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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.

June 27, 2018 with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf

On June 27, 2018, the Food and Drug Administration approved encorafenib and binimetinib (BRAFTOVI and MEKTOVI, Array BioPharma Inc.) in combination for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

Approval was based on a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453) in 577 patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma. Patients were randomized (1:1:1) to receive binimetinib 45 mg twice daily plus encorafenib 450 mg once daily, encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity.

The major efficacy measure was progression-free survival (PFS) using RECIST 1.1 response criteria and assessed by blinded independent central review. The median PFS was 14.9 months for patients receiving binimetinib plus encorafenib, and 7.3 months for the vemurafenib monotherapy arm (hazard ratio 0.54, 95% CI: 0.41, 0.71, p<0.0001). Overall response rates assessed by central review were 63% and 40%, respectively. Median response duration was 16.6 months vs. 12.3 months, respectively.

The most common (≥25%) adverse reactions in patients receiving the combination were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia. Discontinuation of therapy due to adverse reactions occurred in 5% of patients receiving the combination; the most common reasons were hemorrhage and headache.

FDA today also granted approval of the THxID BRAF Kit (bioMérieux) as a companion diagnostic for these therapeutics.

The recommended doses are binimetinib 45 mg orally twice daily and encorafenib 450 mg orally once daily.

View full prescribing information for Braftovi.

View full prescribing information for Mektovi.

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 mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Pharmacist’s Applications to Practice

Encorafenib and Binimetinib in Combination for the Treatment of Unresectable or Metastatic BRAF V600E or V600K Mutation–Positive Melanoma

Author: Brendan Mangan, PharmD
PGY-1 Pharmacy Resident
Vanderbilt University Medical Center
Nashville, TN

What is the potential role for encorafenib and binimetinib in the treatment of BRAF V600E or V600K-mutated metastatic melanoma?

