- Combination reduced the risk of disease worsening by half compared
to Vemurafenib alone -
- CoBRIM results will be presented today during the Presidential
Symposium at the European Society for Medical Oncology (ESMO) and
published in the New England Journal of Medicine -
- Partner Roche has submitted EU Marketing Authorization Application;
U.S.
filing anticipated later this year -
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Sep. 29, 2014--
Exelixis Inc. (NASDAQ:EXEL) today announced the positive results from
coBRIM, the phase 3 pivotal trial conducted by Exelixis’ collaborator
Genentech, a member of the Roche Group, evaluating cobimetinib, a
specific MEK inhibitor discovered by Exelixis, in combination with
vemurafenib in previously untreated patients with unresectable locally
advanced or metastatic melanoma harboring a BRAF V600 mutation.
The trial met its primary endpoint of demonstrating a statistically
significant increase in investigator-determined progression-free
survival (PFS). The median PFS was 9.9 months for the combination of
cobimetinib and vemurafenib versus 6.2 months for vemurafenib alone
(hazard ratio [HR]=0.51, 95 percent CI 0.39-0.68; p<0.0001),
demonstrating the combination reduced the risk of the disease worsening
by half (49 percent). The median PFS by independent review committee
(IRC), a secondary endpoint, was 11.3 months for the combination arm
compared to 6.0 months for the control arm (HR=0.60, 95 percent CI
0.45-0.79; p=0.0003). Objective response rate (ORR), another secondary
endpoint, was 68% for the combination versus 45% for vemurafenib alone
(p<0.0001). Overall survival data are not yet mature (HR=0.65, 95
percent CI 0.42-1.00; p=0.046), and at the interim analysis the p-value
did not cross the prespecified boundary for significance. The safety
profile of the combination was consistent with that observed in a
previous study.
The coBRIM data will be presented at ESMO 2014 today, Monday, September
29, during the Presidential Symposium by Professor Grant McArthur, Peter
MacCallum Cancer Centre, Australia (Abstract #LBA5_PR, Monday, September
29, 2014, 4:00-5:20 p.m. CEST) and are also part of the official press
program. Additionally, the study was published online today in the New
England Journal of Medicine.
Roche has submitted a Marketing Authorization Application (MAA) to the
European Medicines Agency, and Genentech plans to submit a New Drug
Application (NDA) to the U.S. Food and Drug Administration later this
year.
“Today’s presentation of data from the coBRIM trial underscore the
potential for the combination of cobimetinib, an Exelixis-discovered
compound, and vemurafenib to provide significant clinical benefit for
patients with previously untreated BRAF V600 mutation-positive advanced
melanoma,” said Michael M. Morrissey, Ph.D., president and chief
executive officer of Exelixis. “Our partner Genentech sponsored a
rigorous and well-run trial, and the results, including a significant
increase in PFS and a high objective response rate, are compelling. The
regulatory filing process is underway with the submission of the EU
filing of the MAA. We look forward to the U.S. filing later this year
and then ultimately, if approved, to supporting cobimetinib’s
commercialization through our longstanding collaboration that includes a
co-promotion component in the United States.”
About the coBRIM study
The coBRIM trial is an international, randomized, double-blind,
placebo-controlled Phase III study evaluating the safety and efficacy of
60 mg once daily of cobimetinib in combination with 960 mg twice daily
of vemurafenib, compared to 960 mg twice daily of vemurafenib alone. In
the study, 495 patients with BRAF V600 mutation-positive unresectable
locally advanced or metastatic melanoma (detected by the cobas® 4800
BRAF Mutation Test) and previously untreated for advanced disease, were
randomized to receive vemurafenib every day on a 28-day cycle plus
either cobimetinib or placebo for days 1-21. Treatment was continued
until disease progression, unacceptable toxicity or withdrawal of
consent. Median follow up was 7.4 months for the combination arm and 7.2
months for the control arm.
