- BRAFTOVI in combination with cetuximab and mFOLFOX6 is the
first and only combination regimen with targeted therapy approved
for use as early as first-line for patients with metastatic
colorectal cancer with a BRAF V600E mutation
- Accelerated approval is based on 61% overall response rate
compared to 40% in control arm in the Phase 3 BREAKWATER trial
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®) and mFOLFOX6
(fluorouracil, leucovorin, and oxaliplatin) for the treatment of
patients with metastatic colorectal cancer (mCRC) with a BRAF V600E
mutation, as detected by an FDA-approved test.i The indication was
approved based on a statistically significant and clinically
meaningful improvement in response rate and durability of response
in treatment-naïve patients treated with BRAFTOVI in combination
with cetuximab and mFOLFOX6 from the Phase 3 BREAKWATER trial.
Continued approval for this indication is contingent upon
verification of clinical benefit. This accelerated approval is
among the first in the industry to be conducted under the FDA’s
Project FrontRunner, which seeks to support the development and
approval of new cancer drugs for advanced or metastatic
disease.
“Historically, treatment options have been limited and outcomes
poor for patients diagnosed with metastatic colorectal cancer with
BRAF mutations,” said Scott Kopetz, M.D., Ph.D., FACP, Professor
and Deputy Chair of Gastrointestinal Medical Oncology at The
University of Texas MD Anderson Cancer Center and co-principal
investigator of the BREAKWATER trial. “As the first and only
combination regimen featuring a BRAF-targeted therapy for this
patient population, usable even in first-line treatment, the
encorafenib regimen has demonstrated high response rates that are
rapid and durable. This represents an encouraging sign of continued
disease control and a source of renewed hope for patients.”
The ongoing BREAKWATER trial is evaluating BRAFTOVI plus
cetuximab with or without chemotherapy (mFOLFOX6) in previously
untreated mCRC patients who harbor a BRAF V600E mutation. It is the
only Phase 3 trial for a BRAF-targeted therapy regimen in
first-line BRAF V600E-mutant mCRC. The trial met one of the dual
primary endpoints of confirmed overall response rate (ORR), with a
statistically significant improvement over standard of care: ORR
61% (95% confidence interval [CI]: 52, 70) for BRAFTOVI in
combination with cetuximab and mFOLFOX6 compared with ORR 40% (95%
CI: 31, 49) for chemotherapy, with or without bevacizumab
(p=0.0008).1 The median duration of response (DoR) was 13.9 months
(95% CI: 8.5, not estimable) for the BRAFTOVI combination regimen
versus 11.1 months (95% CI: 6.7, 12.7) for chemotherapy, with or
without bevacizumab.1 The Phase 3 BREAKWATER trial is ongoing, and
results from the full dataset will be presented at upcoming medical
meetings.
“For more than a decade, Pfizer has been a pioneer in delivering
targeted therapies for molecular-driven cancers. With today’s
accelerated approval of the BRAFTOVI regimen, patients with
metastatic colorectal cancer with a BRAF V600E mutation now have a
first-line treatment option, which contains a targeted therapy
specifically for a mutation that is driving their cancer,” said
Chris Boshoff, M.D., Ph.D., Chief Oncology Officer, Executive Vice
President, Pfizer. “This milestone adds to our legacy of developing
innovative medicines in BRAF tumors, some of the hardest-to-treat
cancers. We look forward to continuing to expand our portfolio,
including the exploration of a next-generation brain-penetrant BRAF
inhibitor.”
The safety profile of BRAFTOVI in combination with cetuximab and
mFOLFOX6 in the BREAKWATER trial was consistent with the known
safety profile of each respective agent. No new safety signals were
identified. The most common adverse reactions (≥25%) were
peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased
appetite, vomiting, hemorrhage, abdominal pain, and pyrexia.1 Among
patients receiving BRAFTOVI in combination with cetuximab and
mFOLFOX6, 12% experienced an adverse reaction that resulted in
permanent discontinuation of BRAFTOVI; the most common adverse
reactions (≥1%) included elevated lipase levels.
