BOULDER, Colo., July 5, 2017 /PRNewswire/ -- Array BioPharma
(Nasdaq: ARRY) today announced the submission of two New Drug
Applications (NDAs) to the U.S. Food and Drug Administration (FDA)
to support use of the combination of binimetinib 45 mg twice daily
and encorafenib 450 mg once daily (COMBO450) for the treatment of
patients with BRAF-mutant advanced, unresectable or
metastatic melanoma. The submissions are supported by data from the
pivotal Phase 3 COLUMBUS study, which showed that patients who
received binimetinib and encorafenib had a significantly longer
progression free survival (PFS) compared to patients receiving
vemurafenib.
"The totality of the COLUMBUS results, including estimated
progression free survival, objective response rate, dose intensity
and tolerability of the combination, provide a strong and
consistent theme across multiple endpoints for this study," said
Ron Squarer, Chief Executive Officer, Array BioPharma. "We look
forward to working with the FDA as they review the NDA and, if
approved, hope the combination of binimetinib and encorafenib will
become a new option for patients with BRAF-mutant advanced
melanoma."
COLUMBUS Results
As presented at the 2016 Society for
Melanoma Research Annual Congress, results from Part 1 of the
COLUMBUS study showed that COMBO450 significantly extend PFS in
patients with advanced BRAF-mutant melanoma, with a PFS of
14.9 months compared with 7.3 months observed with vemurafenib
[hazard ratio (HR) 0.54, (95% CI 0.41-0.71, P<0.001)]. As part
of the trial design, the primary analysis was based on a Blinded
Independent Central Review (BICR) of patient scans, while results
by local review at the investigative site were also analyzed. The
table below outlines the median PFS (mPFS) results, as determined
by both assessments, for COMBO450 versus vemurafenib, COMBO450
versus encorafenib, and encorafenib versus vemurafenib:
|
|
mPFS
BICR
|
|
mPFS Local
Review
|
COMBO450 vs.
Vemurafenib
|
|
COMBO450
|
Vemurafenib
|
|
COMBO450
|
Vemurafenib
|
|
14.9
months
|
7.3 months
|
|
14.8
months
|
7.3 months
|
|
HR (95% CI): 0.54
(0.41-0.71); P<0.001
|
|
HR (95% CI): 0.49
(0.37-0.64); P<0.001
|
|
COMBO450 vs.
Encorafenib
|
|
COMBO450
|
Encorafenib
|
|
COMBO450
|
Encorafenib
|
|
14.9
months
|
9.6 months
|
|
14.8
months
|
9.2 months
|
|
HR (95% CI): 0.75
(0.56-1.00); P=0.051
|
|
HR (95% CI): 0.68
(0.52-0.90); P=0.006
|
|
Encorafenib vs.
Vemurafenib
|
|
Encorafenib
|
Vemurafenib
|
|
Encorafenib
|
Vemurafenib
|
|
9.6 months
|
7.3 months
|
|
9.2 months
|
7.3 months
|
|
HR (95% CI): 0.68
(0.52-0.90); P=0.007
|
|
HR (95% CI): 0.70
(0.54-0.91); P=0.008
|
In this study, COMBO450 was generally well-tolerated, with a
median duration of treatment of 51 weeks and median relative dose
intensity for encorafenib and binimetinib of 100% and 99.6%,
respectively. Grade 3/4 adverse events (AEs) that occurred in more
than 5% of patients receiving COMBO450 were increased blood
creatine phosphokinase (CK) (9%), increased
gamma-glutamyltransferase (GGT) (7%) and hypertension (6%). The
incidence of any grade of AEs of special interest, defined based on
toxicities commonly associated with commercially available
MEK+BRAF-inhibitor treatments for patients receiving COMBO450
included: rash (23%), pyrexia (18%), retinal pigment epithelial
detachment (13%) and photosensitivity (5%). Full safety
results of COLUMBUS Part 1 were presented at the 2016 Society for
Melanoma Research Annual Congress.
COLUMBUS Part 2 was designed specifically to assess the
contribution of binimetinib to the combination of binimetinib and
encorafenib by reducing the dose of encorafenib to 300mg in the
combination arm to allow for a comparison of equal doses across
arms. In COLUMBUS Part 2, the primary analysis compared PFS in
patients treated with binimetinib 45mg twice daily plus encorafenib
300mg daily (COMBO300) to patients treated with encorafenib 300mg
daily as a single agent. Top-line results showed the mPFS for
patients treated with COMBO300 was 12.9 months compared to 9.2
months for patients treated with single agent encorafenib, with HR
of 0.77 [95% CI 0.61-0.97, p=0.029]. COMBO300 was generally
well-tolerated and reported dose intensity and AEs were consistent
with COMBO450 results in COLUMBUS Part 1. Further results from
COLUMBUS Part 2 will be presented at a medical meeting during the
second half of 2017.
