1. Hackethal, Veronica

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The FDA recently approved the first medical treatment for neurofibromatosis type 1 (NF1), based on results from the SPRINT trial published April 2020 in the New England Journal of Medicine (2020;382:1430-1442). The decision is a potential game changer for this rare autosomal dominant genetic disorder that affects about 1 in 3000 people and causes significant pain and suffering.

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The FDA gave priority review, breakthrough therapy, and orphan drug designation to selumetinib for the treatment of NF1 in children aged 2 years and over who have symptomatic, inoperable plexiform neurofibromas (PNs). Over the past 20 years, many different clinical trials have investigated treatments for PNs in NF1, but none have led to significant tumor shrinkage.


"There is now an option that will at least slow, if not shrink, these tumors in the majority of patients, which was never observed before," said author Andrea Gross, MD, Assistant Research Physician in the Pediatric Oncology Branch of the National Cancer Institute (NCI).


Selumetinib blocks MAPK kinase (MEK) and has also been investigated in the treatment of cancers like non-small cell lung cancer and thyroid cancer. MEK lies within the RAS pathway, which is overactive in NF1. Scientists were clued into selumetinib when they realized that blocking MEK could address this overactivity and potentially slow tumor growth in NF1.


Plexiform neurofibromas are benign tumors that grow along the sheath of peripheral nerves. They occur in 30-50 percent of people with NF1, and can develop virtually anywhere in the body. They tend to grow quite large-sometimes more than a liter in volume-and cause substantial pain and morbidity. Complications include disfigurement, breathing impairment, bowel or bladder incontinence, and permanent blindness.


Few treatment options exist beyond surgery, and many of these tumors are inoperable because they lie on or near vital structures. These tumors also tend to have abundant blood supplies, making surgery dangerous. Complete resection is frequently not feasible, and even debulking can cause complications. If incompletely removed, these tumors tend to grow back, especially in younger patients.


"Until now, there really hasn't been an effective treatment outside of surgery, and surgery was not always an option," Gross said. "We think the FDA approval is a huge step. Selumetinib is not a magic bullet, but it's better than anything that has come before."


One issue is that selumetinib did not make these tumors completely disappear. Most patients in the SPRINT trial experienced shrinkage in the 20-30 percent range, and the best shrinkage was between 50-55 percent.


Another issue: children in the SPRINT study who came off therapy tended to show tumor regrowth: among six patients who showed disease progression, five had undergone dose reductions.


"We believe that a young child will most likely need to be treated throughout childhood, at least until adolescence or young adulthood," Gross said.


Studies of the natural history of PNs show that they grow quickly during childhood, but their speed of growth tends to plateau in adolescence or young adulthood. Researchers would like to know whether selumetinib can be used early to help these children get over that "hump" of early, rapid growth, and potentially prevent permanent complications like blindness.


Other areas of future research include how long children will need to stay on therapy for optimal effect; how to get deeper, better maintained tumor shrinkage; and continued follow-up of long-term adverse effects.



SPRINT was led by Brigitte Widemann, MD, Chief of the Pediatric Oncology Branch and head of the Pharmacology and Experimental Therapeutics Section at the NCI.


The phase II, open-label, single-arm trial took place at four clinical sites in the U.S. from August 2015 to August 2016. It included 50 children with NF1 and symptomatic inoperable PNs. Children had a median age of 10.2 years and median NF volume of 487 mL at baseline. The most frequent PN complications included disfigurement (88%, n=44), motor dysfunction (66%, n=33), pain (52%, n=26), and airway impairment (32%, n=32).


Children received oral selumetinib twice daily at a dose of 25 mg/m2 of body-surface area on a 28-day cycle for a median of 36 cycles.


Researchers evaluated tumor response using volumetric MRI, which provides a much more sensitive, time-efficient way to detect change in volume of these slow-growing tumors, compared to standard imaging methods. The volumetric MRI method used in this study was developed specifically for SPRINT.


Seventy percent of children (n=35) showed confirmed partial response, defined as 20 percent decrease in tumor volume compared to baseline and verified on separate exams at least 3 months apart. Most of these partial responses (56%, n=28) were durable and lasted at least a year or more.


At best response, the median tumor shrinkage was 27.9 percent, which translated into dramatic improvement for some patients. One child was able to undergo tracheostomy removal, while three experienced resolution of bowel incontinence and two showed resolution of daytime urinary incontinence. Among 44 children with disfigurement, 24 parents and 11 children reported improved appearance.


Overall, selumetinib was well-tolerated. The most common side effects were stomach upset and skin issues, usually an eczema-like rash in younger patients and an acne-type rash in older patients.


Twenty-eight percent (n=14) needed dose reductions to manage side effects, and 10 percent (n=5) had to discontinue selumetinib due to possible treatment-related side effects. The most common of these was elevated creatinine phosphokinase, although all patients with this abnormality remained asymptomatic.


"The side effects that were serious enough to require a dose reduction or drug discontinuation were all reversible when selumetinib was stopped. We did not see any side effects that failed to resolve after stopping treatment," Gross noted.


To gain FDA approval, researchers also had to show that selumetinib was associated with clinically meaningful improvement. So they asked participants about pain, quality of life, disfigurement, and functioning on at least four separate occasions. They also conducted functional evaluations such as testing vision and motor strength.


Sixty-eight percent of patients reported improvement in at least one PN complication. Clinically meaningful improvements were found in the following: neurofibroma-related pain (reported by 74% of children), pain-related interference in daily life (reported by 38% of children and 50% of parents), health-related quality of life (reported by 48% of children and 58% of parents), Global Impression of Change scale (reported by 72% of children and 86% of parents), improved strength (56% of children), and increased range of motion (38% of children).


Researchers also compared children treated with selumetinib to 93 age-matched patients in the NCI natural history study of NF1. At the 3-year follow-up, progression-free survival was 15 percent among untreated patients and 84 percent in the selumetinib group.


Lessons for the Future

Ironically, FDA approval of selumetinib for NF1 was far from a sprint. Widemann and colleagues began investigating treatments for NF1 over 20 years ago. But research was slowed by blind alleys and treatments that failed to work. Getting the support of pharmaceutical companies also presented a challenge. Many questioned whether it was a good idea to treat young children who did not necessarily have a life-threatening cancer condition.


Looking to the future, Widemann would like to see if lessons learned from NF1 studies can help people with similar genetic tumor predisposition conditions. Perhaps applying this information to other conditions can more rapidly ease their burden.


"When I started to study treatments for NF1, I had more of a scientific motivation. That started to change when I met the patients and families with this genetic disorder," Widemann noted. "When I saw that the problems increase over time and that the clinical trials were not successful, I developed a very personal connection to them. The desire became stronger and stronger to make a difference. That definitely has been a strong motivation to continue."


Veronica Hackethal is a contributing writer.