BOULDER, Colo., Sept. 13, 2018 /PRNewswire/ -- Array
BioPharma Inc. (NASDAQ: ARRY) today announced the publication of
detailed overall survival (OS) results from the COLUMBUS trial in
The Lancet Oncology. The pivotal Phase 3 trial evaluated the
efficacy and safety of the combination of BRAFTOVI®+
MEKTOVI® compared to vemurafenib monotherapy in patients
with unresectable or metastatic melanoma with a
BRAFV600E or BRAFV600K
mutation. BRAFTOVI + MEKTOVI reduced the risk of death compared to
treatment with vemurafenib [hazard ratio (HR) of 0.61, (95% CI
0.47-0.79, p <0.0001)] in the planned analysis of OS. 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 analysis of OS and updated efficacy and safety
data extend findings of previously announced results.
Based on data from the previously reported primary analysis of
the COLUMBUS trial, the U.S. Food and Drug
Administration (FDA) approved BRAFTOVI capsules in combination
with MEKTOVI tablets on June 27, 2018 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. Further, on July 16, 2018, Array submitted supplementary
New Drug Applications to seek inclusion of OS data from the
COLUMBUS trial in the BRAFTOVI and MEKTOVI labels.
Mature median progression-free survival (mPFS) for BRAFTOVI +
MEKTOVI was 14.9 months (95% CI 11.0–20.2) compared to vemurafenib
with 7.3 months (5.6–7.9), [HR 0.51, (95% CI 0.39–0.67; two-sided
p<0.0001)].
"The publication of updated findings from the COLUMBUS trial in
The Lancet Oncology underscores the value that BRAFTOVI +
MEKTOVI bring to patients with BRAF-mutant melanoma," said
Keith T. Flaherty, M.D., Director of
the Termeer Center for Targeted Therapy, Massachusetts General
Hospital Cancer Center and Professor of Medicine, Harvard Medical School. "Based on the observed
efficacy and tolerability, this targeted combination is an
important new treatment option for patients with this
life-threatening form of melanoma."
Use of post-trial immunotherapy was limited and consistent with
other published pivotal trials of BRAF + MEK inhibitors in advanced
BRAF-mutant melanoma. The manuscript also noted that the
performance of vemurafenib, the control arm, was consistent across
efficacy endpoints with its performance in other trials of BRAF +
MEK inhibitor combinations where it also served as a control.
Finally, the authors conclude the data represent a new benchmark
for BRAF + MEK inhibitors in metastatic or unresectable
BRAF-mutant melanoma.
With 18 months of additional follow-up relative to the initial
publication of COLUMBUS results, the safety profile of the
combination remained generally consistent with the prior report.
Observed grade 3 or 4 adverse events in more than 5% of patients
with BRAFTOVI + MEKTOVI were increased gamma-glutamyltransferase
(9%), increased blood creatine phosphokinase (7%) and hypertension
(6%). Additional safety information can be found in the manuscript
and in the Important Safety Information below.
For more information about treatment of BRAFTOVI in combination
with MEKTOVI, visit www.braftovimektovi.com.
The full prescribing information for BRAFTOVI can be found
here:
http://www.arraybiopharma.com/documents/Braftovi_Prescribing_information.pdf
The full prescribing information for MEKTOVI can be found
here:
http://www.arraybiopharma.com/documents/Mektovi_Prescribing_information.pdf
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
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 Co,
Ltd. 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 (excluding Japan and South
Korea) and Latin America.
BRAFTOVI and MEKTOVI are not approved outside of the
U.S. The European Medicines Agency (EMA), 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 (PMDA) is currently reviewing the Manufacturing and
Marketing Approval Applications for 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 of overall survival,
are descriptive in nature. Over 200 sites across North America, Europe, South
America, 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 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
[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
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 13, 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 registered trademark of Array
BioPharma Inc. in the United
States and various other countries.
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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