“Finding out that your cancer has spread can be a frightening
time for those with colorectal cancer and their loved ones. The
prognosis for those receiving a metastatic colorectal cancer
diagnosis has improved slightly in recent years, but the same
cannot be said for those with a BRAF mutation who unfortunately
face an especially aggressive disease and worse outcomes,” said
Michael Sapienza, Chief Executive Officer of the Colorectal Cancer
Alliance. “Today’s approval of the first combination regimen
including a BRAF-targeted therapy for BRAF V600E-mutant metastatic
colorectal cancer, which can be used for previously untreated
patients, offers new promise for the community and marks an
important step forward in our collective mission to end this
disease.”
This application was granted priority review, used the Real-Time
Oncology Review (RTOR) pilot program, and was conducted under
Project Orbis, with application reviews ongoing for Project Orbis
partners, including Canada and Brazil. The BREAKWATER data are also
being discussed with other regulatory authorities around the world
to support potential future additional license applications for the
BRAFTOVI combination regimen in this indication. This accelerated
approval follows the previous FDA approval for BRAFTOVI in
combination with cetuximab for adults with mCRC with a BRAF V600E
mutation after prior therapy.
About Colorectal Cancer (CRC)
CRC is the third most common type of cancer in the world, with
approximately 1.8 million new diagnoses in 2022.2 Overall, the
lifetime risk of developing CRC is about 1 in 23 for men and 1 in
25 for women.3 In the U.S. alone, an estimated 152,810 people will
be diagnosed with cancer of the colon or rectum in 2024, and
approximately 53,000 are estimated to die from the disease each
year.4 For 20% of those diagnosed with CRC, the disease has
metastasized, or spread, making it harder to treat.5
BRAF mutations are estimated to occur in 8-10% of people with
mCRC and represent a poor prognosis for these patients.6 The BRAF
V600E mutation is the most common BRAF mutation and the risk of
mortality in CRC patients with the BRAF V600E mutation is more than
double that of patients with no known mutation present.6,7 Despite
the high unmet need in BRAF V600E-mutant mCRC, prior to today there
were no approved biomarker-driven therapies specifically indicated
for people with previously untreated BRAF V600E-mutant mCRC.8,9
About BREAKWATER
BREAKWATER is a Phase 3, randomized, active-controlled,
open-label, multicenter trial of BRAFTOVI with cetuximab, alone or
in combination with chemotherapy, in participants with previously
untreated BRAF V600E-mutant mCRC. In the Phase 3 portion of the
study, patients were randomized to receive BRAFTOVI 300 mg orally
once-daily in combination with cetuximab (discontinued after
randomization of 158 patients), BRAFTOVI 300 mg orally once-daily
in combination with cetuximab and mFOLFOX6 (n=236), or mFOLFOX6,
FOLFOXIRI, or CAPOX each with or without bevacizumab (control arm)
(n=243).
The dual primary endpoints are ORR and progression-free survival
(PFS), as assessed by blinded independent central review (BICR).
Key secondary endpoints include DoR as assessed by BICR, time to
response by BICR, overall survival, and safety.
About BRAFTOVI® (encorafenib)
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 CRC.
Pfizer has exclusive rights to BRAFTOVI in the U.S., Canada,
Latin America, Middle East, and Africa. 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
and Asia (excluding Japan and South Korea).
U.S. INDICATION AND USAGE
BRAFTOVI® (encorafenib) is indicated, in combination with
cetuximab and mFOLFOX6, for the treatment of patients with
metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as
detected by an FDA-approved test. This indication is approved under
accelerated approval based on response rate and durability of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in a
confirmatory trial(s).
BRAFTOVI is indicated, in combination with cetuximab, for the
treatment of adult patients with mCRC with a BRAF V600E 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.
IMPORTANT SAFETY INFORMATION
Refer to the prescribing information for cetuximab and
individual product components of mFOLFOX6 for recommended dosing
and additional safety information.
WARNINGS AND PRECAUTIONS
New Primary Malignancies: New primary malignancies,
cutaneous and non-cutaneous, can occur. In BEACON CRC (previously
treated BRAF V600E mutation-positive mCRC), 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. In
BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC)
skin papilloma was reported in 2.6%, basal cell carcinoma in 1.3%,
squamous cell carcinoma of skin in 0.9%, keratoacanthoma in 0.4%
and malignant melanoma in situ in 0.4% of patients who received
BRAFTOVI in combination with cetuximab and mFOLFOX6. 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
mutation-positive non-cutaneous malignancies. Monitor patients for
new malignancies prior to initiation of treatment, while on
treatment, and after discontinuation of treatment.