  • Encorafenib is a tyrosine kinase inhibitor that targets BRAF V600 as well as wild type BRAF and CRAF in in-vitro assays.1 BRAF mutations occur in up to 35%–50% of patients with melanoma because of genetic alterations resulting in the activation of the MAPK pathway and cell proliferation.2
  • Binimetinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activity. MEK proteins are upstream regulators of the extracellular signal–related kinase (ERK) pathway.3 The addition of an MEK-inhibitor treatment regimen to a BRAF-inhibitor regimen improves efficacy and reduces MAPK activation-related toxicity, when compared to BRAF-inhibitor monotherapy.
  • On June 27, 2018, the U.S. Food and Drug Administration (FDA) approved encorafenib plus binimetinib in combination for the treatment of unresectable or metastatic BRAF V600E or V600K mutation–positive melanoma based on the results of the COLUMBUS trial. This is the third BRAF/MEK inhibitor combination approved by the FDA for this indication, preceded by dabrafenib plus trametinib and vemurafenib plus cobimetinib.1-7
  • The COLUMBUS trial is a randomized open-label phase-3 study that compared encorafenib 450 mg daily plus binimetinib 45 mg twice daily combination therapy with encorafenib 300 mg daily monotherapy and vemurafenib 960 mg twice-daily monotherapy in 577 patients with locally advanced unresectable or metastatic BRAF V600-mutant melanoma. Enrolled patients had a BRAF V600E or V600K mutation, had an Eastern Cooperative Oncology Group performance status of 0–1, and were either treatment-naive or had experienced disease progression on or after previous first-line immunotherapy. The primary end point was progression-free survival (PFS) for encorafenib plus binimetinib versus vemurafenib. Key secondary end points included PFS for encorafenib plus binimetinib versus encorafenib, best overall response rate (ORR), and duration of response. When assessed by a blinded independent central review, the median PFS was 14.9 months (95% confidence interval [CI] 11–18.5) in the encorafenib plus binimetinib group, compared to 9.6 months (95% CI 7.5–14.8) in the encorafenib monotherapy group and 7.3 months (95% CI 5.6–8.2) in the vemurafenib monotherapy group. The risk of disease progression or death was statistically significantly improved for the encorafenib plus binimetinib combination group when compared to vemurafenib monotherapy (hazard ratio [HR] 0.54, 95% CI 0.41–0.71; two-sided p < .0001); however, it was not statistically significant when compared to encorafenib monotherapy (HR 0.75, 95% CI 0.56–1.00; two-sided p = .051). There was a 63% ORR in the encorafenib plus binimetinib group, compared to 40% in the vemurafenib group. The most common all-grade adverse reactions (20% or greater) in the encorafenib plus binimetinib group were nausea (grade 1–2, 40%), diarrhea (grade 1–2, 34%), vomiting (grade 1–2, 28%), fatigue (grade 1–2, 27%), arthralgia (grade 1–2, 25%), constipation (grade 1–2, 22%), and headache (grade 1–2, 20%). The most common (>5%) grade 3–4 adverse events in the encorafenib plus binimetinib group were increased gamma-glutamyltransferase (9%), increased creatine phosphokinase (CPK) (7%), and hypertension (6%). Adverse events leading to discontinuation occurred less frequently in the encorafenib plus binimetinib combination group than in the encorafenib or vemurafenib monotherapy groups. Fewer photosensitivity and febrile reactions were observed with the encorafenib plus binimetinib group when compared to the vemurafenib group.2
  • The National Comprehensive Cancer Network recognizes encorafenib plus binimetinib as a category-1 first-line therapy for metastatic or unresectable melanoma with BRAF V600-activating mutation if clinically needed for early response, similar to the other BRAF-/MEK-inhibitor combinations of dabrafenib plus trametinib and vemurafenib plus cobimetinib. All three options are also listed as appropriate options for second-line or subsequent therapy because of disease progression in patients with V600-activating mutations.8
  • Although a randomized controlled trial is needed before head-to-head comparisons of BRAF-/MEK-inhibitor regimens can be made, it is theorized that the longer dissociation half-life (about 30 hours) and more potent BRAF V600E proliferation inhibition of encorafenib are advantages over dabrafenib and vemurafenib.1,2,4,6

What role can the pharmacist play in the management of patients on the encorafenib plus binimetinib combination?

  • Serious bleeding (19%) and clotting (6%) complications can occur with this regimen. Patients should be counseled on the signs and symptoms of bleeding and clotting and advised when to contact their healthcare provider.1-3
  • QTc prolongation can occur with this regimen. Patients should receive a 12-lead electrocardiogram prior to initiation, and all new and existing medications should be reviewed for QTc prolongation interactions.1-3
  • Patients should receive an echocardiogram prior to initiation, 1 month into treatment, and every 2–3 months for the duration of treatment because binimetinib can cause heart failure.1-3
  • Liver enzyme tests should be done prior to initiation of treatment and monthly during treatment because binimetinib was shown to increase alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphate (ALT 6%, AST 2.6%, alkaline phosphate 0.5%).1-3
  • Serous retinopathy occurred in 20% of patients enrolled in the COLUMBUS trial. Patients should be counseled to be cognizant of visual changes and contact their healthcare provider if any occur.1-3
  • Cutaneous squamous cell carcinomas may occur with BRAF inhibitor monotherapy but are seen less commonly when a BRAF inhibitor is used in combination with a MEK inhibitor.1-3
  • For patients with moderate (total bilirubin > 1.5 and ≤ 3 times the upper limit of normal [ULN] and any AST) or severe (total bilirubin > 3 times the ULN and any AST) hepatic impairment, the binimetinib dosage should be reduced to 30 mg twice daily.3
  • No renal adjustments are required for the use of encorafenib in patients with mild to moderate renal impairment (creatinine clearance [CrCl] 30 to less than 90 ml/min). No dosing has been established for patients with severe renal dysfunction (CrCl less than 30 ml/min). Binimetinib does not require renal adjustments.1,3
  • The use of strong or moderate CYP3A4 inhibitors should be avoided during treatment with encorafenib. If concomitant use is unavoidable, the dose should be reduced to one-third of the dose prior to administration of the strong CYP3A4 inhibitor or one-half of the dose prior to administration of the moderate CYP3A4 inhibitor. Upon discontinuation of the inhibitor, 3 to 5 elimination half-lives must elapse prior to increasing to the original dosing.1
  • Array BioPharma has a Co-Pay Savings Program in which commercially insured patients may be eligible for a $0 co-pay for a month’s supply of encorafenib and binimetinib.9
  • ArrayACTS is a patient assistance program that can help provide co-pay assistance or assistance with medication costs if the patient does not have insurance or prescription drug coverage.9

