BOULDER, Colo., Jan. 14, 2019 /PRNewswire/ -- Array BioPharma
Inc. (Nasdaq: ARRY) today announced updated safety and efficacy
results, including mature overall survival (OS), from the safety
lead-in of the Phase 3 BEACON CRC trial evaluating the triplet
combination of BRAFTOVI® (encorafenib), a BRAF
inhibitor, MEKTOVI® (binimetinib), a MEK
inhibitor and ERBITUX® (cetuximab), an anti-EGFR
antibody, in patients with BRAFV600E-mutant
metastatic colorectal cancer (mCRC). The results showed that mature
median OS was 15.3 months (95% CI, 9.6–not reached) for patients
treated with the triplet. These data will be presented on
Saturday, January 19 at the ASCO 2019
Gastrointestinal Cancers Symposium in San
Francisco, California.
Updated median progression-free survival (mPFS) and updated
confirmed overall response rate (ORR) results for patients treated
with the triplet in the safety lead-in remain the same, as
previously reported, with 8 months mPFS (95% CI, 5.6-9.3) and
a 48% ORR (95% CI, 29.4–67.5). Among the 17 patients who received
only one prior line of therapy, the ORR was 62%.
A BRAF mutation is present in up to 15% of all patients
with mCRC and V600 is the most common BRAF
mutation. [1-5] BRAFV600E-mutant mCRC
patients have a mortality risk more than double that of mCRC
patients without the mutation, and currently there are no U.S. Food
and Drug Administration (FDA)-approved therapies specifically
indicated for this high unmet need population. [3-10]
"The mature median overall survival of 15.3 months demonstrated
in the safety lead-in of the BEACON CRC trial is unprecedented in
this patient population and, for context, represents a substantial
improvement compared to the observed historical published
benchmarks of approximately 4 to 6 months for median overall
survival with current standards of care in patients with
BRAF-mutant mCRC," said Axel
Grothey, M.D., BEACON CRC trial lead investigator and
Co-Chair of the National Cancer Institute's Gastrointestinal Cancer
Steering Committee, West Cancer Center, Memphis, TN. "These updated data further
underscore the potential of this triplet for patients with
BRAF-mutant mCRC who are in desperate need of effective new
treatment options."
The triplet combination was generally well-tolerated with no
unexpected toxicities. The most common grade 3 or 4 adverse events
seen in at least 10% of patients were fatigue (13%), anemia (10%),
increased creatine phosphokinase (10%), increased aspartate
aminotransferase (10%) and urinary tract infections (10%). The rate
of grade 3 or 4 skin toxicities continued to be lower than
generally observed with ERBITUX in mCRC.
"We are delighted with the updated results from the BEACON CRC
safety lead-in. Following consultations with the FDA and European
Medicines Agency, we initiated an amendment to the BEACON CRC
protocol to allow for an interim analysis based primarily on
confirmed ORR and durability of response endpoints, which we
believe could support an accelerated approval with positive
results," said Victor Sandor, M.D.,
Chief Medical Officer, Array BioPharma. "We anticipate topline
results from this interim analysis in the first half of this year.
This timing allows for the subset of patients required for the
interim analysis of ORR to achieve a response and for the
durability of responses to be appropriately evaluated."
On August 7, 2018, Array
announced that the FDA granted Breakthrough Therapy
Designation to BRAFTOVI, in combination with MEKTOVI and ERBITUX
for the treatment of patients with
BRAFV600E-mutant mCRC as detected by an
FDA-approved test, after failure of one to two prior lines of
therapy for metastatic disease.
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.
BEACON CRC Safety
Lead-In Data
|
|
Title:
|
Abstract #688:
Updated results of the BEACON CRC safety lead-in: Encorafenib
(ENCO) + binimetinib (BINI) + cetuximab (CETUX) for
BRAFV600E-mutant metastatic colorectal cancer
(mCRC)
|
Presenter:
|
Scott Kopetz, M.D.,
Department of Gastrointestinal Medical Oncology, Division of Cancer
Medicine, The University of Texas MD Anderson Cancer
Center
|
Date:
|
Saturday, January 19, 2019
|
Times:
|
7:00 - 7:55 a.m. and
12:15 - 1:45 p.m. Pacific Time
|
Location:
|
Poster N13; Moscone
West Building
|
Following the presentation, the slides will be available as a
PDF on the Publications section of the Array website.
Array will host an investor webcast presentation of the BEACON
CRC safety lead-in data.
Investor
Webcast:
|
|
Presenter:
|
Axel Grothey, M.D.,
BEACON CRC trial lead investigator and Co-Chair of the National
Cancer Institute's Gastrointestinal Cancer Steering Committee, West
Cancer Center, Memphis, TN
|
Date:
|
Tuesday, January
15
|
Time:
|
9:00 a.m. Eastern
Time
|
Toll-Free:
|
(844)
464-3927
|
Toll:
|
(765)
507-2598
|
Pass
Code:
|
6774596
|
Webcast, including replay and conference call
slides: https://edge.media-server.com/m6/p/y85tt94b
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 1.4 million new diagnoses in 2012. Globally in 2012,
approximately 694,000 deaths were attributed to colorectal cancer.
[11] In the U.S. alone, an estimated 140,250 patients will be
diagnosed with cancer of the colon or rectum in 2018, and
approximately 50,000 are estimated to die of their disease. [12]
BRAF mutations are estimated to occur in up to 15% of
patients with mCRC and represent a poor prognosis for these
patients. [1-5] 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.
[1,10,13] 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.
These benchmarks include ORR of 4% to 8%, mPFS of 2 to 3 months and
median OS of 4 to 6 months. [3-9,14] BRAF
V600E-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. [15-17] 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. MSI-H, 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. Approximately 615 patients are expected
to be randomized 1:1:1 to receive triplet combination, 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., 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.
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,
Latin American and Asia (excluding
Japan and South Korea).
BRAFTOVI + MEKTOVI have received regulatory approval in
the United States, European Union,
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.
[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 Loxo Oncology), ipatasertib (partnered
with Genentech), tucatinib (partnered with Seattle Genetics) and
ARRY-797. Vitrakvi® (larotrectinib, partnered with
Loxo Oncology) 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] Sorbye, et al., PLoS One. 2015.
[2] Vecchione, et al., Cell. 2016.
[3] Saridaki, et al., PLoS One. 2013.
[4] Loupakis, et al., Br J Cancer. 2009.
[5] Corcoran, et al., Cancer
Discovery. 2012
[6] Kopetz, et al., ASCO 2017.
[7] De Roock, et al., Lancet Oncol. 2010.
[8] Ulivi, et al., J Transl Med. 2012.
[9] Peeters, et al., ASCO 2014.
[10] Ardekani, et al., PLoS One. 2012.
[11] 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.
[12] 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.
[13] Safaee, et al., PLoS One. 2012.
[14] Seymour, et al., Lancet Oncol. 2013 (supplementary
appendix).
[15] NCCN Clinical Practice Guidelines in Oncology for Colon
Cancer. Version 4.2018. National Comprehensive Cancer
Network.
[16] Van Cutsem, et al., Annals of Oncology. 2016.
[17] Ursem, et al., Gastrointest Cancer, 2018.
[18] BRAFTOVI® (encorafenib) Prescribing Information.
Array BioPharma Inc., June 2018.
[19] 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, 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 January 14, 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. Vitrakvi® is a registered trademark of
Bayer AG. All trademarks are properties of their respective
owners.
Statements attributed to Dr. Grothey are his alone and do not
reflect the opinion of the National Cancer Institute.
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
212-303-2305
erika.hackmann@yr.com
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