BOULDER, Colo., March 18, 2019 /PRNewswire/ -- Array
BioPharma Inc. (NASDAQ: ARRY) today announced that the National
Comprehensive Cancer Network®
(NCCN®) has 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 metastatic
colorectal cancer (mCRC), after failure of one or two prior lines
of therapy for metastatic disease. The BRAFV600E
mutation is associated with a poor prognosis compared to patients
with CRC who do not carry the BRAF mutation, and currently
there are no FDA-approved therapies specifically for this high
unmet need population. [1-5]
"With no current FDA-approved therapies for BRAF CRC,
this combination represents an important treatment option for this
patient population," 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. "Historical published benchmarks in
BRAFV600E-mutant mCRC patients, whose disease has
progressed after one or two prior lines of therapy, are an overall
response generally between 4% to 8%, a median progression-free
survival of 2 to 3 months and median overall survival of 4 to 6
months. The NCCN recommendation underscores the potential for this
triplet combination to benefit these patients in critical
need."
The NCCN based their recommendation on data from the safety
lead-in of the BEACON CRC trial evaluating the triplet combination
of BRAFTOVI in combination with MEKTOVI and
ERBITUX® (cetuximab), in 29 patients with
BRAFV600E-mutant mCRC. As presented at the
ASCO 2019 Gastrointestinal Cancers Symposium (ASCO GI), confirmed
overall response rate (ORR) and median progression-free survival
(mPFS) results for patients treated with the triplet in the safety
lead-in demonstrated 48% ORR (95% CI, 29.4–67.5) and 8 months mPFS
(95% CI, 5.6-9.3). ORR by central assessment, 41% (95% CI 24%–61%),
was consistent with local assessment. Mature median overall
survival (OS) was 15.3 months (95% CI, 9.6–not reached) for
patients with BRAF-mutant mCRC treated with the triplet.
"Patients with BRAFV600E-mutant mCRC are in
great need of effective treatment options," said Ron Squarer,
Chief Executive Officer. "Based on data from the safety lead-in
portion of the BEACON CRC Phase 3 trial, the FDA granted
Breakthrough Therapy Designation in August
2018 for BRAFTOVI, in combination with MEKTOVI and cetuximab
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. We look forward to the interim
analysis of the randomized portion of the trial in the first half
of this year."
As presented at ASCO GI, 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 was
lower than generally observed with ERBITUX in mCRC.
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. [6] 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. [7] BRAF mutations are estimated to
occur in up to 15% of patients with mCRC and represent a poor
prognosis for these patients. [4,8-11] 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. [4-5]
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. [9-16]
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. [1-3] 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. 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. 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 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. [17-18]
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] NCCN Clinical Practice Guidelines
in Oncology for Colon Cancer. Version 3.2018. National
Comprehensive Cancer Network.
[2] Van Cutsem, et al., Annals of Oncology. 2016.
[3] Ursem, et al., Gastrointest Cancer, 2018.
[4] Sorbye, et al., PLoS One. 2015.
[5] Safaee, et al. PLoS One. 2012.
[6] 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.
[7] 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.
[8] Vecchione, et al., Cell. 2016.
[9] Saridaki, et al., PLoS One. 2013.
[10] Loupakis, et al., Br J Cancer.
2009.
[11] Corcoran, et al., Cancer Discovery. 2012
[12] Kopetz, et al., ASCO 2017.
[13] De Roock, et al., Lancet Oncol. 2010.
[14] Ulivi, et al., J Transl Med. 2012.
[15] Peeters, et al., ASCO 2014.
[16] Seymour, et al., Lancet Oncol. 2013 (supplementary
appendix).
[17] BRAFTOVI® (encorafenib) Prescribing
Information. Array BioPharma Inc., June
2018
[18] 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 March 18, 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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