Σάββατο, 31 Δεκεμβρίου 2016

SELUMETINIB REDUCES TUMOR VOLUME IN NEUROFIBROMATOSIS

Oral selumetinib (AstraZeneca) reduces tumor volume in children with inoperable plexiform neurofibroma, benign tumors of peripheral nerves related to neurofibromatosis type 1 (NF1), with acceptable rates of toxic effects, a new phase 1 study shows.
Currently, no therapies are considered effective for NF1-related large plexiform neurofibromas, but in this trial, treatment of tumors previously growing at a rate of about 20% per year resulted in partial response, defined as a 20% or more reduction in tumor volume, in more than 70% of patients.
The study, with lead author Eva Dombi, MD, Center for Cancer Research, Pediatric Oncology Branch, National Cancer Institute (NCI), Bethesda, Maryland, was published online December 29 in the New England Journal of Medicine.
Senior author was Brigitte C. Widemann, MD, acting chief of the NCI's Pediatric Oncology Branch, and the trial was sponsored by NCI's Cancer Therapy Evaluation Program. Conducted at the National Institutes of Health (NIH)'s Clinical Center and three participating sites, the study used techniques developed by Dr Widemann's team, enabling very precise measurement of the plexiform neurofibromas, a press statement from the NIH notes.
"Some may say that a 20% volume reduction is too small to be meaningful, but to me, just stopping the growth of these devastating tumors is an important achievement," said Dr Widemann said in the NIH release. "The difference we see in these patients is truly unprecedented."
"This is an extremely important, exciting study demonstrating that molecular targeted therapies for patients with neurofibromatosis type 1 can have tremendous benefit," said Roger J. Packer, MD, senior vice president, Center for Neuroscience and Behavioral Medicine; director, Gilbert Family Neurofibromatosis Institute; and director, Brain Tumor Institute, Children's National Health System, Washington, DC. Dr Packer was not involved in the study but was asked by Medscape Medical News to comment on the findings.
Plexiform neurofibromas develop in 20% to 50% of patients with NF1, a multisystem disorder also characterized by cutaneous findings and skeletal dysplasias. They can cause substantial complications, including pain, functional impairment, and disfigurement.
Selumetinib selectively blocks subtypes 1 and 2 of the mitogen-activated protein kinase (MEK). MEK 1 and 2 are critical components of the RAS-ERK pathway, activation of which is implicated in driving cancer growth.
The analysis included 24 patients (11 girls and 13 boys), median age, 10.9 years, with NF1 and inoperable plexiform neurofibromas. The median volume of the target neurofibromas at baseline was 1205 mL
The children took selumetinib capsules about every 12 hours on a continuous dosing schedule of 28-day cycles. They received the drug at one of three dose levels: 12 patients at 20 mg/m2body surface area, 6 patients at 25 mg/m2, and 6 patients at 30 mg/m2.
The researchers found that, similar to what has been observed in adults, skin and gastrointestinal toxic effects were the most common adverse events. Most patients in the current trial had a largely asymptomatic elevation of creatine kinase, which according to the authors has not previously been reported.
Few patients had potentially chronic or cumulative toxic effects, such as oral mucositis, and none had ophthalmologic toxic effects of concern. A reversible decrease in left ventricular function that required a dose reduction of selumetinib occurred in only one patient. The drug had no effect on height or weight.
Several patients experienced slow tumor regrowth after the maximum response had been reached, and most of them required at least one dose reduction as a result of toxic effects. "This finding suggests a dose-dependent effect of MEK inhibition on neurofibroma growth," said the authors.
The 25 mg/m2 dose had an acceptable side-effect profile and was determined to be the maximum tolerated dose. This dose, which is about 60% of the recommended fixed dose for adults, is what the authors recommend for a phase 2 trial.
The pharmacokinetics of selumetinib in plasma were evaluated during cycle 1. The mean plasma concentration-time profiles, and the results of pharmacokinetic studies in the 18 patients for whom consent was provided, showed limited variability. The drug was absorbed rapidly, and drug exposures increased with increasing doses. Results of this analysis were similar to those in adults.
Tumor Volume
All patients had a decrease in plexiform neurofibroma volume (median change, –31%). The maximum response to selumetinib was reached after a median of 20 cycles. About 71% of the patients met the criteria for confirmed partial response (defined as a tumor volume decrease of at least 20% for at least 4 weeks), including 9 patients in the 20-mg group, 5 in the 25-mg group, and 3 in the 30-mg group.
Partial responses to selumetinib were seen in 56% of patients who had documented progressive disease (defined as a tumor volume increase of at least 20%) and in 67% who had growing tumors that did not meet the criteria for progressive disease. Such responses were also found in the 2 patients who had tumors that were assessed as stable (defined as a tumor volume change of less than 20%) and in 86% of those who did not have previous volumetric data available at enrollment.
The partial responses were sustained for a median of 23 cycles, and 15 of 17 patients with partial response maintain their response status to date. So far, no patient has had disease progression, and the 9 patients with confirmed tumor growth before enrollment are free of progression after a median of 26 cycles.
The researchers also collected data on the activity of selumetinib in an animal model of neurofibroma. Pharmacokinetic results in the mouse were similar to those in humans.
In the mouse model, intermittent dosing was efficacious, suggesting that "even limited inhibition of MEK may be sufficient" to shrink some tumors, the authors write.
"In the future, evaluation of intermittent dosing in patients may be considered as a way to minimize toxic effects while retaining efficacy."
According to Dr Packer, the animal model "certainly pointed us in the direction that this drug would be an effective approach, and in many ways substantiated the validity of the animal model to help us guide therapy."
Anecdotal decreases in pain and disfigurement and increases in motor function reported by patients in this study "suggest that even small decreases in tumor volumes may result in clinical benefit," the authors write.
Few Options
Surgery can be difficult or impossible in patients with NF1-related plexiform neurofibromas. According to Dr Packer, this is because of the location of the tumor and because it involves "an infiltrative process oftentimes without clear borders."
Other than surgery, there has been little in the way of a proven effective therapy for these patients. For example, chemotherapeutic agents, thalidomide and interferon, have only limited benefit.
"This is the first time that we have seen any type of agent, be it a chemotherapeutic agent or molecular targeted agent, actually shrink these tumors and also preliminarily improve both the quality of life of these patients and decrease their pain," said Dr Packer.
"Clearly, we need larger studies to see what the true long-term benefit of the treatment is, but this study represents a tremendous advance for the field."
It's estimated that over time, 6% to 13% of initially benign plexiform neurofibromas will turn into malignancies, which are often lethal. The risk for transformation is usually highest late in adolescence or early in adulthood.
"What this study did not show was whether treatment with this class of drugs [MEK inhibitors] will prevent that malignant transformation," said Dr Packer. "That will require further studies, and much longer-term studies."
At least four pharmaceutical companies are developing an MEK inhibitor, noted Dr Packer, who is also group chair, Department of Defense Neurofibromatosis Clinical Trial Consortium.
It's likely that these agents will all work differently and have varying toxicity profiles, said Dr Packer.
This research was supported by NCI's Center for Cancer Research and the Cancer Therapy Evaluation Program; by the Children's Tumor Foundation to Michael Fisher to support participating sites other than the NCI; and by AstraZeneca, providing selumetinib and funding for the pharmacokinetic analysis. Dr Widemann reports other support from AstraZeneca during the conduct of the study. Dr Dombi and Dr Packer have disclosed no relevant financial relationships.
N Engl J Med. Published online December 29, 2016

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