BOULDER, Colo., May 29, 2019 /PRNewswire/ -- Array BioPharma
Inc. (Nasdaq: ARRY) announced that that it will present data from
the Phase 3 COLUMBUS Trial of BRAFTOVI + MEKTOVI in advanced
BRAF-mutant melanoma in an oral poster discussion on
June 3, 2019, at the 55th
Annual Meeting of the American Society of Clinical Oncology (ASCO)
in Chicago, Illinois. Landmark
overall survival (OS) and progression-free survival (PFS), as well
as subgroup analyses and updated safety and tolerability, will be
presented.
"We are pleased to report a 4-year landmark analysis of the
long-term benefit of BRAFTOVI + MEKTOVI from the COLUMBUS
trial," said Ron Squarer, Chief Executive Officer. "Both the
overall survival and progression-free survival data remain
consistent with prior reports and continue to represent new
benchmarks for BRAF + MEK inhibitor combinations in the treatment
of BRAFV600-mutant advanced melanoma. We remain
steadfastly committed to developing products that treat cancers in
dire need of effective therapies."
Across arms, median follow-up for OS was 48.6 months, with a
median OS of 33.6 months (95% CI, 24.4–39.2) for BRAFTOVI, 450 mg
daily + MEKTOVI, 45 mg twice daily, compared to 16.9 months (95%
CI, 14.0–24.5) for vemurafenib, consistent with prior readouts.
Compared to vemurafenib, BRAFTOVI, 450 mg daily + MEKTOVI, 45 mg
twice daily, decreased the risk of death by 39% (HR, 0.61 [95% CI,
0.48–0.79]).
Updated median progression-free survival (PFS) also remained
consistent and was 14.9 months (95% CI, 11.0–20.2) with BRAFTOVI,
450 mg daily + MEKTOVI, 45 mg twice daily, compared to 7.3 months
(95% CI, 5.6–8.2) with vemurafenib (HR, 0.52 [95% CI,
0.40–0.67]).
Poster Discussion
Title:
|
Update on Overall
Survival in COLUMBUS: A Randomized Phase 3 Trial
of Encorafenib (ENCO) Plus Binimetinib (BINI) versus
Vemurafenib (VEM) or ENCO in Patients with BRAF V600–Mutant
Melanoma
|
Presenter:
|
Paolo Ascierto, M.D.,
Director, Unit of Melanoma, Cancer Immunotherapy and Innovative
Therapy at the National Tumor Institute Fondazione G. Pascale,
Naples, Italy.
|
Abstract:
|
Abstract
#9512
|
Session:
|
Melanoma/Skin
Cancers
|
Date:
|
Monday, June 3,
2019
|
Poster
session:
|
1:15 – 4:15 PM
Central Time
|
Poster
discussion:
|
4:30 PM – 6:00 PM
Central Time
|
Location:
|
Hall A
|
The abstracts can be accessed through
the ASCO website, http://abstract.asco.org/.
Following the poster presentation on Monday, June 3, 2019, the
poster will be available as a PDF on Array's website
at www.arraybiopharma.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. [1-5]
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.
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. In Japan, the
combination is approved for unresectable melanoma with
a BRAF mutation.
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, Latin American
and Asia (excluding Japan and South
Korea).
BRAFTOVI + MEKTOVI have received regulatory approval in the
United States, European
Union, Australia and Japan. The Swiss Medicines
Agency (Swissmedic) is currently reviewing the Marketing
Authorization Applications for BRAFTOVI and MEKTOVI submitted
by Pierre Fabre.
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. See
full Prescribing Information for BRAFTOVI and for MEKTOVI for dose
modifications for adverse reactions.
Warnings and Precautions
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. Manage suspicious skin lesions with excision and
dermatopathologic evaluation. Dose modification is not recommended
for new primary cutaneous malignancies. Based on its mechanism of
action, BRAFTOVI may promote malignancies associated with
activation of RAS through mutation or other mechanisms. Monitor
patients receiving BRAFTOVI for signs and symptoms of non-cutaneous
malignancies. Discontinue BRAFTOVI for RAS mutation-positive
non-cutaneous malignancies.
Tumor Promotion in BRAF Wild-Type Tumors: Confirm
evidence of BRAFV600E or V600K mutation
prior to initiating BRAFTOVI.
Cardiomyopathy, manifesting as left ventricular
dysfunction associated with symptomatic or asymptomatic decreases
in ejection fraction, has been reported in patients. 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. 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.
Patients with cardiovascular risk factors should be monitored
closely.
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.
The most frequent hemorrhagic events were gastrointestinal,
including rectal hemorrhage (4.2%), hematochezia (3.1%), and
hemorrhoidal hemorrhage (1%).
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. RVO is a known
class-related adverse reaction of MEK inhibitors and may occur in
patients treated with MEKTOVI in combination with encorafenib. In
patients with BRAF mutation-positive melanoma across
multiple clinical trials, 0.1% of patients experienced retinal vein
occlusion (RVO). The safety of MEKTOVI has not been established in
patients with a history of RVO or current risk factors for RVO
including uncontrolled glaucoma or a history of hyperviscosity or
hypercoagulability syndromes. Perform ophthalmological evaluation
for patient-reported acute vision loss or other visual disturbance
within 24 hours. 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 ophthalmological evaluation at
regular intervals and for any visual disturbances, and to follow
new or persistent ophthalmologic findings.
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), and 0.5% for alkaline phosphatase. 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 and creatinine levels prior to
initiating MEKTOVI, periodically during treatment, and as
clinically indicated.
QTc Prolongation: BRAFTOVI is associated with
dose-dependent QTc interval prolongation in some patients. 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. BRAFTOVI can render
hormonal contraceptives ineffective. Non-hormonal 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. Avoid
co-administration of BRAFTOVI with medicinal products with a known
potential to prolong QT/QTc interval.
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
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
in the United States and with
partners in other major worldwide markets. 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 metastatic
colorectal cancer. Array's pipeline includes several additional
programs being advanced by Array or current license-holders,
including the following programs currently in registration trials:
selumetinib (partnered with AstraZeneca), LOXO-292 (partnered with
Eli Lilly), ipatasertib (partnered with Genentech), tucatinib
(partnered with Seattle Genetics) and ARRY-797.
Vitrakvi® (larotrectinib, partnered with Bayer AG) is
approved in the United States and
Ganovo® (danoprevir, partnered with Roche) is approved
in China. For more information on
Array, please visit www.arraybiopharma.com or follow
@arraybiopharma on Twitter and LinkedIn.
References
[1] A Snapshot of Melanoma. National Cancer
Institute. Available
at: https://seer.cancer.gov/statfacts/html/melan.html.
Accessed January 2018.
[2] Melanoma Skin Cancer. American Cancer Society. Available
at: https://www.cancer.org/cancer/melanoma-skin-cancer.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
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, 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 May 29, 2019. 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.
Erbitux® is a registered trademark of Eli Lilly and
Company. Vitrakvi® is a registered trademark of Bayer
AG. All trademarks are properties of their respective owners.
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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