BOULDER, Colo., July 6, 2019 /PRNewswire/ -- Array BioPharma Inc.
(Nasdaq: ARRY) today announced the presentation of results from the
Phase 3 BEACON CRC trial evaluating 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. Data presented
included primary and secondary endpoints, waterfall plots
describing tumor reduction, subgroup analyses, and exploratory
analyses comparing overall survival (OS) of the BRAFTOVI Triplet
and BRAFTOVI Doublet (BRAFTOVI and cetuximab) in a subset of
patients with mature follow-up, including the first 331 randomized
patients, as well as safety and tolerability.
Results showed that BRAF-mutant mCRC patients treated
with the BRAFTOVI Triplet combination demonstrated a statistically
significant improvement in OS (9.0 months vs. 5.4 months, [HR 0.52,
(95% CI 0.39-0.70), p<0.0001]) and objective response rate (ORR)
(26.1% vs. 1.9%, p<0.0001, as assessed by Blinded Independent
Central Review (BICR)) compared to cetuximab plus
irinotecan-containing regimens (Control). Median progression-free
survival (mPFS) for patients treated with the BRAFTOVI Triplet was
4.3 months [HR 0.38, (95% CI 0.29, 0.49), p<0.0001] compared to
1.5 months observed with the Control arm.
These data were presented in an oral presentation on Saturday,
July 6, at the ESMO 21st World Congress on
Gastrointestinal Cancer in Barcelona, Spain.
"It's exciting to see the interim analysis results from the
potentially practice-changing BEACON CRC trial, which demonstrated
a significant improvement in outcomes compared to available
standard of care options for patients with
BRAFV600E-mutant metastatic colorectal cancer,"
said 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.
"These data add to the body of evidence supporting the BRAFTOVI
Triplet as a potential new standard of care regimen for this
patient population, who currently have limited treatment options
available."
The interim analysis also showed an improvement in secondary
efficacy endpoints. Patients treated with the BRAFTOVI Doublet
demonstrated a statistically significant improvement in OS (median
8.4 months vs. 5.4 months, [HR 0.60, 95% CI (0.45-0.79), p=0.0003])
and ORR (20.4% vs. 1.9%, p<0.0001, per BICR) compared to
Control. Further, mPFS for patients treated with the BRAFTOVI
Doublet was 4.2 months [HR 0.40, 95% (CI 0.31-0.52), p<0.0001]
versus 1.5 months with Control.
A descriptive comparison of the BRAFTOVI Triplet to the BRAFTOVI
Doublet demonstrated a positive trend across endpoints including
ORR and OS [HR 0.79, 95% CI (0.59-1.06)].
The control arm of the BEACON CRC trial was consistent with past
reported studies and historical data across efficacy endpoints,
underscoring that patients with BRAF-mutant mCRC generally
have a poor prognosis with current available treatments. Currently
there are no FDA-approved therapies specifically indicated for this
high unmet need population. [1-13] BRAF mutations are
estimated to occur in up to 15% of patients with mCRC and V600E is
the most common mutation. [1-3,12-14]
The BRAFTOVI Triplet and Doublet were generally well-tolerated
with no unexpected toxicities. The safety profiles of the BRAFTOVI
Triplet and Doublet were consistent with prior reported experience
with each regimen and with effects of MEK, RAF and EGFR therapies.
Grade 3 or higher adverse events were seen in 58%, 50% and 61% of
patients in the BRAFTOVI Triplet, Doublet and Control arms
respectively. Discontinuation of therapy due to adverse events was
seen in 7%, 8% and 11% of patients in the Triplet, Doublet and
Control arms respectively.
On May 21, 2019, Array announced initial results from the
interim analysis of the Phase 3 BEACON mCRC trial, which showed
statistically significant improvement in OS and ORR with the
BRAFTOVI Triplet compared to Control, reducing the risk of death by
48%.
Array intends to submit the results of the BEACON CRC trial for
marketing approval in the second half of 2019.
In March 2019, the National Comprehensive Cancer Network®
(NCCN®) updated their Clinical Practice Guidelines in Oncology for
Colon and Rectal Cancer to include BRAFTOVI in combination with
MEKTOVI and an anti-EGFR antibody as a Category 2A treatment for
patients with BRAFV600E-mutant mCRC, after
failure of one or two prior lines of therapy for metastatic
disease. The NCCN based their recommendation on data from the
safety lead-in of the BEACON CRC trial.
The use of BRAFTOVI, MEKTOVI and ERBITUX for the treatment
of patients with BRAFV600E-mutant mCRC is
investigational and not approved by the FDA.
A PDF of the ESMO World Congress on Gastrointestinal Cancer
presentation will be available on Array's website
at https://www.arraybiopharma.com/our-science/publications.
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. [15,16] 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. [17] BRAF mutations are estimated to occur
in up to 15% of patients with mCRC and represent a poor prognosis
for these patients. [1-3,12-14] 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.
[12,13] 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.
Benchmarks from a recent prospective Phase 2 study in a
similar population include median OS of 5.9 months,
median PFS of 2.0 months, and ORR of 4%.
[4] 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. [9-11] 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 was 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).
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. BRAFTOVI + MEKTOVI have received
regulatory approval in Australia
and the Swiss Medicines Agency (Swissmedic) is currently reviewing
the Marketing Authorization Applications for BRAFTOVI and MEKTOVI
submitted by Pierre Fabre.
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).
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. [18-19] 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] Saridaki, et al., PLoS One. 2013.
[2] Loupakis, et al., Br J Cancer. 2009.
[3] Corcoran, et al., Cancer Discovery. 2012.
[4] Kopetz, et al., ASCO 2017.
[5] De Roock, et al., Lancet Oncol. 2010.
[6] Ulivi, et al., J Transl Med. 2012.
[7] Peeters, et al., ASCO 2014.
[8] Seymour, et al., Lancet Oncol. 2013 (supplementary
appendix).
[9] Referenced with permission from the NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines®) for Colon
Cancer. V.2.2019.
[10] Van Cutsem, et al., Annals of Oncology. 2016.
[11] Ursem, et al., Gastrointest Cancer. 2018.
[12] Sorbye, et al., PLoS One. 2015.
[13] Safaee, et al. PLoS One. 2012.
[14] Vecchione, et al., Cell. 2016.
[15] 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.
[16] Bray, et al. CA Cancer J
Clin. 2018.
[17] 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.
[18] BRAFTOVI® (encorafenib) Prescribing Information. Array
BioPharma Inc., June 2018.
[19] 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 July 6, 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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