BOULDER, Colo., Sept. 20, 2018 /PRNewswire/ -- Array BioPharma
Inc. (NASDAQ: ARRY) today announced that the European Commission
(EC) has approved BRAFTOVI® in combination with
MEKTOVI® for the treatment of adult patients with
unresectable or metastatic melanoma with a
BRAFV600 mutation, as detected by a validated
test. This approval is applicable to all 28 European Union (EU)
member states, as well as Liechtenstein, Iceland and Norway.
"With an even greater number of patients with advanced
BRAF-mutant melanoma in Europe than in the U.S., we are delighted
BRAFTOVI + MEKTOVI will be available to these patients who are in
critical need of additional options that delay disease progression
and improve overall survival," said Ron Squarer, Chief Executive
Officer. "Our European partner, Pierre
Fabre, has a strong legacy in oncology, and with over a
thousand employees dedicated to this therapeutic area, we are very
pleased they have made BRAFTOVI + MEKTOVI a top priority for their
team."
The EC approval is based on results from the Phase 3 COLUMBUS
trial, of which the primary endpoint was median progression-free
survival (mPFS). BRAFTOVI + MEKTOVI achieved an 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].
BRAFTOVI + MEKTOVI is the first targeted treatment to achieve
over 30 months median overall survival (OS). As published in The
Lancet Oncology in September 2018, BRAFTOVI + MEKTOVI reduced
the risk of death compared to 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.
Detailed recommendations for the use of these
products in the EU are described in the summary of product
characteristics (SmPC), which are published in the European public
assessment report (EPAR) and made available in all official EU
languages at http://www.ema.europa.eu.
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, Latin
America and Asia (excluding
Japan and South Korea).
In June 2018, the U.S. Food and Drug Administration (FDA)
approved BRAFTOVI + MEKTOVI 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.
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.
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
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. In
Europe, the combination is
approved for adult patients with unresectable or metastatic
melanoma with a BRAFV600 mutation, as detected by
a validated test.
The Swiss Medicines Agency (Swissmedic) and the Australian
Therapeutic Goods Administration (TGA) are currently reviewing the
Marketing Authorization Applications for BRAFTOVI and MEKTOVI
submitted by Pierre Fabre, and
Japan's Pharmaceuticals and
Medical Devices Agency (PMDA) is currently reviewing 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. The primary
endpoint of the trial was mPFS; all secondary efficacy analyses,
including the prospectively planned analysis overall survival, are
descriptive in nature. Over 200 sites across North America, Europe, South
America, Africa,
Asia and Australia participated in the trial.
BRAFTOVI + MEKTOVI Indications and Usage
BRAFTOVI® (encorafenib) and MEKTOVI®
(binimetinib) are kinase inhibitors indicated for use in
combination for the treatment of adult patients with unresectable
or metastatic melanoma with a BRAFV600E
mutation.
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 BRAFV600Kmutation
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
[6,7]. 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 transformative and well-tolerated targeted small molecule drugs
to treat patients afflicted with cancer and other high-burden
diseases. Array markets in the United
States BRAFTOVI® (encorafenib) capsules in
combination with MEKTOVI® (binimetinib) tablets for the
treatment of patients with unresectable or metastatic melanoma with
a BRAFV600E or BRAFV600K
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 programs being advanced by Array or
current license-holders, 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
[8] European Medicines Agency. BRAFTOVI® (encorafenib)
Summary of Product Characteristics. Available at:
http://www.ema.europa.eu. Publication pending (September 2018).
[9] European Medicines Agency. MEKTOVI® (binimetinib)
Summary of Product Characteristics. Available at:
http://www.ema.europa.eu. Publication pending (September 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 September 20, 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® and MEKTOVI® are registered trademarks 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
212-303-2305
erika.hackmann@yr.com
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