BRAFTOVI plus cetuximab is the first-and-only
FDA-approved targeted regimen specifically for adults with
previously treated metastatic CRC with a BRAFV600E mutation
Pfizer Inc. (NYSE: PFE) today announced that the U.S. Food and
Drug Administration (FDA) has approved BRAFTOVI® (encorafenib) in
combination with cetuximab (marketed as ERBITUX®) for the treatment
of adult patients with metastatic colorectal cancer (CRC) with a
BRAFV600E mutation, as detected by an FDA-approved test, after
prior therapy.1 The approval is based on results from the BEACON
CRC trial, the only Phase 3 trial to specifically study patients
with previously treated metastatic CRC with a BRAFV600E
mutation.
“We are pleased by the FDA’s approval of BRAFTOVI in combination
with cetuximab, as we are committed to developing targeted
medicines that can help people living with certain mutation-driven
cancers,” said Chris Boshoff, M.D., Ph.D., Chief Development
Officer, Oncology, Pfizer Global Product Development. “We are
grateful to the patients and study investigators who participated
in the Phase 3 BEACON CRC trial and are proud to now be able to
offer a targeted treatment option for people with BRAFV600E-mutant
metastatic CRC who have received prior therapy. Looking ahead,
we’re committed to continuing to investigate this treatment regimen
across earlier lines of therapy.”
Based on results from the BEACON CRC trial, BRAFTOVI plus
cetuximab showed a median overall survival (OS) of 8.4 months (95%
CI: 7.5, 11.0) compared with 5.4 months (95% CI: 4.8, 6.6) for
Control (irinotecan with cetuximab or FOLFIRI with cetuximab) ([HR
0.60, (95% CI: 0.45, 0.79), p=0.0003]). Additionally, BRAFTOVI plus
cetuximab showed an improved objective response rate (ORR) of 20%
(95% CI: 13%, 29%) compared with 2% (95% CI: 0%, 7%) for Control
(p<0.0001) and median progression-free survival (mPFS) was 4.2
months with BRAFTOVI plus cetuximab (95% CI: 3.7, 5.4) versus 1.5
months with Control (95% CI: 1.4, 1.7) ([HR 0.40, (95% CI: 0.31,
0.52), p<0.0001]).
“BRAF mutations are estimated to occur in up to 15% of people
with metastatic colorectal cancer and represent a poor prognosis
for these patients,” said Scott Kopetz, M.D., Ph.D., FACP,
Associate Professor of Gastrointestinal Medical Oncology at The
University of Texas MD Anderson Cancer Center. “As the
first-and-only targeted regimen for people with BRAFV600E-mutant
metastatic CRC who have received prior therapy, BRAFTOVI in
combination with cetuximab is a much-needed new treatment option
for these patients.”
The most common adverse reactions (AR) (≥ 25%) seen in patients
treated with BRAFTOVI in combination with cetuximab were fatigue,
nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased
appetite, arthralgia and rash. The full prescribing information for
BRAFTOVI can be found here.
The FDA granted this application Priority Review and
Breakthrough Therapy designation. The FDA grants Priority Review to
medicines that may offer significant advances in treatment or may
provide a treatment where no adequate therapy exists.
Pfizer is committed to ensuring that patients who are prescribed
BRAFTOVI have access to this important treatment option. Pfizer is
here to help patients in the U.S. understand their benefits and
connect them with financial assistance resources for their
prescribed Pfizer Oncology medicines.
For more information about treatment of BRAFTOVI in combination
with cetuximab, visit www.braftovihcp.com.
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 1.8 million new diagnoses in 2018.2,3 In the U.S.
alone, an estimated 147,950 people will be diagnosed with cancer of
the colon or rectum in 2020, and approximately 53,000 are estimated
to die of their disease each year.4 BRAF mutations are estimated to
occur in up to 15% of people with metastatic CRC and represent a
poor prognosis for these patients.5,6,7,8,9,10 The BRAFV600E
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.7,8 BRAFV600E-mutant
metastatic CRC is an area of high unmet need as there are currently
no approved therapies specifically indicated for people with
BRAFV600E-mutant metastatic CRC.11,12,13
About BEACON CRC
BRAFTOVI in combination with cetuximab was evaluated in the
randomized, active-controlled, open-label, multicenter, Phase 3
BEACON CRC trial. Eligible patients were required to have BRAFV600E
mutant metastatic CRC, as detected by an FDA-approved test, with
disease progression after one or two prior regimens.
