FDA Burst: Issue 16, July 2018

Published on 7/3/2018 3:00:00 PM

FDA Approves BRAFTOVITM (Encorafenib) and MEKTOVI® (Binimetinib) to be used in Combination for Unresectable or Metastatic Melanoma with a BRAF V600E or V600K Mutation

On June 27, 2018, the US Food and Drug Administration (FDA) approved BRAFTOVI TM (encorafenib) and MEKTOVI® (binimetinib) individually with the indication to be used in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test. The approved recommended dosage regimen is BRAFTOVI 450 mg orally once daily in combination with MEKTOVI 45 mg orally twice daily, with or without food, until disease progression or unacceptable toxicity. Recommendations for safety monitoring and management of adverse reactions for BRAFTOVI and MEKTOVI when used in combination are described in the full prescribing information linked below. Additional dosage modifications are recommended for BRAFTOVI when coadministered with strong or moderate CYP3A4 inhibitors, and for MEKTOVI in patients with moderate or severe hepatic impairment.
Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD)
MOA: Both act as kinase inhibitors, however encorafenib targets BRAF V600E and binimetinib targets MEK1 and MEK2. 
Dose Proportionality: Systemic exposure of encorafenib increases proportionally with single doses of 50 to 700 mg (i.e., 0.1 to 1.6 times the approved recommended BRAFTOVI dosage) and increases less than proportionally with once daily doses of 50 mg to 800 mg (0.1 to 1.8 times the approved recommended BRAFTOVI dosage). Systemic exposure of binimetinib is approximately dose proportional.
Absorption: The median time to peak concentration is 2 hours for encorafenib and 1.6 hours for binimetinib. 
Plasma Protein Binding: Protein binding is 86% for encorafenib and 97% for binimetinib. 
Elimination Half-Life: Mean elimination half-life is 3.5 hours for both encorafenib and binimetinib.
Metabolism: Encorafenib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19 and CYP2D6. Binimetinib is primarily metabolized by UGT1A1 and to a lesser extent by CYP1A2 and CYP2C19.
Excretion: A total of 47% of the recovered radiolabeled encorafenib dose was eliminated in feces (5% as unchanged) and 47% in urine (2% as unchanged). A total of 62.3% of the recovered radiolabeled binimetinib dose was recovered in feces (31.7% as unchanged) and 31.4% in urine (6.5% as unchanged).
Cardiac Electrophysiology: Following administration of the approved recommended BRAFTOVI dose in combination with MEKTOVI, based on a central tendency analysis of QTc in a study of adult patients with melanoma, the largest mean (90% CI) QTcF change from baseline was 18 (14 to 22) ms. Following administration of MEKTOVI 45 mg twice daily alone, no clinically meaningful QT interval prolongation was observed.

Drug Interactions

Strong or Moderate CYP3A4 Inhibitors: Avoid concomitant use. If concomitant use is unavoidable, reduce BRAFTOVI to one-third of the BRAFTOVI dosage prior to concurrent use of strong CYP3A4 inhibitors or to one-half of the BRAFTOVI dosage prior to concurrent use of moderate CYP3A4 inhibitors. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the BRAFTOVI dose that was taken prior to initiating the CYP3A4 inhibitor. 
Strong or Moderate CYP3A4 Inducers: Avoid concomitant use.
CYP3A4 Substrates: Coadministration can result in decreased concentrations and loss of efficacy of CYP3A4 substrates, including hormonal contraceptives.
Drugs that Prolong QT Interval: Avoid coadministration. 

No clinically significant drug interactions have been observed with MEKTOVI. 

Use in Specific Populations
Age (19 to 89 years), sex, body weight, mild hepatic impairment (Child-Pugh Class A), and mild to moderate renal impairment (CLcr 30 to < 90 mL/min) do not have a clinically significant effect on the pharmacokinetics of encorafenib. The effect of race/ethnicity, moderate to severe hepatic impairment (Child-Pugh Class B and C), and severe renal impairment (CLcr < 30 mL/min) have not been studied.
Age (20 to 94 years), sex, body weight, and severe renal impairment (eGFR ≤ 29 mL/min/1.73 m2) do not have a clinically significant effect on the systemic exposure of binimetinib. The effect of race/ethnicity on the pharmacokinetics of binimetinib is unknown.
Reduce the MEKTOVI dosage to 30 mg twice daily in patients with moderate (total bilirubin >1.5 and < to 3 x ULN and any AST) or severe (total bilirubin levels > 3 × ULN and any AST) hepatic impairment. No dosage adjustment is recommended in patients with mild hepatic impairment (total bilirubin > 1 and ≤ 1.5 x ULN and any AST or total bilirubin ≤ ULN and AST > ULN). 
Efficacy and Safety
Efficacy and safety of BRAFTOVI in combination with MEKTOVI were demonstrated at the recommended dosage in a randomized, active-controlled, open-label, multicenter trial in patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID™BRAF assay. Additional information regarding the trial can be found in the full prescribing information linked below. 
The most common adverse reactions (≥ 25%) with BRAFTOVI in combination with MEKTOVI are fatigue, nausea, vomiting, abdominal pain, and arthralgia. 

Full prescribing information is available for BRAFTOVI at https://go.usa.gov/xUYqc and for MEKTOVI at https://go.usa.gov/xUYqx
Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.
A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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