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 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.
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 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, 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 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. 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 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 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
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