About the Phase 3 COLUMBUS Study
The COLUMBUS trial,
(NCT01909453), is a two-part, international, randomized, open label
Phase 3 study evaluating the efficacy and safety of the combination
of binimetinib plus encorafenib to vemurafenib and encorafenib
monotherapy in 921 patients with locally advanced, unresectable or
metastatic melanoma with BRAF V600 mutation. Prior
immunotherapy treatment was allowed. Over 200 sites across
North America, Europe, South
America, Africa,
Asia and Australia participated in the study. Patients
were randomized into two parts:
- In Part 1, 577 patients were randomized 1:1:1 to receive 45mg
binimetinib plus 450mg encorafenib (COMBO450), 300mg encorafenib
alone, or 960mg vemurafenib alone. The dose of encorafenib in the
combination arm is 50% higher than the single agent maximum
tolerated dose of 300mg. A higher dose of encorafenib was
possible due to improved tolerability when combined with
binimetinib. The primary endpoint for the COLUMBUS trial was
a PFS comparison of COMBO450 versus vemurafenib. PFS is determined
based on tumor assessment (RECIST version 1.1 criteria) by a
Blinded Independent Central Review (BICR). Secondary endpoints
include a comparison of the PFS of encorafenib monotherapy to that
of COMBO450 and a comparison of overall survival (OS) for COMBO450
to that of vemurafenib alone.
- In Part 2, 344 patients were randomized 3:1 to receive 45mg
binimetinib plus 300mg encorafenib or 300mg encorafenib alone. Part
2 is designed to provide additional data to help evaluate the
contribution of binimetinib to the combination of binimetinib and
encorafenib. As the comparison of COMBO450 to encorafenib in Part 1
did not achieve statistical significance, analyses of other
endpoints including the statistical analysis conducted in Part 2 is
descriptive.
About Melanoma
Metastatic melanoma is the most
serious and life-threatening type of skin cancer and is associated
with low survival rates[1],[2]. Only about 20% of people will
survive for at least five years following a diagnosis with
late-stage disease[1],[2]. There are about 200,000 new cases of
melanoma diagnosed worldwide each year, approximately half of which
have BRAF mutations, a key target in the treatment of
metastatic melanoma[1],[3],[4].
About Binimetinib and Encorafenib
MEK and BRAF are key
protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK).
Research has shown this pathway regulates several key cellular
activities including proliferation, differentiation, survival and
angiogenesis. Inappropriate activation of proteins in this pathway
has been shown to occur in many cancers, such as melanoma,
colorectal and thyroid cancers. Binimetinib is a late-stage small
molecule MEK inhibitor and encorafenib is a late-stage small
molecule BRAF inhibitor, both of which target key enzymes in this
pathway. Binimetinib and encorafenib are being studied in clinical
trials in advanced cancer patients, including the Phase 3 BEACON
CRC trial with encorafenib in combination with cetuximab with or
without binimetinib in patients with BRAF V600E-mutant
colorectal cancer.
Binimetinib and encorafenib are investigational medicines and
are not currently approved in any country.
Array BioPharma retains exclusive rights to binimetinib and
encorafenib in key markets including the U.S., Canada and Israel. Array has granted Ono
Pharmaceutical exclusive rights to commercialize both products in
Japan and South Korea and Pierre
Fabre exclusive rights to commercialize both products in all
other countries, including Europe,
Asia and Latin America.
About Array BioPharma
Array BioPharma Inc. is a
biopharmaceutical company focused on the discovery, development and
commercialization of targeted small molecule drugs to treat
patients afflicted with cancer. Eight registration studies
are currently advancing related to seven Array-owned or partnered
drugs: binimetinib (MEK162), encorafenib (LGX818), selumetinib
(partnered with AstraZeneca), danoprevir (partnered with Roche),
ipatasertib (partnered with Genentech), larotrectinib (partnered
with Loxo Oncology) and tucatinib (partnered with Cascadian
Therapeutics).
References
[1] Melanoma Skin Cancer. American Cancer
Society. Available at:
https://www.cancer.org/cancer/melanoma-skin-cancer.html (link is
external). Accessed June 2017.
[2] A Snapshot of Melanoma. National Cancer Institute. Available
at: https://seer.cancer.gov/statfacts/html/melan.html (link is
external). Accessed June 2017.
[3] Globocan 2012: Estimated Cancer Incidence, Mortality and
Prevalence Worldwide in 2012.
http://globocan.iarc.fr/Pages/fact_sheets_population.aspx (link is
external). Accessed June 2017.
[4] Klein O, Clements A, Menzies AM, et al. BRAF inhibitor activity
in V600R metastatic melanoma. Eur J Cancer. 2013;
49(5):1073-1079.
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 binimetinib and encorafenib, and the timing of
the announcement of further results of clinical trials for
binimetinib and encorafenib; expectations regarding the timing of
regulatory filings for binimetinib and encorafenib and regarding
approval of binimetinib and encorafenib for BRAF-mutant melanoma;
expectations that events will occur that will result in greater
value for Array; and the potential for the results of current and
further clinical trials to support regulatory approval or the
marketing success of binimetinib and encorafenib. 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 that results from clinical trials are not
sufficient to support registration or marketing approval of
binimetinib and encorafenib; 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 within and outside
the United States; 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
July 5, 2017. 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.
CONTACT:
|
Tricia
Haugeto
|
|
(303)
386-1193
|
|
thaugeto@arraybiopharma.com
|
To view the original version on PR Newswire,
visit:http://www.prnewswire.com/news-releases/array-biopharma-submits-new-drug-applications-to-fda-for-binimetinib-and-encorafenib-in-advanced-melanoma-300483156.html
SOURCE Array BioPharma