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Selumetinib for Pediatric Neurofibromatosis Type 1 With Symptomatic, Inoperable Plexiform Neurofibromas


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On April 10, 2020, the oral MEK inhibitor selumetinib was approved for the treatment of patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas.1,2 Selumetinib is the first therapy approved for children who have this disease.

Supporting Efficacy Data

Approval was based on findings in the National Cancer Institute (NCI)-sponsored multicenter SPRINT trial (ClinicalTrials.gov identifier NCT01362803).2,3 In the trial, 50 evaluable pediatric patients with NF1 and a measurable target plexiform neurofibroma that could not be surgically removed without risk of substantial morbidity received selumetinib at 25 mg/m2 twice daily until disease progression or unacceptable toxicity. Patients had to have at least one significant morbidity related to the target plexiform neurofibromas, with those present in at least 20% including disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder or bowel dysfunction. The median age of study patients was 10.2 years (range = 3.5–17.4 years); 60% were male and 84% were white.

OF NOTE

Selumetinib has warnings/precautions for cardiomyopathy, ocular toxicity, gastrointestinal toxicity, skin toxicity, increased CPK levels and rhabdomyolysis, and increased vitamin E levels and risk of bleeding.

The primary efficacy outcome measure was overall response rate, as assessed by Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and defined as the percentage of patients who experienced at least 20% reduction in tumor volume on magnetic resonance imaging confirmed on a subsequent imaging within 3 to 6 months.

On NCI assessment, objective responses (all partial responses) were observed in 33 patients (66%, 95% confidence interval [CI] = 51%–79%). The median time to onset of response was 7.2 months (range = 3.3 months–1.6 years). In 27 responders (82%), response persisted for at least 12 months. An independent central review using the same response criteria showed an objective response rate of 44% (95% CI = 30%–59%).

How It Works

Selumetinib is an inhibitor of mitogen-activated protein kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Both MEK and ERK are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in different types of cancers. In genetically modified mouse models of NF1 generating neurofibromas that recapitulate the genotype and phenotype of human NF1, oral dosing of selumetinib inhibited ERK phosphorylation and reduced neurofibroma numbers, volume, and proliferation.

How It Is Used

The recommended dosage of selumetinib is 25 mg/m2 twice daily. Product labeling provides specific starting dosage
recommendations and reductions in dose for adverse reactions based on body surface area.

Product labeling provides instructions for dose modification for moderate hepatic impairment and for adverse reactions, including cardiomyopathy, ocular toxicity, gastrointestinal toxicity, skin toxicity, increased creatinine phosphokinase (CPK) levels, intolerable grade 2 adverse reactions, and grade 3 or 4 adverse reactions.

Concomitant use of selumetinib with strong or moderate ­CYP3A4 inhibitors or fluconazole should be avoided. Product labeling provides instructions on dose reduction for selumetinib if concomitant use with these agents cannot be avoided. Concomitant use with strong or moderate CYP3A4 inducers should be avoided.

Safety Profile

Among the 50 evaluable patients in the SPRINT trial, 88% were exposed to treatment for at least 12 months and 66% for at least 2 years.

KEY POINTS

  • The oral MEK inhibitor selumetinib was approved for treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas.
  • The recommended dosage of selumetinib for pediatric patients with neurofibromatosis type 1 is 25 mg/m2 twice daily.

The most common adverse events of any grade (≥ 40%) were vomiting (82%), rash (all; 80%), abdominal pain (76%), diarrhea (70%), nausea (66%), dry skin (60%), musculoskeletal pain (58%), fatigue (56%), pyrexia (56%), acneiform rash (50%), stomatitis (50%), headache (48%), paronychia (48%), and pruritus (46%). The most common grade ≥ 3 adverse events included diarrhea (16%), pyrexia (8%), vomiting (6%), rash (6%), and paronychia (6%). The most common grade ≥ 3 laboratory abnormalities were increased CPK levels (7%) and increased lipase levels (5%).

Serious adverse events occurred in 24% of patients, with those occurring in at least two patients consisting of anemia, hypoxia, and diarrhea. Adverse events led to dosage interruption in 80% of patients and dose reductions in 24%. Events requiring dosage interruption or dose reduction (≥ 5%) were vomiting, paronychia, diarrhea, nausea, abdominal pain, rash, skin infection, influenza-like illness, pyrexia, and weight gain. Adverse events led to discontinuation of treatment in 12% of patients, with causes including increased creatinine levels, increased weight, diarrhea, paronychia, malignant peripheral nerve sheath tumor, acute kidney injury, and skin ulcer.

Selumetinib has warnings/precautions for cardiomyopathy, ocular toxicity (including retinal vein occlusion and retinal pigment epithelial detachment), gastrointestinal toxicity, skin toxicity, increased CPK levels and rhabdomyolysis, and increased vitamin E levels and risk of bleeding. Ejection fraction should be assessed prior to initiating treatment, every 3 months during the first year, then every 6 months thereafter and as clinically indicated. Ophthalmic assessments should be performed prior to initiating treatment, at regular intervals during treatment, and for new or worsening visual changes; treatment should be permanently discontinued for retinal vein occlusion.

Patients should be advised to start an antidiarrheal agent immediately after the first episode of loose stool and to increase fluid intake. Patients should be monitored for skin rashes. Serum CPK levels should be monitored prior to initiating treatment, periodically during treatment, and as clinically indicated; if CPK levels increase, patients should be evaluated for rhabdomyolysis or other causes. Selumetinib capsules contain vitamin E, and daily intake of vitamin E that exceeds the recommended or safe limits may increase the risk of bleeding; an increased risk of bleeding may occur in patients coadministered vitamin K antagonists or antiplatelet agents. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves selumetinib for neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selumetinib-neurofibromatosis-type-1-symptomatic-inoperable-plexiform-neurofibromas. Accessed April 22, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Koselugo (selumetinib) capsules, for oral use. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213756s000lbl.pdf. Accessed April 22, 2020.

3. Gross AM, Wolters PL, Dombi E, et al: Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med 382:1430-1442, 2020.

 


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