Click Here to
Subscribe
Breaking
News, Updates,
& More
Stay Up
to Date

Braftovi (Encorafenib) plus Mektovi (Binimetinib) Third BRAF/MEK Inhibition Combination Approved for Metastatic Melanoma with BRAF Mutation

2019 Fourth Annual Oncology Guide to New FDA Approvals - FDA Approvals, Melanoma
Lisa A. Raedler, PhD, RPh, Medical Writer

Melanoma is the most dangerous form of skin cancer.1 The 5-year relative survival rate for Americans with distant melanoma is only 23%.2 The National Cancer Institute estimated that there were 91,270 new cases of skin melanoma and more than 9300 deaths from this disease in 2018.2 This deadly disease is also costly; in the United States, expenditures for the treatment of melanoma exceeded $3 billion in 2018.3

The introduction of novel agents has sharply changed the treatment landscape for patients with all stages of melanoma. Today’s armamentarium of systemic treatments for patients with advanced melanoma includes monoclonal antibodies that target cytotoxic T-lymphocyte antigen-4 (eg, ipilimumab [Yervoy]) or programmed-cell death (PD)-1 (eg, pembrolizumab [Keytruda], nivolumab [Opdivo]), as well as oral small-molecule drugs that inhibit BRAF or MEK proteins.4

Inhibitors of BRAF and MEK are specifically valuable in patients with advanced melanoma and mutations such as BRAF V600, which activate a cell-signaling pathway called MAPK.5 For the 35% to 50% of patients with melanoma who have a mutation in BRAF V600,5 inhibitors of BRAF, such as vemurafenib (Zelboraf) and dabrafenib (Tafinlar), or MEK, such as cobimetinib (Cotellic) and trametinib (Mekinist), block the growth of BRAF mutation–positive cancer cells.6,7

FDA Approved New BRAF/MEK Inhibitor Combination

On June 27, 2018, the US Food and Drug Administration (FDA) approved the combination of 2 oral drugs—encorafenib and binimetinib (Braftovi and Mektovi; Array BioPharma)—for the treatment of patients with unresectable or metastatic melanoma associated with a BRAF V600E or a V600K mutation, as detected by the FDA-approved companion diagnostic test.8-10 On the same day, the FDA approved the THxID BRAF Kit as a companion diagnostic for encorafenib and binimetinib. This new combination therapy is not indicated for the treatment of patients with BRAF wild-type melanoma.8-10

The pivotal clinical trial COLUMBUS supported the approval of encorafenib plus binimetinib for this indication.8,11

“Despite recent advances, there remains a significant unmet need for treatments that are effective and well-tolerated in patients with BRAF-mutant melanoma. Now, physicians and patients have the option to consider treatment with Braftovi plus Mektovi, which has been shown to delay disease progression, improve overall survival and is generally well-tolerated,” said Keith Flaherty, MD, Medical Oncologist, Massachusetts General Hospital Cancer Center and Harvard Medical School.12

Mechanism of Action

Encorafenib, a kinase inhibitor, targets the BRAF V600E and CRAF genes, as well as BRAF wild-type cell lines.9 Binimetinib is a reversible inhibitor of the activity of MEK1 and MEK2.10

Encorafenib and binimetinib target 2 different kinases in the RAS/RAF/MEK/ERK pathway. The coadministration of encorafenib and binimetinib resulted in greater antiproliferative activity in vitro in BRAF mutation–positive cell lines compared with either drug alone.9,10

Dosing and Administration

The recommended dosage of encorafenib is 450 mg orally taken once daily.9 The recommended dosage of binimetinib is 45 mg orally taken twice daily, approximately 12 hours apart.10

Encorafenib and binimetinib are given in combination, with or without food, to patients with unresectable or metastatic melanoma who have a BRAF V600E or V600K mutation until disease progression or until unacceptable toxicity.9,10

Pivotal Clinical Trial: COLUMBUS

The approval of encorafenib and binimetinib was based on the randomized, active-controlled, open-label, multicenter clinical trial COLUMBUS.9-11 This study enrolled 577 patients with unresectable or metastatic melanoma and BRAF V600E or V600K mutation. Patients were randomized to binimetinib 45 mg twice daily plus encorafenib 450 mg once daily, encorafenib 300 mg once daily, or an active control (vemurafenib given at a dosage of 960 mg twice daily). Treatment continued until disease progression or until unacceptable toxicity.9-11

A blinded independent central review panel used the Response Evaluation Criteria in Solid Tumors v1.1 to measure the primary efficacy end point, progression-free survival (PFS). In this study, the median PFS was extended to 14.9 months for patients who received binimetinib plus encorafenib compared with 7.3 months for patients who received vemurafenib monotherapy (hazard ratio, 0.54; 95% confidence interval, 0.41-0.71; P <.0001; Table).9-11

