BOULDER, Colo., Aug. 7, 2018 /PRNewswire/ -- Array BioPharma
Inc. (NASDAQ: ARRY) today announced it has received Breakthrough
Therapy Designation from the U.S. Food and Drug Administration
(FDA) for encorafenib (BRAFTOVI™), in combination with binimetinib
(MEKTOVI®) and cetuximab for the treatment of patients
with BRAFV600E-mutant metastatic colorectal
cancer (mCRC) as detected by an FDA-approved test, after failure of
one to two prior lines of therapy for metastatic disease.
BRAFV600E-mutant mCRC patients have a mortality
risk more than double that of mCRC patients without the mutation,
and currently there are no therapies specifically approved for this
high unmet need population. [1-6]
Breakthrough Therapy Designation is an FDA process designed to
expedite the development and review of drugs that are intended to
treat a serious condition where preliminary clinical evidence
indicates that they may demonstrate substantial improvement over
existing therapies on one or more clinically significant
endpoints.
"We are delighted that the FDA has recognized the potential of
this combination for patients with
BRAFV600E-mutant metastatic colorectal cancer,"
said Victor Sandor, M.D., Chief
Medical Officer. "As there are no regimens approved specifically
for BRAFV600E-mutant mCRC, this designation
provides us with the opportunity to work closely with the FDA to
potentially accelerate our effort to bring an important treatment
option to these patients in critical need."
As presented at the ESMO 20th World Congress on
Gastrointestinal Cancer in June 2018,
the results from the safety lead-in of the ongoing randomized Phase
3 BEACON CRC trial showed that, at the time of analysis, the
overall survival (OS) data were fully mature through 12.6 months
and that the median OS had not yet been reached.
- One-year overall survival rate for this cohort was 62%.
- Median progression-free survival (mPFS) for patients treated
with the triplet was 8 months [95% CI 5.6-9.3] and is similar
between patients receiving one prior line of therapy and patients
receiving two prior lines of therapy.
- Confirmed overall response rate (ORR) was 48% and among the 17
patients who received only one prior line of therapy the ORR was
62%.
- 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 blood creatine kinase (10%) and increased aspartate
aminotransferase (10%).
The triplet combination of BRAFTOVI, MEKTOVI and cetuximab for
the treatment of patients with BRAFV600E-mutant
metastatic colorectal cancer is investigational and not approved by
the FDA.
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. [7] 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. [8] In the U.S., BRAF mutations are
estimated to occur in 10% to 15% of patients with colorectal cancer
and represent a poor prognosis for these patients. [5,6,9,10] The
risk of mortality in CRC patients with the
BRAFV600E mutation is more than two times higher
than for those with wild-type BRAF. [11] Several irinotecan
plus cetuximab-containing regimens, similar to the BEACON CRC
control arm, have established clinical activity benchmarks in
BRAFV600E-mutant mCRC patients, whose disease has
progressed after one or two prior lines of therapy, between 4% to
8% ORR, 1.8 and 2.5 months mPFS and 4 and 6 months mOS.
[1-6,12]
About BEACON CRC
BEACON CRC is a randomized,
open-label, global trial evaluating the efficacy and safety of
BRAFTOVI, MEKTOVI and cetuximab 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
cetuximab per label). Of the 30 patients, 29 had a
BRAFV600E 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 cetuximab with
or without MEKTOVI compared to cetuximab and irinotecan-based
therapy. Approximately 615 patients are expected to be randomized
1:1:1 to receive triplet combination, doublet combination (BRAFTOVI
and cetuximab) or the control arm (irinotecan-based therapy and
cetuximab). The primary endpoint of the trial is overall survival
of the triplet combination compared 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, ORR,
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. Patient
enrollment is expected to be completed around the end of
2018.
About BRAFTOVI + MEKTOVI
BRAFTOVI (encorafenib)
is an oral small molecule BRAF kinase inhibitor and MEKTOVI
(binimetinib) 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, thyroid 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.
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,
Asia and Latin America.
BRAFTOVI and MEKTOVI are not approved outside of the United States. The European Medicines
Agency (EMA), the Swiss Medicines Agency (Swissmedic) and the
Australian Therapeutic Goods Administration (TGA) are currently
reviewing the Marketing Authorization Applications, and the
Pharmaceuticals and Medical Devices Agency (PMDA) in Japan is currently reviewing the Manufacturing
and Marketing Approval Applications for BRAFTOVI and MEKTOVI.
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.
Warnings and Precautions
New Primary Malignancies: 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. Discontinue
BRAFTOVI for RAS mutation-positive non-cutaneous
malignancies.
Tumor Promotion in BRAF Wild-Type
Tumors: Confirm evidence
of BRAFV600E or BRAFV600Kmutation
prior to initiating BRAFTOVI.
Cardiomyopathy: 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. The 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.
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.
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. In patients
with BRAF mutation-positive melanoma across
multiple clinical trials, 0.1% of patients experienced retinal vein
occlusion (RVO). 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 ophthalmic evaluation at regular
intervals and for any visual disturbances.
Interstitial Lung Disease (ILD): ILD, including
pneumonitis, occurred in 0.3% of patients
with BRAFmutation-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). 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 periodically and as
clinically indicated.
QTc Prolongation: 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. Nonhormonal
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.
Please see full Prescribing Information for BRAFTOVI and full
Prescribing Information for MEKTOVI for additional
information. 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
in the United States
BRAFTOVITM (encorafenib) capsules in combination with
MEKTOVI® (binimetinib) tablets for the treatment of
patients with unresectable or metastatic melanoma with a
BRAFV600E or BRAFV600K
mutation. 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 colorectal cancer. Array's pipeline
includes several additional programs being advanced by Array or
current license-holders, including selumetinib (partnered with
AstraZeneca), larotrectinib (partnered with Loxo Oncology),
ipatasertib (partnered with Genentech), tucatinib (partnered with
Seattle Genetics) and ARRY-797 (being developed by Yarra
Therapeutics, a wholly-owned subsidiary of Array), all of which are
currently in registration trials. Ganovo® (danoprevir,
partnered with Roche) was recently approved in China for the treatment of viral hepatitis C.
For more information on Array, please visit www.arraybiopharma.com
or follow @arraybiopharma on Twitter and LinkedIn.
References
[1] Kopetz et al., ASCO 2017
[2] De Roock et al., Lancet Oncol, 2010
[3] Ulivi et
al., J Transl Med. 2012
[4] Peeters et al., ASCO
2014
[5] Saridaki et al., PLoS One. 2013
[6]
Loupakis et al., Br J Cancer. 2009
[7] 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.
[8] 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.
[9] Sorbye H, et al. PLoS One. 2015
[10] Vecchione, et al. Cell. 2016
[11] Safaee Ardekani G, Jafarnejad SM, Tan L, et al. The prognostic
value of BRAF mutation in colorectal cancer and melanoma: a
systematic review and meta-analysis. PLoS One.
2012;7(10):e47054.
[12] Seymour et al., Lancet Oncol, 2013 (supplementary
appendix)
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
statements about the future development plans of encorafenib and
binimetinib; expectations regarding approval of encorafenib and
binimetinib for BRAF-mutant melanoma and timing of such
approvals; expectations that events will occur that will result in
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.
Specifically, there is no assurance that results from the BEACON
CRC and COLUMBUS trials will satisfy the requirements of regulatory
authorities necessary for approval. These statements involve
significant risks and uncertainties, including those discussed 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. Because these
statements reflect our current expectations concerning future
events, 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
determination by the FDA, EMA or other regulatory agencies that
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. We are providing this information as of August 7, 2018. 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.
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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