- Clinically meaningful and statistically significant results
from the Phase 3 BREAKWATER trial show objective response rate of
61% with Pfizer’s BRAFTOVI combination regimen compared to 40% with
investigator’s choice of chemotherapy, representing a doubling of
the odds of achieving an objective response
- BRAFTOVI combination regimen is the first and only targeted
therapy approved by the U.S. FDA for treatment-naïve patients with
metastatic colorectal cancer with a BRAF V600E mutation
Pfizer Inc. (NYSE: PFE) today announced positive results from
the Phase 3 BREAKWATER trial evaluating BRAFTOVI® (encorafenib) in
combination with cetuximab (marketed as ERBITUX®) and mFOLFOX6
(fluorouracil, leucovorin, and oxaliplatin) in patients with
metastatic colorectal cancer (mCRC) with a BRAF V600E mutation. At
the time of this analysis, the BRAFTOVI combination regimen
demonstrated a clinically meaningful and statistically significant
improvement in confirmed objective response rate (ORR) assessed by
blinded independent central review (BICR) compared to patients
receiving chemotherapy with or without bevacizumab (60.9% vs 40.0%,
odds ratio =2.443, p=0.0008). These results will be presented today
in an oral presentation (Abstract 16) at the 2025 American Society
of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI)
and were simultaneously published in Nature Medicine.
“Despite the high unmet need in this patient population, prior
to the recent encorafenib combination regimen approval, there were
no approved biomarker-driven therapies indicated for people with
previously untreated BRAF V600E-mutant metastatic colorectal
cancer,” 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. “These data from the BREAKWATER study show
the potential for this targeted treatment regimen to become the new
standard of care for people with BRAF V600E-mutant metastatic
colorectal cancer, for whom long-term disease control is
critical.”
The estimated median duration of response as assessed by BICR
was 13.9 months (95% Confidence Interval [CI]: 8.5-not estimable
[NE]) with BRAFTOVI plus cetuximab and mFOLFOX6 and 11.1 months
(95% CI: 6.7-12.7) with chemotherapy with or without bevacizumab.
Of patients on BRAFTOVI plus cetuximab and mFOLFOX6, 22.4% (n=15)
had a response lasting 12 months or longer, compared to 11.4% (n=5)
with chemotherapy with or without bevacizumab. The median time to
response as assessed by BICR was 7.1 weeks (range 5.7-53.7) with
BRAFTOVI plus cetuximab and mFOLFOX6 and 7.3 weeks (range 5.4-48.0)
with chemotherapy with or without bevacizumab.
Overall survival (OS) data were immature at the time of this
analysis but demonstrated a promising trend in favor of BRAFTOVI
plus cetuximab and mFOLFOX6 compared to patients receiving
chemotherapy with or without bevacizumab. Median OS with BRAFTOVI
plus cetuximab with chemotherapy was not estimable (95% CI:
19.8-NE) and 14.6 months (95% CI: 13.4-NE) with chemotherapy with
or without bevacizumab (Hazard Ratio [HR]: 0.47, 95% CI:
0.318-0.691). The BREAKWATER trial is ongoing for OS and
progression-free survival (PFS), with PFS results expected in
2025.
“These results of this first analysis were the basis for the
first approval of a targeted therapy regimen for use in the
first-line setting for patients with metastatic colorectal cancer
with a BRAF V600E mutation,” said Roger Dansey, M.D., Chief
Oncology Officer, Pfizer. “We are highly encouraged by these
response results, which are indicative of the clinically meaningful
benefit of BRAFTOVI in reducing tumor size or having no detectable
cancer, along with the promising interim analysis of overall
survival. We look forward to additional read-outs from the
BREAKWATER trial this year.”
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. Serious treatment-emergent adverse events occurred in
37.7% of patients receiving BRAFTOVI in combination with cetuximab
and mFOLFOX6 compared to 34.6% of patients receiving chemotherapy
with or without bevacizumab.
BRAFTOVI in combination with cetuximab and mFOLFOX6 was granted
accelerated approval by the U.S. Food and Drug Administration (FDA)
for the treatment of patients with BRAF V600E-mutant mCRC in
December 2024. The approval was 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. 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.
Pfizer is continuing its commitment to help non-scientists
understand the latest findings with the development of abstract
plain language summaries (APLS) for company-sponsored research
being presented, which are written in non-technical language. Those
interested in learning more can visit www.Pfizer.com/apls to access
the summaries.
About BREAKWATER
BREAKWATER is a Phase 3, randomized, active-controlled,
open-label, multicenter trial of BRAFTOVI with cetuximab, alone or
in combination with mFOLFOX6 in participants with previously
untreated BRAF V600E-mutant mCRC. 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, which was met at the time of analysis, and PFS
as assessed by BICR. OS is a key secondary endpoint.
About Colorectal Cancer (CRC)
CRC is the third most common type of cancer in the world, with
approximately 1.8 million new diagnoses in 2022.1 It is the second
leading cause of cancer-related deaths.2 Overall, the lifetime risk
of developing CRC is about 1 in 24 for men and 1 in 26 for women.2
In the U.S. alone, an estimated 154,270 people will be diagnosed
with cancer of the colon or rectum in 2025, and approximately
53,000 are estimated to die from the disease each year.3 For 20% of
those diagnosed with CRC, the disease has metastasized, or spread,
making it harder to treat, and up to 50% of patients with localized
disease eventually develop metastases.4
BRAF mutations are estimated to occur in 8-12% of people with
mCRC and represent a poor prognosis for these patients.5 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.5,6 Despite
the high unmet need in BRAF V600E-mutant mCRC, prior to December
20, 2024, there were no approved biomarker-driven therapies
specifically indicated for people with previously untreated BRAF
V600E-mutant mCRC.7,8
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 Laboratories has exclusive
rights to commercialize the product in all other countries,
including Europe and Asia (excluding Japan and South Korea).
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 also 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.
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
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Disclosure Notice
The information contained in this release is as of January 25,
2025. 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
an indication in the U.S. for the treatment of metastatic
colorectal cancer (mCRC) 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; whether the BREAKWATER trial
will meet the primary endpoint of PFS or the secondary endpoint of
OS; 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 BRAFV600E 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
- 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: January 2025.
- 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: January 2025.
- American Cancer Society. Cancer Facts & Figures 2025.
Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2025/2025-cancer-facts-and-figures-acs.pdf.
Last accessed: January 2025.
- 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.
- Josep Tabernero et al., The Evolving Treatment Landscape in
BRAF-V600E–Mutated Metastatic Colorectal Cancer. Am Soc Clin Oncol
Educ Book 42, 254-263(2022). DOI:10.1200/EDBK_349561
- 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.
- 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 version of the
guideline, go online to NCCN.org.
- Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal
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and follow-up. Ann Oncol. 2023;34(1):10–32.
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