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.
Cardiomyopathy: Cardiomyopathy manifesting as left
ventricular dysfunction associated with symptomatic or asymptomatic
decreases in ejection fraction, has been reported in patients.
Assess left ventricular ejection fraction (LVEF) by echocardiogram
or multi-gated acquisition (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 (LLN). Patients
with cardiovascular risk factors should be monitored closely.
Withhold, reduce dose, or permanently discontinue based on severity
of adverse reaction.
Hepatotoxicity: Hepatotoxicity can occur. In BREAKWATER
(previously untreated BRAF V600E mutation-positive mCRC), the
incidence of Grade 3 or 4 increases in liver function laboratory
tests in patients receiving BRAFTOVI in combination with cetuximab
and mFOLFOX6 was 2.2% for alkaline phosphatase, 1.3% for ALT, and
0.9% for AST. Monitor liver laboratory tests before initiation of
BRAFTOVI, monthly during treatment, and as clinically indicated.
Withhold, reduce dose, or permanently discontinue based on severity
of adverse reaction.
Hemorrhage: In BEACON CRC (previously treated BRAF V600E
mutation-positive mCRC), 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%). In BREAKWATER (previously untreated BRAF
V600E mutation-positive mCRC), hemorrhage occurred in 30% of
patients receiving BRAFTOVI in combination with cetuximab and
mFOLFOX6; Grade 3 or 4 hemorrhage occurred in 3% of patients.
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. In
BREAKWATER (previously untreated BRAF V600E mutation-positive
mCRC), an increase of QTcF >500 ms was measured in 3.6% (8/222)
of patients receiving BRAFTOVI in combination with cetuximab and
mFOLFOX6. 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 pregnant women. BRAFTOVI can render hormonal
contraceptives ineffective. Advise females of reproductive
potential to use effective nonhormonal contraception during
treatment with BRAFTOVI and for 2 weeks after the final dose.
Risks Associated with Combination Treatment: BRAFTOVI is
indicated for use as part of a regimen in combination with
cetuximab, or in combination with cetuximab and mFOLFOX6. Refer to
the prescribing information for cetuximab and individual product
components of mFOLFOX6 for additional risk information.
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.
ADVERSE REACTIONS
BREAKWATER Trial (previously untreated BRAF V600E
mutation-positive mCRC)
- Serious adverse reactions occurred in 38% of patients
who received BRAFTOVI in combination with cetuximab and mFOLFOX6.
Serious adverse reactions in >3% of patients included intestinal
obstruction (3.5%) and pyrexia (3.5%).
- Fatal gastrointestinal perforation occurred in 0.9% of
patients who received BRAFTOVI in combination with cetuximab and
mFOLFOX6.
- Most common adverse reactions (≥25%, all grades) in the
BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the control
arm (mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ±
bevacizumab) were peripheral neuropathy (62% vs 53%), nausea (51%
vs 48%), fatigue (49% vs 38%), rash (31% vs 4%), diarrhea (34% vs
47%), decreased appetite (33% vs 25%), vomiting (33% vs 21%),
hemorrhage (30% vs 18%), abdominal pain (26% vs 27%), and pyrexia
(26% vs 14%).
- Most common laboratory abnormalities (≥10%, grade 3 or
4) in the BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the
control arm (mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or
CAPOX ± bevacizumab) were: increased lipase (51% vs 25%), decreased
neutrophil count (36% vs 34%), decreased hemoglobin (13% vs 5%),
decreased white blood cell count (12% vs 7%), and increased glucose
(11% vs 2%).
BEACON CRC Trial (previously treated BRAF V600E
mutation-positive mCRC)
- 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.
- Most common laboratory abnormalities (all grades) (≥20%)
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
Strong or moderate CYP3A4 inhibitors: Avoid
coadministration of BRAFTOVI with strong or moderate CYP3A4
inhibitors, including grapefruit juice. If coadministration is
unavoidable, reduce the BRAFTOVI dose.
