BOULDER, Colo., June 25, 2019 /PRNewswire/ -- Array
BioPharma Inc. (Nasdaq: ARRY) announced that it will present
updated data from the combination of BRAFTOVI®
(encorafenib), a BRAF inhibitor,
MEKTOVI® (binimetinib), a MEK inhibitor, and
ERBITUX® (cetuximab), an anti-EGFR antibody
(BRAFTOVI Triplet), in patients with advanced
BRAFV600E-mutant metastatic colorectal cancer
(mCRC), following one or two lines of therapy. These data will be
presented in an oral presentation on Saturday, July 6, at the ESMO 21st
World Congress on Gastrointestinal Cancer in Barcelona, Spain.
Oral Presentation:
Title:
|
BEACON CRC: A
Randomized, 3-Arm, Phase 3 Study of Encorafenib and Cetuximab With
or Without Binimetinib vs. the Choice of Either Irinotecan or
FOLFIRI plus Cetuximab in BRAFV600E-Mutant
Metastatic Colorectal Cancer
|
Presenter:
|
Scott Kopetz, M.D.,
Ph.D., FACP, Associate Professor, Department of
Gastrointestinal Medical Oncology, Division of Cancer
Medicine at The University of Texas MD Anderson Cancer
Center
|
Abstract:
|
LBA-006
|
Session:
|
Session XX:
Colorectal Cancer (Part I)
|
Date:
|
Saturday July 6,
2019
|
Session
Time:
|
9:20 AM – 10:05 AM
CEST (3:20 AM – 4:05 AM ET)
|
Location:
|
Auditorium A, Level
0
|
Following the presentation, the slides will be available as a
PDF on Array's website at www.arraybiopharma.com.
About Colorectal Cancer
Worldwide, colorectal cancer is the third most common type of
cancer in men and the second most common in women, with
approximately 1.8 million new diagnoses in 2018. [1,2] In the
U.S. alone, an estimated 140,250 patients were diagnosed with
cancer of the colon or rectum in 2018, and approximately 50,000 are
estimated to die of their disease each year.
[3] BRAF mutations are estimated to occur in up to
15% of patients with mCRC and represent a poor prognosis for these
patients. [4-8] The V600 mutation is the most
common BRAF mutation and the risk of mortality in
CRC patients with
the BRAFV600E mutation is more than two
times higher than for those with wild-type BRAF. [7,9]
Several irinotecan and cetuximab-containing regimens, similar to
the BEACON CRC control arm, have established observed historical
published benchmarks in BRAFV600E-mutant
mCRC patients, whose disease has progressed after one or two prior
lines of therapy. Previous benchmarks include median OS
of 5.9 months, median PFS of 2.0 months, and
ORR of 4%. [4-6,10-15] BRAFV600E-mutant
mCRC is an area of high unmet need as there are currently
no FDA-approved therapies specifically indicated for
patients with BRAF-mutant mCRC, and these patients
derive limited benefit from available chemotherapy regimens.
[16-18] For more information
about BRAFV600E-mutant mCRC
visit www.brafmcrc.com.
About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating
the efficacy and safety of BRAFTOVI, MEKTOVI and ERBITUX in
patients with BRAFV600E-mutant mCRC whose
disease has progressed after one or two prior regimens. BEACON CRC
is the first and only Phase 3 trial designed to test a BRAF/MEK
combo targeted therapy in BRAFV600E-mutant
mCRC. Thirty patients were treated in the safety lead-in and
received the triplet combination (BRAFTOVI 300 mg daily, MEKTOVI 45
mg twice daily and ERBITUX per label). Of the 30 patients, 29 had
a BRAFV600 mutation.
Microsatellite instability high, resulting from defective DNA
mismatch repair, was detected in only 1 patient. As previously
announced, the triplet combination demonstrated good tolerability,
supporting initiation of the randomized portion of the trial. The
randomized portion of the BEACON CRC trial is designed to assess
the efficacy of BRAFTOVI in combination with ERBITUX with or
without MEKTOVI compared to ERBITUX and irinotecan-based therapy.
665 patients were randomized 1:1:1 to receive the triplet
combination, the doublet combination (BRAFTOVI and ERBITUX) or the
control arm (irinotecan-based therapy and ERBITUX). The study has
been amended to include an interim analysis of endpoints including
ORR. The primary overall survival endpoint is a comparison of the
triplet combination to the control arm. Secondary endpoints address
efficacy of the doublet combination compared to the control arm,
and the triplet combination compared to the doublet therapy. Other
secondary endpoints include PFS, duration of response, safety and
tolerability. Health related quality of life data will also be
assessed. The trial is being conducted at over 200 investigational
sites in North America, South
America, Europe and the Asia Pacific region.
The BEACON CRC trial is being conducted with support from Ono
Pharmaceutical Co. Ltd., Pierre Fabre and Merck
KGaA, Darmstadt, Germany (support is for sites outside
of North America).
The triplet combination of BRAFTOVI, MEKTOVI and ERBITUX for the
treatment of patients with BRAFV600E-mutant
mCRC is investigational and not approved by the FDA.
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 V600Kmutation
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. [19-20] 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] Global Cancer Facts & Figures 3rd Edition. American
Cancer Society. Available
at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/global-cancer-facts-and-figures/global-cancer-facts-and-figures-3rd-edition.pdf. Accessed January
2018.
[2] Bray, et al. CA Cancer J
Clin. 2018.
[3] Cancer Facts & Figures 2018. American Cancer
Society. Available
at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf.
Accessed January 2018.
[4] Saridaki, et al., PLoS One. 2013.
[5] Loupakis, et al., Br J Cancer. 2009.
[6] Corcoran, et al., Cancer Discovery. 2012
[7] Sorbye, et al., PLoS One. 2015.
[8] Vecchione, et al., Cell. 2016.
[9] Safaee, et al. PLoS One. 2012.
[10] Clinicaltrials.gov. US National Library of Medicine. S1406
phase II study of irinotecan and cetuximab with or without
vemurafenib in BRAF mutant metastatic colorectal cancer.
https://clinicaltrials.gov/ct2/show/results/NCT02164916. Accessed
December 14, 2018.
[11] Kopetz, et al., ASCO 2017.
[12] De Roock, et al., Lancet Oncol. 2010.
[13] Ulivi, et al., J Transl Med. 2012.
[14] Peeters, et al., ASCO 2014.
[15] Seymour, et al., Lancet Oncol. 2013
(supplementary appendix).
[16] Referenced with permission from the NCCN Clinical
Practice Guidelines in Oncology (NCCN Guidelines®) for
Colon Cancer. V.2.2019.
[17] Van Cutsem, et al., Annals of
Oncology. 2016.
[18] Ursem, et al., Gastrointest Cancer,
2018.
[19] BRAFTOVI® (encorafenib) Prescribing
Information. Array BioPharma Inc., June 2018
[20] MEKTOVI® (binimetinib) Prescribing
Information. Array BioPharma Inc., June 2018
® National Comprehensive Cancer Network,
Inc. 2019. To view the most recent and complete version of the
guideline, go online to NCCN.org.
NCCN makes no warranties of any kind whatsoever regarding
their content, use or application and disclaims any responsibility
for their application or use in any way.
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 as part of an accelerated or regular review
process of the triplet combination of encorafenib, binimetinib and
cetuximab; 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 June 25, 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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