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Data from BRIM7, ongoing phase 1b trial in patients with locally
advanced/unresectable or metastatic melanoma with the BRAFV600
mutation
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Although trial was primarily designed to evaluate safety, objective
responses observed in 85% of BRAFi-naive patients receiving combination
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Sep. 28, 2013--
Exelixis, Inc. (NASDAQ:EXEL) today announced updated results from BRIM7,
an ongoing phase 1b clinical trial conducted by Roche and Genentech,
Exelixis' collaborator and a member of the Roche Group (SIX: RO, ROG;
OTCQX: RHHBY), of the BRAF inhibitor (BRAFi) vemurafenib in combination
with the MEK inhibitor cobimetinib (GDC-0973/XL518) in patients with
locally advanced/unresectable or metastatic melanoma carrying a BRAFV600
mutation. Grant McArthur, M.D., Head of the Medical Oncology Skin and
Melanoma Clinical Service at the Peter MacCallum Cancer Centre in
Australia, and an investigator on the trial, presented the data today at
the European Cancer Congress (ECC) 2013 (Abstract #3703) which is taking
place in Amsterdam, The Netherlands.
“The data presented today, while early-stage, suggest that the
preliminary safety profile and activity of the investigational
combination of cobimetinib and vemurafenib is promising in BRAFi-naïve
patients,” said Michael Morrissey, Ph.D., president and CEO of Exelixis.
“Importantly, responses in these patients generally occurred early in
their course of treatment. We are pleased with the progress Roche has
made in advancing cobimetinib, and believe that this Exelixis-discovered
compound warrants further study in melanoma, as people with this
incurable disease desperately need new options.”
Exelixis received notice from Genentech in January 2013 that the first
patient was dosed in a phase 3 pivotal trial (coBRIM) evaluating
vemurafenib alone or in combination with cobimetinib in previously
untreated patients with malignant melanoma harboring the BRAFV600
mutation. This study is ongoing and currently enrolling globally.
Top-line data from the trial are expected to be available next year.
Study Design
The phase 1b dose escalation study was designed to evaluate the safety
and tolerability of cobimetinib in combination with vemurafenib. The
dose escalation stage of the trial comprised 10 dosing cohorts of 3-6
patients and evaluated three different dosing schedules for the two
active treatments. Cohorts that met the protocol-specified criteria for
MTD were expanded and included BRAFi-naïve or vemurafenib-progressing
patients.
Study Results
As of June 21, 2013, 128 patients had been treated, comprising 65
patients who had disease progression while receiving vemurafenib and 63
patients who were BRAFi-naïve. Of the 63 BRAFi-naïve patients, 42 (67%)
were previously untreated and 21 (33%) had been treated with agents
other than a BRAFi. The majority of patients had Stage IV, M1c melanoma
at the time of enrollment (vemurafenib-progressors = 82%, BRAFi naïve =
70%). Dose-limiting toxicities were reported in one of six patients in
the dose-escalation stage receiving 960 mg of vemurafenib bid and 60 mg
of cobimetinib qd on a 21/7-day schedule (Grade 3 QT interval
prolongation), and in one of five patients in the dose escalation stage
receiving 960 mg of vemurafenib bid and 80 mg cobimetinib qd on a
14/14-day schedule. Dose-limiting toxicities of Grade 3 mucositis and
Grade 3 arthralgia were each observed in one of four patients in the
dose-escalation stage receiving 960 mg vemurafenib bid and 60 mg
cobimetinib qd on a 28/0-day schedule. Two cohorts receiving 60 mg of
cobimetinib qd on a 21/7-day schedule with vemurafenib at either 720 mg
or 960 mg bid were selected for expansion.
While the study was not designed to measure efficacy, updated results
showed a partial or complete response (tumor shrinkage) in many of the
patients who had not been previously treated with a BRAF inhibitor. Of
the 63 BRAFi-naïve patients, 10% had a complete response, 75% had a
partial response, and 13% had stable disease, for an objective response
rate of 85%. Most objective responses occurred by the time of the first
tumor assessment at 6 weeks. Only two of the BRAFi-naïve patients (3%)
had progressive disease. Sixty-one of the 65 patients who had progressed
on prior vemurafenib therapy were evaluated for tumor response by
RECIST, of which 15% had a partial response, and 43% had stable disease,
for an objective response rate of 15%. As of the June 21, 2013 cut-off
date, with a median follow-up time of three months, 85.2% of
vemurafenib-progressors had already experienced disease progression, and
the median progression-free survival (PFS) was 2.8 months. At a median
follow-up time of 10 months, 33.3% of BRAFi-naïve patients had
experienced disease progression, and the median PFS had not yet been
reached.
