Encorafenib
Indications
Encorafenib is used for:
Melanoma
Adult Dose
Melanoma
Indicated in combination with binimetinib for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test
450 mg PO qDay in combination with binimetinib
Continue until disease progression or unacceptable toxicity
Hepatic impairment
Mild (Child-Pugh A): No dose adjustment required
Moderate-to-severe (Child-Pugh B or C): No recommended dose established
Child Dose
Renal Dose
Renal impairment
Mild-to-moderate (CrCl 30 to <90 mL/min): No dose adjustment required
Severe (CrCl <30 mL/min): A recommended dose has not been established
Administration
May take with or without food
Contra Indications
Precautions
Confirm evidence of BRAF V600E or V600K mutation prior to initiating treatment; in vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells, which are exposed to BRAF inhibitors; not indicated for wild-type BRAF melanoma (see Dosing Considerations)
Hemorrhage can occur when encorafenib is administered in combination with binimetinib; hemorrhagic events include GI, hemorrhoidal, rectal, and intracranial hemorrhage and hematochezia; withhold, reduce dose, or discontinue drug (see Dosage Modifications)
Uveitis (eg, iritis, iridocyclitis) reported in patients treated with encorafenib in combination with binimetinib; assess for visual symptoms at each visit; perform an ophthalmologic evaluation regularly and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings (see Dosage Modifications)
Dose-dependent QTc interval prolongation reported; monitor patients who already have or who are at significant risk of developing QTc prolongation (eg, patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, those taking medications associated with QT prolongation); correct hypokalemia and hypomagnesemia prior to and during administration
Pregnancy-Lactation
Pregnancy
Based on its mechanism of action, fetal harm may occur when administered to pregnant women
There are no available clinical data on the use of encorafenib during pregnancy
Advise pregnant women of the potential risk to a fetus
Contraception
Verify the pregnancy status of females of reproductive potential prior to initiating treatment
Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose
Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking encorafenib and binimetinib.
Infertility
Based on findings in male rats at doses ~13 times the human exposure at the 450-mg clinical dose, use of encorafenib may impact fertility in males
Lactation
The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed child or from the underlying maternal condition
Interactions
Adverse Effects
Side effects of Encorafenib :
>10%
Increased creatinine (93%)
Increased gamma glutamyl transferase (GGT) (45%)
Fatigue (43%)
Nausea (41%)
Anemia (36%)
Vomiting (30%)
Increased AST/ALT (27-29%)
Hyperglycemia (28%)
Abdominal pain (28%)
Arthralgia (26%)
Hyperkeratosis (23%)
Myopathy (23%)
Headache (22%)
Rash (22%)
Constipation (22%)
Increased alkaline phosphatase (21%)
Hemorrhage (19%)
Hyponatremia (18%)
Pyrexia (18%)
Dry skin (16%)
Dizziness (15%)
Alopecia (14%)
Pruritus (13%)
Leukopenia (13%)
Lymphopenia (13%)
Neutropenia (13%)
Peripheral neuropathy (12%)
Pain in extremity (11%)
Increased GGT, Grades 3 and 4 (11%)
1-10%
Hypermagnesemia (10%)
Facial paresis (<10%)
Pancreatitis (<10%)
Panniculitis (<10%)
Drug hypersensitivity (<10%)
Increased ALT/AST, Grades 3 and 4 (2.6-6%)
Hyperglycemia, Grades 3 and 4 (5%)
Pyrexia, Grades 3 and 4 (4%)
Abdominal pain, Grades 3 and 4 (4%)
Anemia, Grades 3 and 4 (3.6%)
Increased creatinine, Grades 3 or 4 (3.6%)
Hyponatremia, Grades 3 or 4 (3.6%)
Neutropenia, Grades 3 and 4 (3.1%)
Fatigue, Grades 3 and 4 (3%)
Dizziness, Grades 3 and 4 (3%)
Hemorrhage, Grades 3 and 4 (3%)
Lymphopenia, Grades 3 and 4 (2.1%)
Nausea, Grades 3 and 4 (2%)
Vomiting, Grades 3 and 4 (2%)
Headache, Grades 3 and 4 (2%)
Hypomagnesemia, Grades 3 and 4 (1%)
Arthralgia, Grades 3 and 4 (1%)
Pain, Grades 3 and 4 (1%)
Hyperkeratosis, Grades 3 and 4 (1%)
Peripheral neuropathy, Grades 3 and 4 (1%)
Rash, Grades 3 and 4 (1%)
Pruritus, Grades 3 and 4 (1%)
Mechanism of Action
Kinase inhibitor that targets BRAF V600E
This pathway regulates several key cellular activities, including proliferation, differentiation, survival, and angiogenesis; inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma
Encorafenib and binimetinib target 2 different kinases in the RAS/RAF/MEK/ERK pathway; compared with either drug alone, coadministration resulted in greater antiproliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice
Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone