proximity to vital structures, tumor invasiveness, or tumors with high vascularity. In the study, the primary end points were overall response rate using 3-dimensional MRI and the REiNS [Response Evaluation in Neurofibromatosis and Schwannomatosis] response criteria. This included percentage of complete responses or confirmed partial responses that were greater than or equal to 20% reduction in target tumor volume with confirmed subsequent MRI in 3 to 6 months.
There were also secondary end points in the SPRINT trial, including duration of response and safety profile. There was also an exploratory end point. Those included pain-intensity ratings of the affected children. In terms of efficacy of the drug in this trial, 66% of the cohort—roughly 33 patients—achieved a confirmed partial response. There weren’t any actual complete responses, but those PRs [partial responses] were seen in two-thirds of people. About 82% of those patients with PRs remained a response after 12 months of follow-up. The median best percentage change in target tumor volume from baseline was —27.85%, which is again a significant tumor reduction in what’s supposed to be a slow-growing benign tumor. The median time to onset of response was 7.2 months. In terms of the duration of response, by 12 months or more, 82% of the patients were still responding with their PR. In 16 months, 67% of patients were still responding with their partial response.
In terms of the exploratory end point of pain intensity rating, there were 24 patients that were able to give pain-intensity rating responses, and 50% of those noted improvement of pain of 2 points or more by prior to cycle 13. In terms of common adverse reactions in the study, in terms of the most common things seen across all grades, the most common things noted were vomiting, abdominal pain, diarrhea, nausea, stomatitis, rash, and paronychia. In terms of reactions at grade 3 or grade 4, they were limited to vomiting, diarrhea, rash, and pyrexia.
In terms of the clinical significance of the SPRINT trial, it’s important to note that in a natural history study of NF1-related plexiform neurofibromas, they were noted to have a strong tendency to grow over time and are often very symptomatic. They almost never spontaneously resolve or improve on their own. It’s now important that we have an FDA-approved chemotherapy option for these inoperable tumors with improvement benefit in terms of tumor shrinkage and possibly improving patient symptoms. I feel that selumetinib should be considered for any patient who has NF1 with a plexiform tumor that is symptomatic and inoperable, especially tumors that are large and cause significant pain, weakness, or disfigurement.
The question always comes up: should the treatment be started early or later on? In general, an earlier approach is better since the drug can often cause tumor shrinkage and improve symptoms. This is more likely in a smaller tumor, which has less permanent damage to surrounding nerves, structures in the region, and soft tissues. Then there’s a question about if selumetinib is better than just using symptomatic treatment. I think it is much better than that because you have a greater than 50% chance of shrinking the tumor and improving tumor-related symptoms, which were pain, disfigurement, weakness, and gait difficulty, whereas symptomatic treatment will really not help those symptoms very much.