Safety
The most common adverse events (AEs) regardless of attribution to study
treatment in the 128 patients treated to date were: non-acneiform rash
(35% [2% ≥ Grade 3] for vemurafenib-progressors; and 89% [13% ≥ Grade 3]
for BRAFi-naïve), diarrhea (48% [3%]; 81% [8%]),
photosensitivity/sunburn (48% [3%]; 70% [0%])), fatigue (28% [2%]; 67%
[10%]), nausea (32% [3%]; 56% [3%]), arthralgia (11% [2%]; 48% [11%]),
CPK elevation (15% [2%]; 43% [3%]), fever (14% [0%]; 43% [2%]),
peripheral edema (20% [0%]; 41% [0%]), vomiting (19% [2%]; 37% [0%]),
and acneiform rash (12% [2%]; 33% [3%]). Selected AEs were:
choreoretinopathy (2% [0]; 9% [0%]), cardiomyopathy [0% [0%]; 2% [2%]),
and squamous cell carcinoma/keratocanthoma (8% [6%]; 10% [5%]).
Temporary interruptions in vemurafenib, cobimetinib, or the combination
of both agents were reported in 20%, 20%, and 19% of the 65
vemurafenib-progressor patients, respectively. Dose reductions were
reported in 5% 3%, and 3% of vemurafenib-progressor patients,
respectively, and permanent discontinuation was reported for vemurafenib
(3%) only. Among the 63 BRAFi-naïve patients, temporary interruptions in
vemurafenib, cobimetinib, or the combination of both agents were
reported in 67%, 49%, and 46%, and dose reductions were reported in 19%,
16% and 2% of patients, respectively. Permanent discontinuation of
cobimetinib was reported for one BRAFi-naïve patient (2%). None of the
128 patients receiving the combination of vemurafenib and cobimetinib
discontinued treatment due to an adverse event to date.
About Cobimetinib (GDC-0973/XL518)
Cobimetinib is an inhibitor of MEK, a serine/threonine kinase that is a
component of the RAS/RAF/MEK/ERK pathway. This pathway mediates
signaling downstream of growth factor receptors, and is prominently
activated in a wide variety of human tumors. In preclinical studies,
oral dosing of cobimetinib resulted in sustained inhibition of MEK in
RAS or BRAF mutant tumor models. Cobimetinib is being developed by
Genentech, a member of the Roche Group under a collaboration agreement
with Exelixis.
About the Collaboration
Exelixis discovered cobimetinib (GDC-0973/XL518) 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 end of phase 1,
at which point Genentech exercised its option to further develop the
compound.
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.
Exelixis has the option to co-promote in the United States.
About Exelixis
Exelixis is a biotechnology company committed to developing small
molecule therapies for the treatment of cancer. Exelixis is focusing its
proprietary resources and development efforts exclusively on COMETRIQ®
(cabozantinib). Exelixis has also established a portfolio of other novel
compounds that it believes have the potential to address serious unmet
medical needs, many of which are being advanced by partners as part of
collaborations. 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 and therapeutic potential of cobimetinib (GDC-0973/XL518); the
potential benefit of the investigational combination of cobimetinib and
vemurafenib to BRAFi-naïve patients; the belief that cobimetinib
warrants further study in melanoma; developments with respect to coBRIM,
including the expected availability of top-line data therefrom; the
designs, plans and goals for BRIM7; the plan of Genentech and Exelixis
to share U.S. profits and losses for cobimetinib and U.S. marketing and
commercialization costs for cobimetinib; Exelixis' potential receipt of
royalties for cobimetinib products sales outside the United States; and
Exelixis’ option to co-promote in the United States. Words such as
“ongoing,” “suggest,” “promising,” “believe,” “warrants,” “further,”
“new,” “currently,” “enrolling,” “expected,” “available,” “designed,”
“entitled,” “share,” “will,” “potential,” and similar expressions are
intended to identify forward-looking statements. These forward-looking
statements are based upon Exelixis' current plans, assumptions, beliefs
and expectations. Forward-looking statements involve risks and
uncertainties. Exelixis' actual results and the timing of events could
differ materially from those anticipated in such forward-looking
statements as a result of these risks and uncertainties, which include,
without limitation: risks related to the potential failure of
cobimetinib to demonstrate safety and efficacy in clinical testing; the
availability of data at the expected times; the clinical, therapeutic
and commercial value of cobimetinib; Exelixis' dependence on its
relationship with Genentech/Roche and Exelixis’ ability to maintain its
rights under the collaboration; the uncertainty of regulatory approval
processes; market competition; and changes in economic and business
conditions. These and other risk factors are discussed under “Risk
Factors” and elsewhere in Exelixis' quarterly report on Form 10-Q for
the three months ended June 28, 2013, filed with the Securities and
Exchange Commission (SEC) on August 6, 2013, and Exelixis' other filings
with the SEC. 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.
Charles Butler, 650-837-7277
Vice
President, Investor Relations and Corporate Communications
cbutler@exelixis.com
