April 10, 2020

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213756s000lbl.pdf.

On April 10, 2020, the Food and Drug Administration approved selumetinib (KOSELUGO, AstraZeneca) for pediatric patients, 2 years of age and older, with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).

Selumetinib, a kinase inhibitor, is the first therapy approved for pediatric patients who have this debilitating, and often disfiguring, rare disease. 

Efficacy of selumetinib was investigated in SPRINT (NCT01362803), a National Cancer Institute (NCI) sponsored, open-label, multicenter, single-arm trial in pediatric patients with NF1 and a measurable target PN that could not be surgically removed without risk of substantial morbidity. Patients in the efficacy population (N=50) were also required to have at least one significant morbidity related to the target PN. Morbidities present in ≥20% of patients included disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder/bowel dysfunction. Patients received selumetinib 25 mg/m2 orally twice a day until disease progression or unacceptable toxicity.

The primary efficacy outcome measure was overall response rate (ORR) as assessed by NCI and defined as the percentage of patients who experienced ≥20% reduction in tumor volume on Magnetic Resonance Imaging (MRI) confirmed on a subsequent MRI within 3-6 months. The ORR was 66% (n=33; 95% CI: 51,79). All patients had a partial response, and 82% of responders had sustained responses lasting at least 12 months. An independent central review of ORR was performed using the same response criteria and demonstrated an ORR of 44% (95% CI: 30,59).

The primary safety data were from 74 pediatric patients with NF1 and PN who received selumetinib during SPRINT. The most common adverse reactions (≥40% of patients) were vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, fever, acne, stomatitis, headache, paronychia, and pruritus.

Selumetinib can also cause cardiomyopathy, ocular toxicity including retinal vein occlusion, retinal pigment epithelial detachment and impaired vision, and increased creatinine phosphokinase. Selumetinib should be withheld, dosage reduced, or permanently discontinued based on the severity of adverse reactions.

The recommended selumetinib dose is 25 mg/m2 orally twice a day on an empty stomach until disease progression or unacceptable toxicity.

View full prescribing information for KOSELUGO.

FDA granted this application priority review and Breakthrough Therapy designation. Selumetinib also received fast track and orphan drug designations. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics .

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Pharmacist’s Applications to Practice

Selumetinib for the Treatment of Pediatric Patients with Neurofibromatosis Type 1 and Symptomatic, Inoperable Plexiform Neurofibromas

Authors: Samira Zantout, Pharm.D. Candidate Class of 2021
University of Missouri – Kansas City School of Pharmacy
Kansas City, MO

Diana Tamer, PharmD, BCOP
Clinical Assistant Professor
University of Missouri – Kansas City School of Pharmacy
Kansas City, MO

What is the potential role for Selumetinib in the treatment of plexiform neurofibromas?2-6

  • On April 10, 2020, the Food and Drug Administration (FDA) approved selumetinib for pediatric patients, 2 years of age and older, with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).
  • Mitogen-activated protein kinases 1 and 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.
  • While other MEK1/2 inhibitors have been studied for PN, selumetinib is the first and only single-agent, oral MEK1/2 inhibitor therapy FDA-approved for pediatric patients who have this debilitating, and often disfiguring, rare disease. The FDA granted selumetinib Breakthrough Therapy designation in addition to fast track and orphan drug designations.
  • Approval was based on data from the open-label, phase-2 SPRINT trial (NCT01362803), which investigated the efficacy of selumetinib in 50 children (aged 2 to 18 years) with NF1 and symptomatic, inoperable PN. Patients were required to have at least one PN-related complication, such as disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder/bowel dysfunction.
    • In this National Cancer Institute-sponsored, multicenter, single-arm trial, pediatric patients received oral selumetinib twice daily at a dose of 25 mg/m2 body-surface area (BSA) on a continuous dosing schedule (28-day cycle) until disease progression or unacceptable toxicity.
    • The primary endpoint, overall response rate (ORR), was 66% in all patients who received at least one dose of selumetinib (n = 33; 95% Confidence Interval [CI]: 51, 79).
      • All responders had a partial response (> 20% reduction in tumor volume at 3 to 6-month assessments) and 82% of all responders sustained those responses for at least 12 months.
      • An independent, centralized review of ORR was conducted and demonstrated an ORR of 44% (95% CI: 30, 59).
    • Secondary outcomes included patient-reported, observer-reported, and functional outcome measures in clinical benefit.
      • Regarding child-reported tumor pain intensity as measured by the Numeric Pain Rating Scale (NRS-11), there was a mean score change of -2.14 points (95% CI: -3.14, -1.14).
      • Of the 18 patients with baseline motor dysfunction and data on strength that could be evaluated, 14 (78%) improved their strength with a median increase in total strength score of 4.8% (95% CI: 1.1, 11.1) with the use of manual muscle testing after cycle 12.