There was a higher overall frequency of Grade 3 or higher adverse events
in the combination arm (65 vs. 59 percent), with close to half of these
due to lab abnormalities. Common adverse events of any grade that
occurred in more than 20 percent of patients and were observed at a
higher frequency in the combination arm compared to the vemurafenib arm
included diarrhea (57 vs. 28 percent), nausea (39 vs. 24 percent),
photosensitivity (28 vs. 16 percent), lab abnormalities (increased
alanine aminotransferase [24 vs. 18 percent], increased aspartate
aminotransferase [22 vs. 13 percent], increased creatine phosphokinase
[an enzyme released by muscles, 30 vs. 3 percent]), and vomiting (21 vs.
12 percent). Common adverse events observed at a lower frequency in the
combination arm included hair loss (14 vs. 29 percent), thickening of
the outer layer of the skin (10 vs. 29 percent), and joint pain (33 vs.
40 percent). Most instances of each common adverse event were grade 1 or
2 in severity.
Other select adverse events that were lower in the combination arm
included cutaneous squamous cell carcinomas (3 vs. 11 percent; all
grades) and keratoacanthomas (<1 vs. 8 percent; all grades). Serous
retinopathy (collection of fluid under the retina) was observed at a
higher frequency in the combination arm (20 vs. <1 percent) with most of
these events either Grade 1 or 2 and temporary in nature. Specific
adverse events leading to withdrawal from treatment were similar in both
study arms, as was the overall discontinuation rate from treatment (13
vs. 12 percent).
About the Cobimetinib Development Collaboration
Exelixis discovered cobimetinib internally and advanced the compound to
investigational new drug (IND) status. In late 2006, Exelixis entered
into a worldwide co-development agreement with Genentech, under which
Exelixis received initial upfront and milestone payments for signing the
agreement and submitting the IND. Exelixis was responsible for
development of cobimetinib through the determination of the maximum
tolerated dose in phase 1, at which point Genentech exercised its option
to further develop the compound.
In November 2013, Exelixis exercised its option to co-promote
cobimetinib, if approved, in the United States. Exelixis is entitled to
an initial equal share of U.S. profits and losses, which will decrease
as sales increase, and will share equally in the U.S. marketing and
commercialization costs. Exelixis is eligible to receive royalties on
any sales of the product outside the United States.
About the Cobimetinib and Vemurafenib Combination
Cobimetinib is a selective inhibitor that blocks the activity of MEK, a
protein kinase that is part of a key pathway (the RAS-RAF-MEK-ERK
pathway) that promotes cell division and survival. This pathway is
frequently activated in human cancers including melanoma, where mutation
of one of its components (BRAF) causes abnormal activation in about 50%
of tumors. Tumors with BRAF mutations may develop resistance and
subsequently progress after treatment with a BRAF inhibitor. In
preclinical melanoma models, co-treatment with vemurafenib and the MEK
inhibitor cobimetinib may delay the emergence of resistant tumors. In
addition to the combination with vemurafenib in melanoma, cobimetinib is
also being investigated in combination with several investigational
medicines, including an immunotherapy, in several tumor types, including
non-small cell lung cancer and colorectal cancer.
About Melanoma and its BRAF V600 Mutation-Positive Form
Melanoma is the less common, but more serious category of skin cancer
that starts in the skin’s pigment producing cells known as melanocytes.
According to the American Cancer Society, approximately five percent of
skin cancer diagnoses are melanoma, but melanoma accounts for a large
majority of skin cancer deaths. Cases of melanoma have been increasing
for at least 30 years, and in 2014 it is estimated that in the United
States more than 76,100 people will be diagnosed with melanoma and more
than 9,700 people will die from the disease. It is thought that
approximately half of all melanomas, and eight percent of solid tumors,
contain a mutation of the BRAF protein. BRAF is a key component of the
RAS-RAF-MEK-ERK pathway involved in normal cell growth and survival.
