FDA Approves Braftovi + Mektovi Combination

Array BioPharma Announces FDA Approval of Braftovi (encorafenib) in Combination with Mektovi (binimetinib) for Unresectable or Metastatic Melanoma with BRAF Mutations

BOULDER, Colo., June 27, 2018 /PRNewswire/ -- Array BioPharma Inc. (Nasdaq: ARRY) today announced that the U.S. Food and Drug Administration (FDA) has approved Braftovi capsules in combination with Mektovi tablets for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. Braftovi is not indicated for the treatment of patients with wild-type BRAF melanoma.

Braftovi + Mektovi are now available to order through select specialty pharmacies in the U.S. market.

The approval of Braftovi + Mektovi is based on results from the Phase 3 COLUMBUS trial, which demonstrated the combination doubled median progression-free survival (mPFS) compared to vemurafenib, alone (14.9 months versus 7.3 months, respectively [HR (0.54), (95% CI 0.41-0.71), p<0.0001]). Only 5% of patients who received Braftovi + Mektovi discontinued treatment due to adverse reactions.

The most common adverse reactions (≥25%) in patients receiving Braftovi + Mektovi were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia.

As announced in February 2018, Braftovi + Mektovi reduced the risk of death compared to treatment with vemurafenib 960 mg daily [hazard ratio (HR) of 0.61, [95% CI 0.47, 0.79, p <0.001] in the planned analysis of overall survival (OS) from the COLUMBUS trial. Median OS was 33.6 months for patients treated with the combination, compared to 16.9 months for patients treated with vemurafenib as a monotherapy. These positive results add to the growing body of clinical evidence supporting the BRAF/MEK inhibitor combination therapy and Array and its partners are working to formally submit these results with global regulatory authorities.

Array BioPharma is committed to providing access and reimbursement support to all patients. Array offers a $0 copay for eligible, commercially-insured patients. For more information about treatment of Braftovi in combination with Mektovi, visit www.braftovimektovi.com.

About BRAF-mutant Metastatic Melanoma

Melanoma develops when unrepaired DNA damage to skin cells triggers mutations that may lead them to multiply and form malignant tumors. Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. [1, 2] There are a variety of gene mutations that can lead to metastatic melanoma. The most common genetic mutation in metastatic melanoma is BRAF. There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma. [1, 3, 4, 5]

About Braftovi + Mektovi

Braftovi is an oral small molecule BRAF kinase inhibitor and Mektovi is an oral small molecule MEK inhibitor which target key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma, colorectal cancer, non-small cell lung cancer, thyroid and others. In the U.S., Braftovi + Mektovi are approved for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. Braftovi is not indicated for treatment of patients with wild-type BRAF melanoma.

Array has exclusive rights to Braftovi and Mektovi in the U.S. and Canada. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America.

Braftovi + Mektovi are not approved outside of the U.S. The European Medicines Agency (EMA), as well as the Swiss Medicines Agency (Swissmedic) and the Australian Therapeutic Goods Administration (TGA), are currently reviewing the Marketing Authorization Applications submitted by Pierre Fabre, and Japan's Pharmaceuticals and Medical Devices Agency has accepted the Manufacturing and Marketing Approval applications submitted by Ono Pharmaceutical Co, Ltd.

About COLUMBUS

The COLUMBUS trial (NCT01909453) is a two-part, international, randomized, open label Phase 3 trial evaluating the efficacy and safety of Braftovi (encorafenib) in combination with Mektovi (binimetinib) compared to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation. All secondary efficacy analyses, including overall survival, are descriptive in nature. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the trial.

Indications and Usage

Braftovi (encorafenib) and Mektovi (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.

Limitations of Use: Braftovi is not indicated for the treatment of patients with wild-type BRAF melanoma.

Braftovi + Mektovi Important Safety Information

The information below applies to the safety of the combination of Braftovi and Mektovi unless otherwise noted.

Warnings and Precautions

New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma, including keratoacanthoma, occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Discontinue Braftovi for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: Confirm evidence of BRAFV600E or BRAFV600K mutation prior to initiating Braftovi.

Cardiomyopathy: In the COLUMBUS trial, cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. Cardiomyopathy resolved in 87% of patients. Assess left ventricular ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal.

Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism.

Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients.

Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). Permanently discontinue Mektovi in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis, was reported in 4% of patients. Assess for visual symptoms at each visit. Perform ophthalmic evaluation at regular intervals and for any visual disturbances.

Interstitial Lung Disease (ILD): ILD, including pneumonitis, occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD.

Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT) and 2.6% for aspartate aminotransferase (AST). Monitor liver laboratory tests before and during treatment and as clinically indicated.

Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum creatine phosphokinase (CPK) occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Monitor CPK periodically and as clinically indicated.

QTc Prolongation: In the COLUMBUS trial, an increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation. Correct hypokalemia and hypomagnesemia prior to and during Braftovi administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms.

Embryo-Fetal Toxicity: Braftovi or Mektovi can cause fetal harm when administered to pregnant women. Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking Braftovi + Mektovi.

Adverse Reactions

The most common adverse reactions (≥20%, all Grades, in the COLUMBUS trial) were: fatigue, nausea, diarrhea, vomiting, abdominal pain, arthralgia, myopathy, hyperkeratosis, rash, headache, constipation, visual impairment, serous retinopathy.

In the COLUMBUS Trial, the most common laboratory abnormalities (≥20%, all Grades) included: increased creatinine, increased CPK, increased gamma glutamyl transferase, anemia, increased ALT, hyperglycemia, increased AST, and increased alkaline phosphatase.

Drug interactions

Avoid concomitant use of strong or moderate CYP3A4 inhibitors or inducers and sensitive CYP3A4 substrates with Braftovi. Modify Braftovi dose if concomitant use of strong or moderate CYP3A4 inhibitors cannot be avoided.

Please see full Prescribing Information for Braftovi and full Prescribing Information for Mektovi for additional information. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Array at 1-844-Rx-Array (1-844-792-7729).