BOULDER, Colo., July 27, 2018 /PRNewswire/ -- Array
BioPharma Inc. (NASDAQ: ARRY) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European
Medicines Agency (EMA) adopted a positive opinion recommending approval of BRAFTOVI™ in combination with
MEKTOVI® for the treatment of adult patients with unresectable or metastatic melanoma with a
BRAFV600 mutation. The CHMP recommendation will now be reviewed by the European Commission (EC), which has the
authority to approve medicines for the European Union (EU). The final EC decision, expected by the end of September, will be
applicable to all 28 EU member states, as well as Liechtenstein, Iceland and Norway.
"Following the recent U.S. FDA approval of BRAFTOVI + MEKTOVI for advanced BRAF-mutant melanoma, we are pleased to move
one step closer to European approval," said Ron Squarer, Chief Executive Officer. "We are proud that the combination of BRAFTOVI
+ MEKTOVI represents a new standard of care for BRAF-mutant melanoma patients in critical need of additional treatment
options."
The positive CHMP opinion is based on results from the Phase 3 COLUMBUS trial, which demonstrated that the combination
BRAFTOVI + MEKTOVI achieved a median progression-free survival (mPFS) of nearly 15 months [14.9 months versus vemurafenib
monotherapy at 7.3 months; hazard ratio (HR) 0.54 (95% CI, 0.41–0.71), p<0.0001].
In June 2018, Array also announced updated results from the COLUMBUS trial, which demonstrated that BRAFTOVI + MEKTOVI was the first
targeted therapy to achieve over 30 months overall survival (OS) in a Phase 3 trial and reduced the risk of death compared to
treatment with vemurafenib [HR (0.61), (95% CI 0.47-0.79, p <0.0001]. 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.
The most common grade 3-4 adverse events seen in more than 5% of patients were increased gamma-glutamyltransferase (9%),
increased blood creatine phosphokinase (7%) and hypertension (6%).
In the U.S., BRAFTOVI + MEKTOVI are approved for the treatment of unresectable or metastatic melanoma with a BRAF
V600E or BRAF V600K mutation, as detected by an FDA-approved test. BRAFTOVI is
not indicated for treatment of patients with wild-type BRAF melanoma.
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.
Detailed recommendations for the use of these products will be described in the summary of product characteristics (SmPC),
which will be published in the European public assessment report (EPAR) and made available in all official EU languages after the
marketing authorization has been granted by the EC. Pierre Fabre has exclusive rights to
commercialize both products in Europe, Asia and Latin America.
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. [1-5]
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 BRAF
V600E or BRAF V600K 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, Medison exclusive
rights to commercialize both products in Israel and Pierre Fabre exclusive rights to
commercialize both products in all other countries, including Europe, Asia and Latin America.
BRAFTOVI and MEKTOVI are not approved outside of the United States. The European Medicines
Agency (EMA), the Swiss Medicines Agency (Swissmedic) and the Australian Therapeutic Goods Administration (TGA) are
currently reviewing the Marketing Authorization Applications, and the Pharmaceuticals and Medical Devices Agency (PMDA) in
Japan is currently reviewing the Manufacturing and Marketing Approval Applications for BRAFTOVI and MEKTOVI.
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).
About Array BioPharma
Array BioPharma Inc. is a fully-integrated, biopharmaceutical company focused on the discovery, development and
commercialization of safe and effective targeted small molecule drugs to treat patients afflicted with cancer and other
conditions. Array markets in the United States BRAFTOVITM capsules in combination
with MEKTOVI® tablets for the treatment of patients with unresectable or metastatic melanoma with a BRAF
V600E or BRAF V600K mutation. Array's lead clinical programs, encorafenib and binimetinib, are being
investigated in over 30 clinical trials across a number of solid tumor indications, including a Phase 3 trial in
BRAF-mutant colorectal cancer. Array's pipeline includes several additional advanced programs including selumetinib
(partnered with AstraZeneca), larotrectinib (partnered with Loxo Oncology), ipatasertib (partnered with Genentech), tucatinib
(partnered with Seattle Genetics) and ARRY-797 (being developed by Yarra Therapeutics, a wholly-owned subsidiary of Array), all
of which are currently in registration trials. Ganovo® (danoprevir, partnered with Roche) was recently approved in
China for the treatment of viral hepatitis C. For more information on Array, please visit
www.arraybiopharma.com or follow @arraybiopharma on
Twitter and LinkedIn.
References
[1] Melanoma Skin Cancer. American Cancer Society. Available at: https://www.cancer.org/cancer/melanoma-skin-cancer.html. Accessed January 2018.
[2] A Snapshot of Melanoma. National Cancer Institute. Available at: https://seer.cancer.gov/statfacts/html/melan.html.
Accessed January 2018.
[3] Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed January 2018.
[4] Klein O, et al. Eur J Cancer, 2013.
[5] American Cancer Society. What Causes Melanoma Skin Cancer? 2016. https://www.cancer.org/cancer/melanoma-skin-cancer/causes-risks-prevention/what-causes.html. Accessed April 11, 2018.
[6] BRAFTOVI™ (encorafenib) Prescribing Information. Array BioPharma Inc., June 2018
[7] MEKTOVI® (binimetinib) Prescribing Information. Array BioPharma Inc., June 2018
Array BioPharma Forward-Looking Statement
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform
Act of 1995, including, among others, statements about the future development plans of encorafenib and binimetinib; expectations
that events will occur that will create greater value for Array; and the potential for the results of current and future clinical
trials to support regulatory approval or the marketing success of encorafenib and binimetinib. Because these statements reflect
our current expectations concerning future events and involve significant risks and uncertainties, our actual results could
differ materially from those anticipated in these forward-looking statements as a result of many factors. These factors include,
but are not limited to, the potential that the FDA, EMA or other regulatory agencies determine results from clinical trials are
not sufficient to support registration or marketing approval of encorafenib and binimetinib; our ability to effectively and
timely conduct clinical trials in light of increasing costs and difficulties in locating appropriate trial sites and in enrolling
patients who meet the criteria for certain clinical trials; risks associated with our dependence on third-party service providers
to successfully conduct clinical trials and to manufacture drug substance and product within and outside the U.S.; our ability to
grow and successfully develop commercialization capabilities; our ability to achieve and maintain profitability and maintain
sufficient cash resources; and our ability to attract and retain experienced scientists and management. Additional information
concerning these and other risk factors can be found in our most recent annual report filed on Form 10-K, in our quarterly
reports filed on Form 10-Q, and in other reports filed by Array with the Securities and Exchange Commission. We are providing
this information as of July 27, 2018. We undertake no duty to update any forward-looking statements
to reflect the occurrence of events or circumstances after the date of such statements or of anticipated or unanticipated events
that alter any assumptions underlying such statements.
BRAFTOVI™ is a trademark of Array BioPharma Inc.
MEKTOVI® is a registered trademark of Array BioPharma Inc. in the United States
and various other countries.
CONTACTS:
Investor Relations
Array BioPharma
Andrea N. Flynn, Ph.D.
Senior Director, Investor Relations & Corporate Communications
(303) 381-6600
ir@arraybiopharma.com
Media
Y&R PR
Erika Hackmann, Media Relations
(917) 538-3375
erika.hackmann@yr.com
View original content with multimedia:http://www.prnewswire.com/news-releases/braftovi-encorafenib--mektovi-binimetinib-receives-positive-chmp-opinion-for-advanced-braf-mutant-melanoma-300687771.html
SOURCE Array BioPharma Inc.