Strong CYP3A4 inducers: Avoid coadministration of
BRAFTOVI with strong CYP3A4 inducers.
Sensitive CYP3A4 substrates: Avoid the coadministration
of BRAFTOVI with CYP3A4 substrates (including hormonal
contraceptives) for which a decrease in plasma concentration may
lead to reduced efficacy of the substrate. If the coadministration
cannot be avoided, see the CYP3A4 substrate product labeling for
recommendations.
Dose reductions of drugs that are substrates of OATP1B1,
OATP1B3, or BCRP may be required when used concomitantly with
BRAFTOVI.
Avoid coadministration of BRAFTOVI with drugs known to
prolong QT/QTc interval.
View the full Prescribing Information. There may be a delay as
the document is updated with the latest information. It will be
available as soon as possible. Please check back for the updated
full information shortly.
About Pfizer Oncology
At Pfizer Oncology, we are at the forefront of a new era in
cancer care. Our industry-leading portfolio and extensive pipeline
includes three core mechanisms of action to attack cancer from
multiple angles, including small molecules, antibody-drug
conjugates (ADCs), and bispecific antibodies, including other
immune-oncology biologics. We are focused on delivering
transformative therapies in some of the world’s most common
cancers, including breast cancer, genitourinary cancer,
hematology-oncology, and thoracic cancers, which includes lung
cancer. Driven by science, we are committed to accelerating
breakthroughs to help people with cancer live better and longer
lives.
About Pfizer: 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
175 years, we have worked to make a difference for all who rely on
us. We routinely post information that may be important to
investors on our website at www.Pfizer.com. In addition, to learn
more, please visit us on www.Pfizer.com and follow us on X at
@Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook
at Facebook.com/Pfizer.
Disclosure Notice
The information contained in this release is as of December 20,
2024. 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) plus cetuximab and mFOLFOX6 combination and
a new indication in the U.S. for the treatment of patients with
metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as
detected by an FDA-approved test, including their potential
benefits and discussions with other regulatory authorities to
support potential future additional license applications for the
BRAFTOVI combination regimen in this indication, 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 and mFOLFOX6; 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 any drug
applications may be filed in any additional jurisdictions for
BRAFTOVI plus cetuximab and mFOLFOX6 for the treatment of patients
with metastatic CRC with a BRAF V600E mutation or in any
jurisdictions for any other potential indications for BRAFTOVI;
whether and when any such other applications may be approved by
regulatory authorities, which will depend on a 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 and mFOLFOX6 will be commercially successful; decisions
by regulatory authorities impacting labeling, manufacturing
processes, safety and/or other matters that could affect the
availability or commercial potential of BRAFTOVI or BRAFTOVI plus
cetuximab and mFOLFOX6; uncertainties regarding the impact of
COVID-19 on Pfizer’s business, operations and financial results;
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, 2023, 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 Eli Lilly and Company and
Merck KGaA, Darmstadt, Germany.
References
______________________
1 BRAFTOVI (encorafenib) Prescribing Information. Array
BioPharma, Inc.; December 2024 2 American Cancer Society. Global
Cancer Facts & Figures 5th Edition. 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-2024.pdf.
Last accessed: December 2024. 3 American Cancer Society. Key
Statistics for Colorectal Cancer. Available at:
https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html.
Last accessed: December 2024. 4 American Cancer Society. Cancer
Facts & Figures 2024. Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf.
Last accessed: December 2024. 5 Ciardiello F, Ciardiello D, Martini
G, et al. Clinical management of metastatic colorectal cancer in
the era of precision medicine. CA Cancer J Clin. 2022;72:372–40. 6
Djanani A, Eller S, Öfner D, et al. The role of BRAF in metastatic
colorectal carcinoma-past, present, and future. Int J Mol Sci.
2020;21(23):9001. 7 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. 8 NCCN Clinical Practice Guidelines in Oncology
(NCCN Guidelines) for Colon Cancer. V.5.2024 © National
Comprehensive Cancer Network, Inc. 2024. All rights reserved.
Accessed December 2024. To view the most recent and complete
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