Patients were randomized 1:1:1 to one of the following treatment
arms:
- BRAFTOVI 300 mg orally once daily in combination with cetuximab
(BRAFTOVI/cetuximab arm)
- BRAFTOVI 300 mg orally once daily in combination with cetuximab
and binimetinib
- Irinotecan with cetuximab or FOLFIRI with cetuximab (control
arm)
The major efficacy outcome measure was OS. Additional efficacy
outcome measures included PFS, ORR, and duration of response (DoR)
as assessed by blinded independent central review (BICR). OS and
PFS were assessed in all randomized patients. ORR and DoR were
assessed in the subset of the first 220 patients included in the
randomized portion of the BRAFTOVI/cetuximab and control arm of the
study. A total of 220 patients were randomized to the
BRAFTOVI/cetuximab arm and 221 to the control arm.
The trial was conducted at over 200 investigational sites in
North America, South America, Europe and the Asia Pacific region.
The BEACON CRC trial was conducted with support from Ono
Pharmaceutical Co. Ltd., Pierre Fabre and Merck KGaA, Darmstadt,
Germany (support is for sites outside of North America).
About BRAFTOVI® (encorafenib) in Metastatic Colorectal
Cancer
BRAFTOVI is an oral small molecule kinase inhibitor that targets
BRAF V600E. Inappropriate activation of proteins in the MAPK
signaling pathway (RAS-RAF-MEK-ERK) has been shown to occur in
certain cancers, including colorectal cancer.
In the U.S., BRAFTOVI is indicated, in combination with
cetuximab, for the treatment of adult patients with metastatic
colorectal cancer (CRC) with a BRAFV600E mutation, as detected by
an FDA-approved test, after prior therapy.
Limitations of Use: BRAFTOVI is not
indicated for treatment of patients with wild-type BRAF CRC.
Pfizer has exclusive rights to BRAFTOVI in the U.S. and Canada.
Ono Pharmaceutical Co. Ltd. has exclusive rights to commercialize
the product in Japan and South Korea, Medison has exclusive rights
to commercialize the product in Israel and Pierre Fabre has
exclusive rights to commercialize the product in all other
countries, including Europe, Latin America and Asia (excluding
Japan and South Korea).
IMPORTANT SAFETY
INFORMATION
Refer to the cetuximab prescribing information for recommended
dosing and safety information.
WARNINGS AND PRECAUTIONS
New Primary Malignancies, cutaneous and non-cutaneous,
can occur with BRAFTOVI. In the BEACON CRC trial, cutaneous
squamous cell carcinoma (cuSCC), including keratoacanthoma (KA),
occurred in 1.4% of patients with CRC, and a new primary melanoma
occurred in 1.4% of patients who received BRAFTOVI in combination
with cetuximab. 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 mutationpositive non-cutaneous malignancies.
Tumor Promotion in BRAF Wild-Type Tumors: In vitro
experiments have demonstrated paradoxical activation of MAP-kinase
signaling and increased cell proliferation in BRAF wild-type cells
exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K
mutation using an FDA-approved test prior to initiating
BRAFTOVI.
Hemorrhage: In BEACON CRC, hemorrhage occurred in 19% of
patients receiving BRAFTOVI in combination with cetuximab; Grade 3
or higher hemorrhage occurred in 1.9% of patients, including fatal
gastrointestinal hemorrhage in 0.5% of patients. The most frequent
hemorrhagic events were epistaxis (6.9%), hematochezia (2.3%), and
rectal hemorrhage (2.3%). Withhold, reduce dose, or permanently
discontinue based on severity of adverse reaction.
Uveitis: Uveitis, including iritis and iridocyclitis, has
been reported in patients treated with BRAFTOVI. Assess for visual
symptoms at each visit. Perform an ophthalmological evaluation at
regular intervals and for new or worsening visual disturbances, and
to follow new or persistent ophthalmologic findings. Withhold,
reduce dose, or permanently discontinue based on severity of
adverse reaction.
QT Prolongation: BRAFTOVI is associated with
dose-dependent QTc interval prolongation in some patients. Monitor
patients who already have or who are at significant risk of
developing QTc prolongation, including patients with known long QT
syndromes, clinically significant bradyarrhythmias, severe or
uncontrolled heart failure and those taking other medicinal
products associated with QT 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 can cause fetal harm when
administered to a pregnant woman. Advise females of reproductive
potential to use effective non-hormonal contraception during
treatment with BRAFTOVI and for 2 weeks after the final dose.
Advise females to contact their healthcare provider of a known or
suspected pregnancy.
Lactation: Advise women not to breastfeed during
treatment with BRAFTOVI and for 2 weeks after the final dose.
Infertility: Advise males of reproductive potential that
BRAFTOVI may impair fertility.
Risks Associated with Combination Treatment: BRAFTOVI is
indicated for use as part of a regimen in combination with
cetuximab. Refer to the prescribing information for cetuximab for
additional risk information.