What role can the pharmacist play in the management of patients on selumetinib?1-4,6

  • The recommended selumetinib dose is 25 mg/m2 orally twice a day on an empty stomach until disease progression or unacceptable toxicity.
    • Selumetinib dosing is based on BSA. The recommended dosage for patients with a BSA less than 0.55 m2 has not been established.
    • Hepatic impairment dosing: For moderate hepatic impairment (Child-Pugh B), the recommended dosage is 20 mg/m2 orally twice daily. The recommended dosage for use in patients with severe hepatic impairment (Child-Pugh C) has not been established.
    • Renal impairment dosing: No dosage adjustment is recommended in patients with renal impairment or end-stage renal disease.
  • Monitoring for patients taking selumetinib should include the following:
    • Ejection fraction by echocardiogram prior to initiating treatment, every 3 months during the first year of treatment, every 6 months thereafter, and as clinically indicated.
    • Comprehensive eye exam prior to initiating treatment, at regular intervals during treatment, and for new or worsening visual changes.
    • Serum creatinine phosphokinase (CPK) prior to initiating treatment, periodically during treatment, and as clinically indicated.
    • Anticoagulant assessments (including international normalized ratio [INR] or prothrombin time) more frequently in patients who are co-administered vitamin-K antagonists or anti-platelet antagonists.
    • Severe skin rashes and skin toxicities throughout treatment.
    • Electrolytes prior to initiating treatment and at regular intervals during treatment
    • Negative pregnancy test prior to initiating treatment in females of reproductive potential.
  • Patients treated with selumetinib should be monitored closely for side effects. Adverse events monitoring should include the following: vomiting (82%), rash (80%), abdominal pain (76%), diarrhea (70%), nausea (66%), dry skin (60%), fatigue (56%), musculoskeletal pain (58%), fever (56%), stomatitis (50%), headache (48%), paronychia (48%), pruritus (46%), epistaxis (28%), and decreased ejection fraction (20%).
  • Serious side effects (Grade > 3) for selumetinib include diarrhea (16%), fever (8%), vomiting (6%), rash (6%), paronychia (6%), dermatitis (4%), skin infections (2%), headache (2%), and hematuria (2%).
  • Dosage interruptions and dose reductions due to side effects occurred in 80% and 24% of patients who received selumetinib, respectively. Side effects were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Dosing modifications for side effects include the following:
    • For asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and less than lower level of normal, withhold selumetinib until resolution and then resume at reduced dose. For symptomatic decreased LVEF or grade 3 or 4 decreased LVEF, permanently discontinue selumetinib.
    • For retinal pigment epithelial detachment, withhold selumetinib until resolution and then resume at reduced dose. For retinal vein occlusion, permanently discontinue selumetinib.
    • For grade 3 diarrhea, withhold selumetinib until improved to grade 0 or 1 and then resume at same dose. If no improvement is seen within 3 days, permanently discontinue selumetinib.
    • For grade 4 diarrhea, permanently discontinue selumetinib.
    • For grade 3 or 4 colitis, permanently discontinue selumetinib.
    • For grade 3 or 4 skin toxicities, withhold selumetinib until improvement and then resume at reduced dose. Sunlight can make symptoms worse, recommend using broad-spectrum SPF. Recommend avoiding over-the-counter acne treatments as they can further dry the skin.
    • For grade 4 increase in CPK or any increase in CPK accompanied by myalgia, withhold selumetinib until improved to grade 0 or 1 and then resume at reduced dose. If no improvement is seen within 3 weeks, permanently discontinue selumetinib. If rhabdomyolysis occurs, permanently discontinue selumetinib.
    • For other intolerable grade 2, grade 3, or grade 4 side effects, withhold selumetinib until improved to grade 0 or 1 and then resume at reduced dose. Consider discontinuation for grade 4 side effects.
  • Dose reductions are BSA-specific and should be managed according to manufacturer recommendations. In general:
    • The first dose reduction ranges from a 25-33% decrease in total daily dose.
    • The second dose reduction ranges from a 50-67% decrease in total daily dose.
    • After two dose reductions, permanently discontinue selumetinib in patients unable if unable to tolerate.
  • Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with selumetinib. The agents must be discontinued for 3 elimination half-lives before initiating or resuming selumetinib. If coadministration cannot be avoided, the selumetinib dose should be reduced according to manufacturer recommendations. In general:
    • If the current dosage is 25 mg/m2 twice daily, reduce to 20 mg/m2 twice daily.
    • If the current dosage is 20 mg/m2 twice daily, reduce to 15 mg/m2 twice daily.
  • Avoid concomitant use of strong and moderate CYP3A4 inducers with selumetinib.
  • Avoid supplemental vitamin E if daily vitamin E intake (including the amount of vitamin E in selumetinib and supplement) will exceed the recommended or safe limits. Monitor for bleeding in patients co-administered with an anti-platelet agent or with a vitamin-K antagonist (increase INR monitoring as appropriate as well).
  • Use of selumetinib during pregnancy may cause fetal harm based on the mechanism of action and data from animal reproduction studies. A pregnancy test should be performed prior to the initiation of therapy in female patients of reproductive age.
  • AstraZeneca’s Access 360 Program:
    • Koselugo Co-pay Savings Program: for commercially insured patients whose insurance does not cover the full cost of the prescription. Patients pay $0 per 30-day supply and the program pays remaining out-of-pocket costs up to a maximum of $26,000 per year.
    • AZ&Me Prescription Savings Program: for uninsured patients, Medicare Part D/Medicare Part B recipients, and patients who have recently experienced a financial crisis.

Clinical Pearls2-4, 6

  • Selumetinib is available as 10-mg and 25-mg capsules.
    • Selumetinib must be taken on an empty stomach. Do not consume food 2 hours before each dose or 1 hour after each dose.
    • Patients must be able to swallow a whole capsule with water: capsules cannot be chewed, dissolved, crushed, or opened.
    • Selumetinib should be taken every 12 hours. Do not take a missed dose unless it is more than 6 hours until the next scheduled dose.
    • If vomiting occurs after administration, do not take an additional dose; continue with the next scheduled dose.
  • Selumetinib must be stored in room temperature and kept out of the reach of children.
  • Advise patients to start an anti-diarrheal agent (e.g., loperamide) immediately after the first episode of unformed, loose stool and to increase fluid intake during diarrhea episodes.
  • Advise females of reproductive potential and their male partners to use effective contraception during treatment with selumetinib and for at least 1 week after the last dose.
  • Clinical studies did not include patients 65 years of age or older.

References

  1. AstraZeneca. Access 360 Support Programs. Koselugo. https://www.koselugo.com/support.html?source=u_c_c_226. Published 2020. Accessed September 6, 2020.
  2. Center for Drug Evaluation and Research. FDA approves selumetinib for neurofibromatosis type 1 with symptomatic. U.S. Food and Drug Administration. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selumetinib-neurofibromatosis-type-1-symptomatic-inoperable-plexiform-neurofibromas. Published 2020. Accessed September 6, 2020.
  3. Dombi E, Baldwin A, Marcus LJ, et al. Activity of selumetinib in neurofibromatosis type 1–related plexiform neurofibromas. N Engl J Med. 2016;375(26):2550-2560.
  4. Gross AM, Wolters PL, Dombi E, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020;382(15):1430-1442.
  5. HOPA. Drug Updates. Hematology/Oncology Pharmacy Association. http://www.hoparx.org/drug-updates-from-the-fda/selumetinib-koselugo-astrazeneca. Published 2020. Accessed September 6, 2020.
  6. Koselugo (selumetinib) [package insert]. Wilmington, DE: AstraZeneca; April 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213756s000lbl.pdf
  7. Mccowage GB, Mueller S, Pratilas CA, et al. Trametinib in pediatric patients with neurofibromatosis type 1 (NF-1)–associated plexiform neurofibroma: A phase I/IIa study. J Clin Oncol. 2018;36(15_suppl):10504.
  8. Vaassen P, Dürr N, Röhrig A, Willing R, Rosenbaum T. Trametinib induces neurofibroma shrinkage and enables surgery. Neuropediatrics. 2019;50(05):300-303.
  9. Weiss B, Plotkin S, Widemann B, et al. Nfm-06. Nf106: Phase 2 trial of the mek inhibitor Pd-0325901 in adolescents and adults with nf1-related plexiform neurofibromas: an nf clinical trials consortium study. Neuro-Oncology. 2018;20(suppl_2):i143.