Clinical Pearls

  • Encorafenib, supplied in 50-mg and 75-mg capsules, is taken once daily without regard to food.1
  • Binimetinib, supplied in 15-mg tablets, is taken every 12 hours without regard to food.3
  • Encorafenib is moisture sensitive and must be stored in the original bottle with the desiccant and a tightly sealed cap.1 Encorafenib and binimetinib can be stored at room temperature.1,3
  • Binimetinib can be dose reduced from 45 mg twice daily to 30 mg twice daily. Dose reductions are indicated for an asymptomatic, absolute decrease in left ventricular ejection fraction of greater than 10% from baseline that is also below the lower limit of normal, uncomplicated deep vein thrombosis or pulmonary embolism if improvement to grade 0–1 is shown upon withholding binimetinib, serous retinopathy if improvement is shown after withholding binimetinib for up to 10 days, grade 1–3 uveitis if improvement is shown after withholding binimetinib for up to 6 weeks, grade 2 interstitial lung disease if improvement to grade 0–1 is shown after withholding binimetinib for up to 4 weeks, CPK elevation if improvement to grade 0–1 is shown after withholding binimetinib for up to 4 weeks, and grade 2–3 dermatologic toxicity. If binimetinib 30 mg twice daily is not tolerated or adverse effects remain, binimetinib must be permanently discontinued. Binimetinib must be discontinued if encorafenib is withheld or discontinued.3
  • Encorafenib can be dose reduced initially from 450 mg daily to 300 mg daily, and if necessary, it can be further reduced to 200 mg daily. Encorafenib must be dose reduced for grade 1–3 uveitis if improvement is shown after withholding encorafenib for up to 6 weeks, QTcF >500 ms and <60 ms increase from baseline after withholding encorafenib until QTcF < 500 ms, grade 2–3 dermatologic toxicity, and recurrent grade 2 hemorrhage or first occurrence grade 3–4 hemorrhage if improvement to grade 0–1 after withholding encorafenib for up to 4 weeks.1
  • If binimetinib therapy is withheld or discontinued, the encorafenib dose must be reduced to 300 mg daily.1
  • Patients should not take a missed dose within 12 hours of the next encorafenib dose or within 6 hours of the next binimetinib dose.1-3,9

References

  1. Braftovi (encorafenib) [package insert]. Boulder, CO: Array BioPharma Inc; 2018.
  2. 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. 2018;19:603-615.
  3. MektovI (binimetinib) [package insert]. Boulder, CO: Array BioPharma Inc; 2018.
  4. Tafinlar (dabrafenib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2013.
  5. Mekinist (trametinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2013.
  6. Zelboraf (vemurafenib) [package inert]. San Francisco, CA: Genentech USA Inc.; 2011.
  7. Cotellic (cobimetinib) [package insert]. San Francisco, CA: Genentech USA Inc.; 2015.
  8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Cutaneous Melanoma (Version 1.2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf. Accessed November 19, 2018.
  9. Array BioPharma. (2018). BraftovI (encorafenib) capsules + Mektovi (binimetinib) tablets. Available at https://www.braftovimektovi.com/hcp/. Accessed August 27, 2018.
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