ADVERSE REACTIONS
The most common adverse reactions (≥25%, all grades) in the
BRAFTOVI with cetuximab arm compared to irinotecan with cetuximab
or FOLFIRI with cetuximab (control) were: fatigue (51% vs 50%),
nausea (34% vs 41%), diarrhea (33% vs 48%), dermatitis acneiform
(32% vs 43%), abdominal pain (30% vs 32%), decreased appetite (27%
vs 27%), arthralgia (27% vs 3%), and rash (26% vs 26%). Other
clinically important adverse reactions occurring in <10% of
patients who received BRAFTOVI in combination with cetuximab was
pancreatitis.
The most common laboratory abnormalities (≥20%, all grades) in
the BRAFTOVI with cetuximab arm compared to irinotecan with
cetuximab or FOLFIRI with cetuximab (control) were: anemia (34% vs
48%) and lymphopenia (24% vs 35%).
DRUG INTERACTIONS
Avoid coadministration of BRAFTOVI with strong or moderate
CYP3A4 inhibitors (including grapefruit juice) or CYP3A4 inducers
and use caution with sensitive CYP3A4 substrates. Modify BRAFTOVI
dose if coadministration with a strong or moderate CYP3A4 inhibitor
cannot be avoided. Avoid coadministration of BRAFTOVI with drugs
known to prolong QT/QTc interval or hormonal contraceptives.
Please see full Prescribing Information for BRAFTOVI for
additional information.
About Pfizer Oncology
At Pfizer Oncology, we are committed to advancing medicines
wherever we believe we can make a meaningful difference in the
lives of patients. Today, Pfizer Oncology has an industry-leading
portfolio of 22 approved innovative cancer medicines and
biosimilars across more than 30 indications, including breast,
prostate, kidney and lung cancers, as well as leukemia and
melanoma.
Pfizer Inc.: Breakthroughs that change patients’
lives
At Pfizer, we apply science and our global resources to bring
therapies to people that extend and significantly improve their
lives. We strive to set the standard for quality, safety and value
in the discovery, development and manufacture of health care
products, including innovative medicines and vaccines. Every day,
Pfizer colleagues work across developed and emerging markets to
advance wellness, prevention, treatments and cures that challenge
the most feared diseases of our time. Consistent with our
responsibility as one of the world's premier innovative
biopharmaceutical companies, we collaborate with health care
providers, governments and local communities to support and expand
access to reliable, affordable health care around the world. For
more than 150 years, we have worked to make a difference for all
who rely on us. We routinely post information that may be important
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DISCLOSURE NOTICE: The information contained in this release is
as of April 8, 2020. Pfizer assumes no obligation to update
forward-looking statements contained in this release as the result
of new information or future events or developments.
This release contains forward-looking information about the
BRAFTOVI® (encorafenib) and cetuximab combination and a new
indication in the U.S. for the treatment of adult patients with
metastatic colorectal cancer (CRC) with a BRAFV600E mutation, as
detected by an FDA-approved test, after prior therapy, including
its potential benefits, that involves substantial risks and
uncertainties that could cause actual results to differ materially
from those expressed or implied by such statements. Risks and
uncertainties include, among other things, uncertainties regarding
the commercial success of BRAFTOVI plus cetuximab; the
uncertainties inherent in research and development, including the
ability to meet anticipated clinical endpoints, commencement and/or
completion dates for our clinical trials, regulatory submission
dates, regulatory approval dates and/or launch dates, as well as
the possibility of unfavorable new clinical data and further
analyses of existing clinical data; the risk that clinical trial
data are subject to differing interpretations and assessments by
regulatory authorities; whether regulatory authorities will be
satisfied with the design of and results from our clinical studies;
whether and when applications for BRAFTOVI plus cetuximab for the
new indication may be filed in any other jurisdictions; whether and
when regulatory authorities in any other jurisdictions where
applications may be pending or filed may approve any such
applications, which will depend on myriad factors, including making
a determination as to whether the product’s benefits outweigh its
known risks and determination of the product’s efficacy and, if
approved, whether BRAFTOVI plus cetuximab will be commercially
successful; decisions by regulatory authorities impacting labeling,
manufacturing processes, safety and/or other matters that could
affect the availability and/or commercial potential of BRAFTOVI® or
BRAFTOVI® plus cetuximab; and competitive developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended
December 31, 2019 and in its subsequent reports on Form 10-Q,
including in the sections thereof captioned “Risk Factors” and
“Forward-Looking Information and Factors That May Affect Future
Results”, as well as in its subsequent reports on Form 8-K, all of
which are filed with the U.S. Securities and Exchange Commission
and available at www.sec.gov and www.pfizer.com.
Erbitux® is a registered trademark of ImClone LLC.
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https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf.
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