Table

Adverse Events

The most common (≥25%) adverse reactions in patients who received the combination of encorafenib and binimetinib included fatigue (43%), nausea (41%), diarrhea (36%), vomiting (30%), and abdominal pain (28%). Overall, 5% of patients who received the regimen discontinued therapy because of adverse reactions, the most common of which were hemorrhage and headache.9,10

Dose interruptions of encorafenib because of adverse reactions occurred in 30% of patients receiving encorafenib plus binimetinib. Dose reductions of encorafenib were required in 14% of patients receiving the combination.9

Dose interruptions of binimetinib because of adverse reactions occurred in 33% of patients. Dose reductions of binimetinib were required in 19% of patients.10

The researchers concluded that the adverse event findings from the COLUMBUS study suggest that encorafenib combined with binimetinib has a different toxicity profile compared with other combinations of BRAF plus MEK inhibitors, particularly related to pyrexia and photosensitivity.11

Contraindications

Encorafenib and binimetinib have no contra­indications.9,10

Drug Interactions

The concomitant use of strong or moderate cytochrome (CY)P3A4 inhibitors can increase the plasma concentration of encorafenib. If concomitant use cannot be avoided, encorafenib’s dose should be modified.9

The concomitant use of encorafenib with strong or moderate CYP3A4 inducers should be avoided. The concomitant use of encorafenib and sensitive CYP3A4 substrates may increase toxicity or decrease efficacy of these agents. The use of hormonal contraceptives should be avoided.9

No clinically important drug interactions have been reported with binimetinib.10

Warnings and Precautions

In vitro experiments have demonstrated paradoxical activation of MAP kinase signaling and increased cell proliferation in BRAF wild-type cells after exposure to BRAF inhibitors. Evidence of BRAF V600E or V600K mutation must be confirmed before initiating encoraf­enib therapy.9

Encorafenib monotherapy is associated with an increased risk for certain adverse reactions compared with the combination of encorafenib plus binimetinib. Severe dermatologic reactions occurred in 21% of patients who received encorafenib monotherapy versus 2% of those who received the combination.9

New primary malignancies, cutaneous and noncutaneous, have been observed in patients who received BRAF inhibitors and can occur with encorafenib. Dose modification is not recommended for new primary cu­taneous malignancies. However, encorafenib should be discontinued if noncutaneous malignancies with RAS mutation are diagnosed.9

The use of encorafenib is associated with dose-dependent corrected QT (QTc) interval prolongation. Patients who are at a significant risk for QTc prolongation should be monitored and managed appropriately.9

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients who received binimetinib in combination with encorafenib. Ejection fraction should be assessed by an echocardiogram or a multigated acquisition scan before initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment.10

Venous thromboembolism was observed in 6% of patients who received binimetinib plus encorafenib in the COLUMBUS study, including 3% of patients who had pulmonary embolism.10

Serous retinopathy occurred in 20% of patients who received binimetinib plus encorafenib—8% were retinal detachment and 6% were macular edema.10 Visual symptoms should be evaluated at each visit and ophthalmologic examination should be performed at regular intervals; for new or worsening visual disturbances; and to follow new or persistent ophthalmologic findings, including signs of retinopathy, retinal vein occlusion, and uveitis.9,10

Interstitial lung disease, including pneumonitis, was observed in patients with BRAF mutation–positive melanoma who received binimetinib plus encorafenib. New or progressive unexplained pulmonary symptoms or findings should be investigated for possible interstitial lung disease.10

Hepatotoxicity can occur when binimetinib is combined with encorafenib. Liver function tests should be assessed before starting binimetinib therapy, monthly during treatment, and as clinically indicated.10

Because rhabdomyolysis has been observed, creatine phosphokinase levels and creatinine levels should be assessed before starting binimetinib therapy, periodically during treatment, and as clinically indicated.10

Hemorrhage can occur when binimetinib and encorafenib are combined. Severe hemorrhage in the clinical study included rectal hemorrhage, hematochezia, and fatal intracranial hemorrhage in the setting of new or progressive brain metastases.9,10

Use in Specific Populations

There are no clinical studies of encorafenib or binimetinib in pregnant women. Pregnant women should be advised of the potential risk to the fetus.9,10

There is no information regarding the presence of encorafenib or binimetinib in human milk, or its effects on the breastfed infant or milk production. Women should not breastfeed during treatment with encorafenib and binimetinib, for 2 weeks after the final dose of encorafenib, and for 3 days after the final dose of binimetinib.9,10

Women of reproductive potential should use effective contraception during treatment with encorafenib plus binimetinib, for 2 weeks after the final dose of encorafenib, and for at least 30 days after the final dose of binimetinib.9,10