However, mutations that keep the BRAF protein in an active state may
cause excessive signaling in the pathway, leading to uncontrolled cell
growth and survival. The BRAF V600 mutation-positive form of melanoma is
associated with high-risk characteristics of the disease, including
early onset, the absence of chronic skin damage, and decreased survival.
About Exelixis
Exelixis, Inc. is a biopharmaceutical company committed to developing
small molecule therapies for the treatment of cancer. Exelixis is
focusing its development and commercialization efforts primarily on
COMETRIQ® (cabozantinib), its wholly-owned inhibitor of
multiple receptor tyrosine kinases. Another Exelixis-discovered
compound, cobimetinib, a highly selective inhibitor of MEK, is being
evaluated by Roche and Genentech (a member of the Roche Group) in a
broad development program under a collaboration with Exelixis. For more
information, please visit the company's web site at www.exelixis.com.
Forward-Looking Statements
This press release contains forward-looking statements, including,
without limitation, statements related to: the continued development and
clinical, therapeutic and commercial potential of cobimetinib in
combination with vemurafenib and other investigational medicines; coBRIM
data presentations; future regulatory filings and potential approvals;
Exelixis’ future U.S. co-promotion efforts with Genentech; the plan of
Genentech and Exelixis to share U.S. profits and losses for cobimetinib
and U.S. marketing and commercialization costs for cobimetinib; and
Exelixis' potential receipt of royalties on sales of cobimetinib
products outside the United States. Words such as “will,” “anticipated,”
“plans,” “underscore,” “potential,” “compelling,” “underway,” “look
forward,” “entitled,” “share,” “estimated,” “eligible,” or other similar
expressions, identify forward-looking statements, but the absence of
these words does not necessarily mean that a statement is not
forward-looking. In addition, any statements that refer to expectations,
projections or other characterizations of future events or circumstances
are forward-looking statements. These forward-looking statements are
based upon Exelixis' current plans, assumptions, beliefs, expectations,
estimates and projections. Forward-looking statements involve risks and
uncertainties. Exelixis' actual results and the timing of events could
differ materially from those anticipated in the forward-looking
statements as a result of these risks and uncertainties, which include,
without limitation: risks related to the potential failure of
cobimetinib or cabozantinib to demonstrate safety and efficacy in
clinical testing; the availability of data at the expected times; the
clinical, therapeutic and commercial value of cobimetinib and
cabozantinib; Exelixis' dependence on its relationship with
Genentech/Roche with respect to cobimetinib and Exelixis’ ability to
maintain its rights under the collaboration; risks and uncertainties
related to regulatory review and approval processes and Exelixis’
compliance with applicable legal and regulatory requirements; the
general sufficiency of Exelixis’ capital and other resources and the
specific risk of unforeseen expenses that could diminish Exelixis’
financial ability to support its operations through the release of
top-line results from METEOR, Exelixis’ phase 3 pivotal trial of
cabozantinib in metastatic renal cell cancer; the uncertain timing and
level of expenses associated with the development of cabozantinib; risks
related to Exelixis’ ability to implement its previously announced
workforce reduction according to plan and its impact on Exelixis’
business; charges, expenses and cash expenditures resulting from the
referenced workforce reduction; market competition; changes in economic
and business conditions; and other factors discussed under the caption
“Risk Factors” in Exelixis’ quarterly report on Form 10-Q filed with the
Securities and Exchange Commission (SEC) on July 31, 2014 and in
Exelixis' other filings with the SEC. The forward-looking statements
made in this press release speak only as of the date of this press
release. Exelixis expressly disclaims any duty, obligation or
undertaking to release publicly any updates or revisions to any
forward-looking statements contained herein to reflect any change in
Exelixis' expectations with regard thereto or any change in events,
conditions or circumstances on which any such statements are based.
Exelixis, the Exelixis logo, and COMETRIQ are registered U.S.
trademarks.
Source: Exelixis, Inc.
Exelixis, Inc.
Susan Hubbard, 650-837-8194
Investor
Relations and
Corporate Communications
shubbard@exelixis.com
