Novel Treatments for Cutaneous Neurofibromas Show Promise

In the opinion of R. Rox Anderson, MD, patients with neurofibromatosis type 1 (NF1) have long been underserved in the medical field.

This tumor-predisposition syndrome affects an estimated 1 in 3500 people and is caused by heterozygous loss of NF1, a gene “that’s the size of a barn and is prone to getting loss of heterozygocity,” Anderson, a dermatologist who directs the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston, said at the annual Maui Derm Hawaii conference.

Affected children are born with café-au-lait spots and sometimes Lisch nodules. During adolescence and young adulthood, more than 19% of affected individuals with NF1 develop cutaneous neurofibromas (cNFs), which can number in the thousands and are a major source of morbidity, including disfigurement.

“We don’t understand what triggers them, but there’s a fair amount of depression, suicide and sort of social isolation that occurs” among those affected, said Anderson, also professor of dermatology, Harvard University, Boston.

No Food and Drug Administration-approved medical therapies exist to treat cNFs. Current approaches rely on destructive methods such as excision, electrodesiccation, or ablative laser therapy. “And although they work, it’s too little, too late, because by the time an adult with NF1 comes in with a big tumor burden, they’ve already suffered a lot,” he said.

A topical MEK inhibitor being developed by Nflection Therapeutics, NFK-179, shows promise as a practical treatment option, he said. He characterized NFK-179 as “a small molecule that is designed to be metabolized rapidly,” and when applied topically, “you get a high concentration in the skin to inhibit the pathway associated with growth of the tumors, but then the systemic level of the active drug is essentially nil.”

According to the first phase 2 clinical trial results to be published, treatment with NFX-179 topical gel resulted in a dose-dependent reduction in p-ERK levels in cNFs at day 28, with a 47% decrease in the 0.5% NFX-179 group compared with the vehicle (P =.0001). “It’s very exciting,” said Anderson, who was not involved with the study. “The same pathway is very likely to be useful in our [squamous cell carcinoma] patients, especially those with immunosuppression,” he added, commenting that he is “more excited by this drug being useful for squamous cell carcinoma than I am for NF-1.” 

In the meantime, Anderson and colleagues are working on ways to repurpose off-label, existing devices and drugs to treat cNFs. In a recently published trial of 19 adults with cNFs that ranged from 2 to 4 mm in size, tumors were randomized to one of four treatment methods: intratumoral 10 mg/mL deoxycholate injection, insulated radiofrequency needle coagulation, 980 nm diode laser, or 755 nm alexandrite laser with suction. The primary endpoint was tolerability, and the secondary endpoint was efficacy (tumor reduction).

Of the four approaches, two showed the most promise: 755 nm alexandrite laser with suction (which resulted in a 33.4% reduction of tumor size) and deoxycholate injection (29.4% reduction in tumor size). Anderson and colleagues are testing these two approaches in a phase 2 study, incorporating a cold air chiller device to make treatment painless, “which is going really well,” he said. “I think in the next year we’ll be trying to clear large areas of tumors to help people who have a large cNF tumor burden and making it practical. At the moment, we can treat somewhere around 10 tumors a minute. You don’t get complete response. We’re going into trials where were doing multiple treatments and trying to really clear these patients.”

The topical gel NFX-179, he added, “makes sense when you have a very large tumor burden, whereas the local treatments that are device- or injection-based in your office make sense for the patients who have a countable number of tumors, like up to 1,000.”
In his view, he said, these approaches “are not really competing with each other but are more likely to be synergistic.”

Anderson reported having no relevant disclosures.