Encorafenib Plus Binimetinib in Unresectable or Metastatic Melanoma With BRAF Mutations


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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

This past June, encorafenib (Braftovi) and binimetinib (Mektovi) were approved in combination for treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by a U.S. Food and Drug Administration (FDA)-approved test.1-3 The THxID BRAF Kit was simultaneously approved as a companion diagnostic for these therapeutics. Encorafenib is not indicated for the treatment of patients with wild-type BRAF melanoma. 

Supporting Efficacy Data 

APPROVAL WAS BASED on the open-label phase III COLUMBUS trial in which 577 patients were randomized 1:1:1 to receive either (1) binimetinib, 45 mg twice daily, plus encorafenib, 450 mg once daily (n = 192), (2) encorafenib, 300 mg once daily (n = 194), or (3) vemurafenib (Zelboraf), 960 mg twice daily (n = 191).2-4 Treatment continued until disease progression or unacceptable toxicity. 

The median progression-free survival was 14.9 months in the combination group vs 7.3 months in the vemurafenib group (hazard ratio = 0.54, P < .0001). Overall response rates were 63% (complete response in 8%) vs 40% (complete response in 6%), and the median response duration was 16.6 vs 12.3 months. 

How They Work 

ENCORAFENIB IS A kinase inhibitor of BRAF V600E as well as wild-type BRAF and CRAF in cell-free assays. It also binds to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and reduces ligand binding at clinically achievable concentrations. Encorafenib inhibits the growth of tumor cell lines expressing BRAF V600E, D, and K mutations and produced tumor regression associated with the RAF/MEK/ERK pathway suppression in mice with tumor cells expressing BRAF V600E. 

Binimetinib is a reversible inhibitor of MEK1 and MEK2 kinase activity. It also inhibits ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models. 

Compared with either drug alone, coadministration produces greater antiproliferative activity in BRAF mutation–positive cell lines and greater antitumor activity in BRAF V600E–mutant human melanoma xenograft models in mice. The combination delayed the emergence of resistance in BRAF V600E–mutant human melanoma xenografts in mice vs either drug alone. 

How They Are Used 

THE RECOMMENDED DOSAGE of encorafenib is 450 mg orally once daily in combination with binimetinib at 45 mg orally twice daily until disease progression or unacceptable toxicity. If binimetinib is withheld, the encorafenib dose should be reduced to a maximum of 300 mg once daily until binimetinib is resumed. If encorafenib is permanently discontinued, binimetinib must be discontinued. For management of adverse events, the dose of encorafenib can be reduced to 300 mg and then to 200 mg once daily, and binimetinib can be reduced to 30 mg twice daily. 

OF NOTE

Encorafenib carries warnings/precautions for new primary malignancies, tumor promotion in BRAF wild-type tumors hemorrhage, uveitis, QT prolongation, and embryofetal toxicity. Binimetinib carries warnings/precautions for cardiomyopathy, venous thromboembolism, ocular toxicities, interstitial lung disease, hepatotoxicity, rhabdomyolysis, hemorrhage, and embryofetal toxicity.

Encorafenib product labeling provides detailed instructions on dose modifications for a new primary malignancy, uveitis, QTc prolongation, hepatotoxicity, dermatologic toxicity, hemorrhage, recurrent grade 2 adverse reactions, and grade 3 or 4 adverse reactions, as well as for coadministration of strong or moderate CYP3A4 inhibitors. Concomitant use of encorafenib with strong or moderate CYP3A4 inhibitors, strong or moderate CYP3A4 inducers, and sensitive CYP3A4 substrates (including hormonal contraceptives) should be avoided. 

Binimetinib product labeling provides detailed instructions on dose modifications for cardiomyopathy, venous thromboembolism, serous retinopathy, retinal vein occlusion, uveitis, interstitial lung disease, hepatotoxicity, rhabdomyolysis or creatine phosphokinase (CPK) elevations, dermatologic toxicity, recurrent grade 2 adverse reactions, grade 3 or 4 adverse reactions, and moderate and severe hepatic impairment. 

Safety Profile 

THE COLUMBUS TRIAL excluded patients with a history of Gilbert’s syndrome, abnormal left ventricular ejection fraction (LVEF), prolonged QTc (> 480 msec), uncontrolled hypertension, and a history or current evidence of retinal vein occlusion. 

The most common (≥ 25%) adverse events of any grade in patients receiving encorafenib in combination with binimetinib were fatigue, nausea, vomiting, abdominal pain, and arthralgia. The most common grade 3 or 4 adverse events included pyrexia and abdominal pain. The most common grade 3 or 4 laboratory abnormalities were increased gamma glutamyl transferase and increased alanine transaminase. 

Adverse events led to dose interruptions of encorafenib in 30% of patients (most common reasons being nausea, vomiting, and pyrexia) and dose reductions in 14% (most common reasons being arthralgia, fatigue, and nausea). Adverse events led to treatment discontinuation in 5%, with the most common reasons being hemorrhage and headache. 

Adverse events led to dose interruptions of binimetinib in 33% of patients (most common reasons being left ventricular dysfunction and serous retinopathy) and dose reductions in 19% (most common reasons being left ventricular dysfunction, serous retinopathy, and colitis). Adverse events led to treatment discontinuation in 5%, with the most common reasons being hemorrhage and headache. 

Encorafenib carries warnings/precautions for new primary malignancies, tumor promotion in BRAF wild-type tumors, hemorrhage, uveitis, QT prolongation, and embryofetal toxicity. Patients should be monitored for malignancies and undergo dermatologic, ophthalmologic, and electrolyte evaluations at regular intervals. 

Binimetinib carries warnings/precautions for cardiomyopathy, venous thromboembolism, ocular toxicities, interstitial lung disease, hepatotoxicity, rhabdomyolysis, hemorrhage, and embryofetal toxicity. LVEF should be assessed before treatment, after 1 month of treatment, and every 2 to 3 months thereafter. Liver function tests as well as CPK and creatine should be monitored at regular intervals. ■

REFERENCES 

1. U.S. Food and Drug Administration: FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm611981.htm. Accessed July 20, 2018. 

2. Braftovi (encorafenib) capsules prescribing information, Array BioPharma Inc, June 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf. Accessed July 20, 2018. 

3. Mektovi (binimetinib) tablets prescribing information, Array Biopharma Inc, June 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf. Accessed July 20, 2018. 

4. Dummer R, Ascierto PA, Gogas HJ, et al: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 19:603-615, 2018.


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