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Binimetinib (Mektovi®)

Finnes, Heidi D. PharmD, BCOP

doi: 10.1097/01.COT.0000577092.64202.b5
Opinion
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What is binimetinib?

Binimetinib is an oral reversible inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1/2.

Mitogen-activated protein kinase (MAPK) pathway activation is vital for cancer cell proliferation and survival. Approximately 50 percent of melanoma patients have a point mutation in BRAF V600 that promotes repetitive activation of the MAPK pathway. Binimetinib inhibits MEK 1/2 downstream from BRAF and halts cancer cell signaling and survival.

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What is this approved for?

Binimetinib is approved in combination with encorafenib, a BRAF inhibitor, for the treatment of unresectable or metastatic melanoma with a BRAF V600E/K mutation, as detected by an FDA-approved test.

Based on results of the COLUMBUS trial, binimetinib, in combination with encorafenib, gained FDA approval in mid-2018. A total of 577 BRAF V600 mutation-positive metastatic melanoma patients were randomized 1:1:1 to receive binimetinib 45 mg twice daily + encorafenib 450 mg once daily, encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was overall survival (OS).

With a median follow-up of 16.6 months, median PFS was 14.9 months versus 7.3 months in the binimetinib + encorafenib versus vemurafenib group, respectively (HR 0.54, 95% CI 0.41-0.71, two-sided p<0.0001) (Lancet Oncol 2018:19:603-615). Median OS was 33.6 months versus 16.9 months again favoring the combination (HR 0.61, 95% CI 0.47-0.79, two-sided p <0.0001) (Lancet Oncol 2018;19:1315-1327). The binimetinib + encorafenib combination showed excellent tolerability with grade 3/4 abnormalities in gamma-glutamyl transferase, creatinine phosphokinase, and hypertension versus arthralgias in vemurafenib patients.

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How do you administer this drug?

Binimetinib 45 mg twice daily is given orally with or without food in combination with encorafenib. Tablets are taken 12 hours apart. Binimetinib may be reduced once to 30 mg twice daily and is available as 15 mg tablets.

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Are there any pre-medications needed?

None required.

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What are the common side effects associated with binimetinib (> or =10%)?

The most common adverse effects of binimetinib (with encorafenib) included fatigue and gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain).

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What are the uncommon side effects associated with binimetinib (less than 10%)?

Less than 1 percent of patients developed interstitial lung disease including pneumonitis. Grade 3/4 increases in ALT and AST occurred in 6 percent and <3 percent, respectively. Colitis and panniculitis are other infrequent toxicities.

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Are there any important drug interactions I should be aware of?

Binimetinib is metabolized by UGT1A1 glucuronidation (61%). Binimetinib is a substrate of P-glycoprotein and breast cancer resistance protein. Binimetinib does not have any inhibitory or induction of transport or cytochrome P450 pathways.

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How do I adjust the dose in the setting of renal or hepatic insufficiency?

Binimetinib is excreted by the biliary (62%) and urinary (31%) tracts. No change to dosing is required in patients with renal impairment. A dose reduction to 30 mg twice daily is required with moderate [total bilirubin > 1.5 and <= 3 times upper limit of normal (ULN) and any AST] or severe (total bilirubin > 3 x ULN and any AST) liver dysfunction.

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What should my patients know about binimetinib?

Binimetinib should be taken continuously as prescribed by a provider. Do not take an extra dose if vomiting occurs. Patients should report the following symptoms to their health care provider: shortness of breath or cough, swelling of your extremities, chest pain, blurred vision or vision changes, weakness or muscle aches, bleeding, and yellowing of the skin or darkening of the urine.

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What else should I know about binimetinib?

Binimetinib may cause cardiomyopathy. Assess cardiac risk factors and left ventricular ejection fraction by echocardiogram or MUGA scan prior to initiating binimetinib at 1 month and every 2-3 months throughout treatment.

Visual changes, including serous retinopathy, retinal vein occlusion and uveitis, occurred in 20 percent of patients. Patients should report any visual changes at each visit and an ophthalmologic evaluation should occur at regular intervals.

Venous thromboembolism and hemorrhage occurred in 6 percent and 19 percent, respectively. Patients should be monitored for signs and symptoms of clots or bleeding.

In the COLUMBUS trial, 58 percent of patients had elevations in serum creatinine phosphokinase (CPK). Monitor CPK and creatinine levels prior to treatment initiation and as symptoms such as weakness or muscle pains occur.

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What useful links are available regarding encorafenib?

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Ongoing clinical trials?

Binimetinib has been studied in BRAF V600E-mutant colorectal cancers in combination with encorafenib and cetuximab (J Clin Oncol 2019; doi: https://doi.org/10.1200/JCO.18.02459) or with fluorouracil, irinotecan, and leucovorin (FOLFIRI) in KRAS-positive metastatic colorectal cancer. Clinical trials are also investigating binimetinib with pembrolizumab in triple-negative breast cancer and in KRAS-mutant non-small cell lung cancer. More information is available about these clinical trials at https://clinicaltrials.gov.

HEIDI D. FINNES, PHARMD, BCOP, is Senior Manager of Pharmacy Cancer Research and Assistant Professor of Pharmacy in the College of Medicine at Mayo Clinic, Rochester, Minn. JANELLE E. MANN, PHARMD, BCOP, is an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and 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.

Heidi D. Finnes, PharmD, BCOP

Heidi D. Finnes, PharmD, BCOP

Janelle E. Mann, PharmD, BCOP

Janelle E. Mann, PharmD, BCOP

Ramaswamy Govindan, MD

Ramaswamy Govindan, MD

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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