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Selumetinib appears beneficial for children with inoperable plexiform neurofibromas
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Children with neurofibromatosis type 1–related plexiform neurofibromas who underwent dose-adjusted therapy with selumetinib showed similar benefit as adults dosed with the same regimen in other trials, according to study results published in The New England Journal of Medicine.
“Selumetinib had acceptable rates of dose-limiting toxic effects when administered on a long-term basis and was associated with a sustained reduction in tumor volume in the majority of patients,” Brigitte C. Widemann, MD, head of pharmacology and experimental therapeutics at Center for Cancer Research of NCI, and colleagues wrote.
Neurofibromatosis type 1 — a common genetic disorder — often is characterized by tumors of the nervous system. Twenty percent to 50% of these patients can develop plexiform neurofibromas, which may cause pain, functional impairment, disfigurement and malignant transformation. Plexiform neurofibromas often cannot be surgically resected and can regrow after incomplete surgical resection.
Widemann and colleagues evaluated the use of selumetinib (AZD6244/ARRY-142886; AstraZeneca/Array BioPharma) — a potent highly selective MEK1/2 inhibitor that has shown promise in adult cancers — in 24 children aged 3 to 18 years (median age, 10.9 years; range, 3-18.5) with inoperable neurofibromatosis type 1–related plexiform neurofibromas. Patients had a median tumor volume of 1,205 mL (range, 29-8,744).
Patients received 20 mg/m2 to 30 mg/m2 of the study drug twice daily in continuous 28-day cycles. The median number of treatment cycles was 30 (range, 6-56).
Response to therapy was classified as an increase or decrease in volume of plexiform neurofibromas from baseline. Researchers defined a partial response as a decrease in volume from baseline of at least 20% for a minimum of 4 weeks, whereas disease progression was defined as tumor volume increase of at least 20%. Stable disease was defined as tumor volume change from baseline that was less than 20%.
Of the patients, 12 received 20-mg/m2, six received 25-mg/m2 and six received 30-mg/m2 dose of selumetinib; the maximum-tolerated dose was 25 mg/m2, which is 60% of the recommended fixed 75-mg dose for adults.
A decrease in plexiform neurofibroma volume from baseline was observed in all patients (median change, –31%; range, –5.8 to –47). Seventeen patients had a confirmed partial response, including nine of 12 in the 20-mg/mg2 group, five of six in the 25-mg/mg2 group and three of six in the 30-mg/mg2 group.
Partial responses were sustained for a median of 23 cycles and 15 of 17 patients maintained their partial response at the time of the analysis. In addition, none of the patients had experienced disease progression.
Researchers also reported anecdotal accounts of decreases in tumor-related pain, disfigurement and functional impairment.
The most common adverse events of any grade included creatine kinase elevation, gastrointestinal toxic effects, acneiform rash in postpubertal patients and maculopaplar rash in prepubertal patients. Most were mild in nature.
The researchers reported that pharmacokinetic evaluations among the children were similar to those published for adults.
In addition, researchers also used a mouse model to test selumetinib’s effect on neurofibromatosis type 1–related plexiform neurofibromas. Pharmacokinetics in this model were similar to the results in humans; selumetinib was associated with decrease in neurofibroma volume from baseline in 12 of 18 mice. However, 14 of 15 control animals experienced increases in volume from baseline.
“Our early phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects,” the researchers wrote. “Further trials are warranted to characterize tumors that no longer response to selumetinib; however, such cases have not yet been observed.” – by Melinda Stevens
Disclosures: Widemann reports other support from AstraZeneca during the conduct of the study. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Neurofibromatosis type 1 (NF1) is a relatively common neurogenetic disease, affecting as many as one in 3,000 people. The condition has myriad clinical manifestations, including the propensity for the development of both intracranial and peripheral nervous system tumors. Plexiform neurofibromas arise in 40% or more of those with NF1. They are thought to be congenital lesions arising from Schwann cells, and may result in crippling neurologic dysfunction, pain and multiorgan compromise. Although, in themselves, they are not frequently lethal; over the lifetime of a patient with NF1, up to 13% of plexiform neurofibromas transform into malignant peripheral nerve sheath tumors.
Since 1990, the gene responsible for NF1 has been known, as has its protein product, neurofibromin. Subsequently, the lack of neurofibromin has been shown to activate multiple molecular pathways, most notably hyperactivation of the RAS-MAPK pathway. There have been various attempts to control aberrant RAS-MAPK signaling, the majority of which have been disappointing. Superb preclinical work by a variety of laboratories, most notably that of Ratner and colleagues in Cincinnati, have utilized genetically engineered mouse models of NF1 to demonstrate that inhibition of mitogen-activated protein kinase (MEK) — a member of the RAS-MAPK pathway — slows plexiform neurofibroma growth.
The paper by Dombi and colleagues is a dramatic translation of this preclinical work into effective therapy for plexiform neurofibromas. The MEK inhibitor, selumetinib (AZD6244/ARRY-142886; AstraZeneca/Array BioPharma), administered twice daily was reasonably well tolerated and, in this phase 1 study, resulted in partial responses — by definition greater than 20% reduction in tumor volume — in 17 of 24 children. These are startling responses in a phase 1 study, especially treating a disease manifestation that has been essentially recalcitrant to previous means of treatment.
This study was led by Widemann and colleagues from the NCI, and treated patients aged 3 to 18.5 years. Treatment was not without side effects, and dose-limiting toxicities included cellulitis and asymptomatic decreased left ventricular ejection fraction. There also were a host of milder side effects, including rash and mucositis; however, patients were able to tolerate the drug for years. Even in this phase 1 study, some of the tumor shrinkages were remarkably associated with anecdotal decreases in tumor-related pain and improvements in disfigurement and motor function. Also, the durability of response was unexpected, as 15 of 17 patients were maintained on the drug for prolonged periods, some for greater than 4 years.
Although still considered preliminary data, despite the excellent degree and duration of responses, the study demonstrates the potential efficacy of molecular-targeted treatment in a single gene disease when the target is well characterized, as well as the utility of preclinical testing.
Multiple issues remain unanswered including:
- How long does the therapy need to be maintained?;
- Will the treatment not only result in tumor size reduction, but also functional improvement?;
- If it results in functional improvement, how long are patients willing to take the drug?; and
- Will the same class of drug be as effective in treating other manifestations of NF1, such as gliomas?
The long-term tolerability of the drug, although seemingly excellent, remains a major issue for patients with a chronic condition such as NF1. Further, the long-term developmental toxicity of drugs such as selumetinib — which interfere with cellular signaling critical in development — are unknown, and this is an extremely important consideration for this and other disease manifestations of NF, such as intracranial gliomas, which are more symptomatic in younger children.
A host of MEK inhibitors and other drugs aimed at the RAS-MAPK pathway are presently in clinical trials, and it will be critical to unravel which drug is most effective and causes the least toxicity especially, when treating the chronic manifestations of NF1. These unanswered questions do not detract from the importance of the study, which gives hope to patients with neurofibromatosis who previously had very limited alternatives.
Jousma E, et al. Pediatr Blood Cancer. 2015;doi:10.1002/pbc.25546.
Ratner N and Miller SJ. Nat Rev Cancer. 2015;doi:10.1038/nrc3911.
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