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More than half of children with inoperable plexiform neurofibromas responded to the mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor selumetinib, and the responses proved durable in most cases, results of a phase II trial showed.

Single-agent selumetinib led to objective responses in 35 of 50 patients, and 28 of the responses lasted for at least a year. The treatment also led to durable improvement in patient-reported pain intensity and other patient- and parent-reported functional and quality-of-life (QoL) outcomes.

The results could lead to the first approved therapy for inoperable plexiform neurofibromas associated with neurofibromatosis type 1 (NF1), as reported in the .

"While this is not yet a cure, this treatment is shrinking tumors and it's making children feel better and have a better quality of life," the study's senior author, Brigitte Widemann, MD, of the Pediatric Oncology Branch at the National Cancer Institute, said in a statement.

"There's a lot more to be done," she added. "Even though these children have tumor shrinkage, many still have disabling tumors. But these findings are a big step forward and inspire us to work even harder towards additional progress in NF1 therapies."

The results confirmed and extended those of an earlier trial that provided the first evidence that the MEK inhibitor could shrink large tumors.

"The thing that was really different and exciting for us is that we looked prospectively at functional and patient-reported outcome measures, which really hasn't been done before in a systematic way," first author Andrea Gross, MD, also of the NCI's Pediatric Oncology Branch, told 名媛直播.

Disease without Options

No approved therapies or standard of care exists for inoperable plexiform neurofibromas, leaving few treatment options for a condition that has multiple progressive tumor and nontumor manifestations. NF1 is associated with dysfunction of the guanosine triphosphate-activating protein neurofibromin and overactivation of the retrovirus-associated DNA sequences (RAS) pathway. RAS pathway inhibition with a MEK inhibitor represents a logical approach to treatment.

Plexiform neurofibromas are benign peripheral-nerve sheath tumors that occur in up to one half of patients with NF1 and can cause substantial complications, the authors noted in their report. In a , selumetinib led to partial responses in 17 of 24 patients, median tumor shrinkage of 31%, and anecdotal evidence of clinical improvement. The data provided the basis for the phase II trial to confirm the antitumor activity and preliminary evidence of improvement in pain and other signs and symptoms.

The 50 patients enrolled in the trial had a median age of 10.2 years (range of 3.5 to 17.4). The most common neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). Selumetinib was administered every 12 hours over 28-day cycles.

Treatment continued for 2 years in patients without progressive disease at trial entry, except those who had a partial response, which was covered by protocol-defined discontinuation criteria. Patients with progressive disease at entry could continue treatment until further disease progression.

The patients had a baseline median tumor volume of 487 mL, and 21 of 50 had progressive NF1 at enrollment. The patients completed a median of 36 treatment cycles.

Key Findings

Overall, 37 of 50 (74%) patients had a partial response, which was a confirmed response in 35 cases (70%). Responses were durable in 28 patients (56% of the total study population). Median tumor shrinkage was 27.9%. Patient age, tumor volume, disease progression status at entry, and tumor location did not identify patients who were more or less likely to achieve partial response.

The results contrasted with those of an age-matched group of control patients enrolled in a natural-history study of NF1, wherein 73 of 93 (78%) had at least a 20% increase in neurofibroma volume over the same period of time as the treatment in the selumetinib study.

Among 29 patients with data on tumor pain, the mean score on a validated pain measure decreased by 2.14 points at 12 months. Both child- and parent-reported pain interference decreased during treatment. Improvement in pain intensity occurred as early as 2 months after the start of treatment and as early as 4 months for pain interference. Patient- and parent-reported QoL scores (29 and 45 patients, respectively) also improved during treatment with selumetinib.

Looking Ahead

Several other MEK inhibitors already have FDA approval. Whether selumetinib turns out to be "special" for plexiform neurofibromas remains to be seen.

"We really don't know whether one will be any better than the others," said Gross. "In terms of our being able to do this study, the Cancer Therapy Evaluation Program had access to selumetinib. There might be different penetration and certainly there are different half-lives. One possible advantage of selumetinib is that it has a relatively short half-life, so if a patient has side effects and stops taking the medication, it will be out of the system relatively quickly."

Other MEK inhibitors have demonstrated preliminary activity in plexiform neurofibromas, providing reason to believe that other drugs in the class might also work, Widemann added.

Future studies of MEK inhibition in neurofibromatosis could include combination therapy with agents that have different mechanisms of action and possibly earlier use in the course of the disease process.

"One of the things we are really interested in is whether we can prevent problems caused by tumors," said Gross. "The tumors tend to develop in young children, and we know that they tend to grow most rapidly in young children. The question is, could we potentially prevent the complications by treating early rather than waiting until they've already caused problems and trying to shrink them."

The neoadjuvant potential of MEK inhibition represents an intriguing possibility that has yet to be explored.

"Most of the tumors we see are inoperable, but if you were to treat them early, could you potentially make them resectable," said Widemann. "That has not been tested prospectively, but it would be another good area to look at."

A study similar to the pediatric trial has already begun with adults who have plexiform neurofibromas, the researchers added.

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