The safety and effectiveness of encorafenib plus binimetinib have not been established in children.9,10

No differences in the safety or efficacy of encorafenib plus binimetinib were observed between patients aged ≥65 years and younger patients who received this combination therapy in clinical studies.9,10

No dose adjustment of encorafenib is recommended for patients with mild-to-moderate renal impairment or for patients with mild hepatic impairment.9

No dose adjustment of binimetinib is recommended for patients with mild hepatic impairment.10

Conclusion

Encorafenib plus binimetinib is the third BRAF and MEK inhibition combination therapy approved for metastatic melanoma with BRAF mutation. The clinical activity and safety of encorafenib plus binimetinib were demonstrated in the large randomized clinical trial ­COLUMBUS, which enrolled patients with BRAF mutation–positive advanced melanoma, as detected by the companion diagnostic THxID BRAF Kit. As data mature, overall survival and long-term safety findings from the COLUMBUS study will offer important additional insights into the clinical benefit of encorafenib plus binimetinib.11


References

  1. Skin Cancer Foundation. What is melanoma? www.skincancer.org/skin-cancer­information/melanoma. Accessed October 4, 2018.
  2. National Cancer Institute SEER Program. Cancer stat facts: melanoma of the skin. http://seer.cancer.gov/statfacts/html/melan.html. Accessed October 4, 2018.
  3. National Cancer Institute. Cancer Trends Progress Report: financial burden of cancer care. Updated February 2018. http://progressreport.cancer.gov/after/economic_burden. Accessed October 4, 2018.
  4. American Cancer Society. Treatment of melanoma skin cancer, by stage. Revised June 28, 2018. www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-treating-by-stage. Accessed October 4, 2018.
  5. Krauthammer M, Kong Y, Bacchiocchi A, et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet. 2015;47:996-1002.
  6. Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439:358-362.
  7. Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17:1248-1260.
  8. US Food and Drug Administration. FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations. June 27, 2018. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm611981.htm. Accessed October 4, 2018.
  9. Braftovi (encorafenib) capsules, for oral use [prescribing information]. Boulder, CO: Array BioPharma; June 2018.
  10. Mektovi (binimetinib) tablets, for oral use [prescribing information]. Boulder, CO: Array BioPharma; June 2018.
  11. 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.
  12. FDA approves encorafenib and binimetinib combo for melanoma with BRAF mutations. July 2, 2018. Clinical Oncology News. www.clinicaloncology.com/FDA-Watch/Article/07-18/FDA-Approves-Encorafenib-and-Binimetinib-­Combo-for-Melanoma-With-BRAF-Mutations/50091. Accessed October 5, 2018.

Related Items
FDA Approves Polivy in Combination with Bendamustine plus rituximab for Patients with Relapsed, Refractory DLBCL
TON - August 2019, Vol 12, No 4 published on August 6, 2019 in FDA Approvals
Xpovio plus Dexamethasone Combination Receives Accelerated Approval for the Treatment of Patients with Relapsed or Refractory MM
TON - August 2019, Vol 12, No 4 published on August 6, 2019 in FDA Approvals
FDA News
TOP - August 2019, Vol 12, No 3 published on July 29, 2019 in FDA Approvals
Noteworthy Numbers: Melanoma
TOP - August 2019, Vol 12, No 3 published on July 29, 2019 in Melanoma, Noteworthy Numbers
Keytruda Approved for Patients with Previously Treated Metastatic Small-Cell Lung Cancer
Yvette Florio Lane
Web Exclusives published on June 26, 2019 in FDA Approvals, In the News
First Chemoimmunotherapy Regimen Granted Accelerated Approval for Patients with Previously Treated DLBCL
Yvette Florio Lane
Web Exclusives published on June 12, 2019 in FDA Approvals, In the News
Welcome to the Fourth Annual Oncology Guide to New FDA Approvals
2019 Fourth Annual Oncology Guide to New FDA Approvals published on June 5, 2019 in FDA Approvals
New Indications Approved by the FDA in 2018 for Oncology Drugs
Dalia Buffery, MA, ABD
2019 Fourth Annual Oncology Guide to New FDA Approvals published on June 5, 2019 in FDA Approvals
FDA Approvals of Novel Brand-Name Prescription Cancer Drugs in 2018
2019 Fourth Annual Oncology Guide to New FDA Approvals published on June 5, 2019 in FDA Approvals
Copiktra (Duvelisib) Approved for Relapsed or Refractory CLL, SLL, and Follicular Lymphoma
Lisa A. Raedler, PhD, RPh, Medical Writer
2019 Fourth Annual Oncology Guide to New FDA Approvals published on June 5, 2019 in FDA Approvals, Lymphoma
Last modified: July 11, 2019