What is selumetinib?
Selumetinib is an oral kinase inhibitor that primarily works by inhibiting MEK 1/2 (mitogen-activated extracellular kinase).
Selumetinib works by inhibiting MEK1/2 proteins which are upstream regulators of the ERK (extracellular signal-related kinase) pathway. The inhibition of ERK phosphorylation leads to reduction in neurofibroma numbers, volume, and proliferation.
What is this approved for?
Selumetinib is FDA-approved for treatment of children (greater than 2 years old) and adolescents with neurofibromatosis type 1 (NF1).
It was approved with breakthrough designation as an orphan drug based on the results of the SPRINT (NCT) trial. This was a Phase II, open-label, single-arm trial including 50 children (ages 2-18) with symptomatic and inoperable plexiform neurofibromas (PN) (N Engl J Med 2020; doi:10.1056/NEJMoa1912735). Patients received selumetinib 25 mg/m2 orally twice daily until disease progression or unacceptable toxicity. The primary endpoint demonstrated a 66 percent overall response rate with 66 percent of patients having a confirmed partial response. Eighty-two percent of patients had a duration of response greater than 12 months. Lastly, 68 percent of children saw an improvement in at least one PN complication (pain, quality of life, disfigurement, and functioning).
How do you administer selumetinib?
Selumetinib is available as a 10 mg and 25 mg capsules and administered orally at a dose of 25 mg/m2/dose twice daily. Capsules should be swallowed whole and on any empty stomach. The manufacturer's package insert provides guidance on starting dose, as well as dose reductions due to toxicity.
Are there any pre-medications needed?
Selumetinib has a low emetic risk. No routine pre-medications are recommended.
What are common side effects (> or =20%)?
The most common adverse events were vomiting (82%), rash (80%), increased creatine phosphokinase (CPK) (79%) abdominal pain (76%), diarrhea (70%), nausea (66%), fatigue (56%), pyrexia (56%), stomatitis (50%), constipation (34%), hair changes (32%), epistaxis (28%), cardiomyopathy (23%), and reduced ejection fraction (22%).
What are uncommon side effects (<20%)?
Acute renal failure, dyspnea, blurred vision, ocular hypertension, photophobia, and xerostomia were also seen in studies. As well as lab abnormalities in liver enzymes, albumin, potassium, and sodium.
What are serious warnings and precautions?
Cardiomyopathy (a small percentage of patients experienced decreased left ventricular ejection fraction), ocular toxicities (including retinal vein occlusion and retinal pigment epithelial detachment), gastrointestinal toxicities (perforation, colitis, ileus, and intestinal obstruction have been reported), dermatologic toxicities including severe palmar-plantar erythrodysesthesia syndrome, increased CPK (rhabdomyolysis has been reported in adults), and increased vitamin E levels resulting in a risk of bleeding.
Are there any important drug interactions?
Selumetinib is a substrate of CYP3A4, BCRP, and P-gp transporters. Coadministration with strong or moderate CYP3A4 inhibitors may result in an increased exposure to selumetinib and these patients should be monitored more frequently for adverse effects. Coadministration with a strong or moderate CYP3A4 inducer should be avoided due to the potential to decrease selumetinib exposure. Coadministration with vitamin E supplementation exceeding the recommended daily Vitamin E intake may increase risk of bleeding, especially in patients receiving an anti-platelet or a vitamin-K antagonist. The 10 mg and 25 mg capsule contains 32 mg and 36 mg of vitamin E, respectively.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
In patients with moderate hepatic impairment (Child-Pugh B), the recommended dose is 20 mg/m2/dose twice daily. In patients with severe hepatic impairment (Child-Pugh C), there is no recommended dose reduction per manufacturer as this has not been established. No dose adjustments are necessary for those with mild or moderate renal dysfunction.
What should my patients know about selumetinib?
Patients should be advised to store capsules in the original bottle with desiccant. Apply water-resistant, broad-spectrum sunscreen (SPF of 30+) every 2 hours while outdoors, or immediately after swimming or sweating. Apply high-quality fragrance-free and alcohol-free moisturizer over the entire body twice daily. Pregnancy should be avoided due to the risk for embryo-fetal toxicity and both men and women should use effective contraception during treatment and at least 1 week following the last dose of selumetinib. Breastfeeding should be avoided during treatment and at least 1 week after the last dose.
Clinical trials related to selumetinib?
Selumetinib is also being studied in clinical trials of various phases in patients with advanced cancers, such as melanoma, peripheral nerve sheath tumors, and various hematologic cancers, etc. More information is available about these trials at http://clinicaltrials.gov.
SASHA HAARBERG, PHARMD, BCOP, is Clinical Oncology Pharmacist at the Siteman Cancer Center and Washington University School of Medicine. JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/ Manager, Clinical Pharmacy Services at Washington University School of Medicine, St. Louis, Mo. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.