Pfizer Inc. (NYSE: PFE) today announced that the U.S. Food and
Drug Administration (FDA) has accepted and granted priority review
to the Company’s supplemental New Drug Application (sNDA) for
BRAFTOVI® (encorafenib) in combination with ERBITUX®
(cetuximab) (BRAFTOVI Doublet) based on results from the Phase 3
BEACON CRC trial, which evaluated the efficacy and safety of
BRAFTOVI in combination with ERBITUX with or without MEKTOVI®
(binimetinib) in patients with advanced BRAFV600E-mutant metastatic
colorectal cancer (mCRC), following one or two lines of
therapy.
As published in The New England Journal of Medicine (NEJM),
results from the BEACON CRC trial showed improvements in overall
survival (OS) and objective response rates (ORR) for both the
BRAFTOVI Doublet and BRAFTOVI Triplet (BRAFTOVI, MEKTOVI and
ERBITUX) combination, compared to ERBITUX plus
irinotecan-containing regimens (Control).1 In descriptive analyses
comparing the Doublet and Triplet arms, the results showed
comparable efficacy between the Doublet and Triplet in the overall
population. The BRAFTOVI Triplet and Doublet showed no unexpected
toxicities.
“The FDA’s acceptance of our application for the BRAFTOVI
Doublet is highly encouraging news for patients with mCRC harboring
a BRAFV600E mutation,” said Chris Boshoff, M.D., Ph.D., Chief
Development Officer, Oncology, Pfizer Global Product Development.
“Currently, there are no FDA-approved treatments specifically for
patients with BRAF-mutant mCRC who have received prior treatment.
If approved, the BRAFTOVI Doublet would become the first targeted
regimen for this patient population, who typically have a poor
prognosis. We also look forward to continuing to explore this
targeted Doublet regimen with or without MEKTOVI in earlier lines
of BRAF-mutant mCRC, including in the ongoing, Phase 2 ANCHOR study
in previously untreated patients.”
The FDA grants Priority Review to medicines that may offer
significant advances in treatment or may provide a treatment where
no adequate therapy exists. The Prescription Drug User Fee Act
(PDUFA) goal date for a decision by the FDA is in April 2020.
On November 2, 2019, the European Medicines Agency (EMA) also
started the review procedure for Pierre Fabre’s Type II variation
applications based on the BEACON CRC trial.
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 140,250 patients were diagnosed with cancer of
the colon or rectum in 2018, and approximately 50,000 are estimated
to die of their disease each year.4 BRAF mutations are estimated to
occur in up to 15% of patients with mCRC and represent a poor
prognosis for these patients.5,6,7,8,9,10 The V600 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 mCRC is an area of
high unmet need as there are currently no approved therapies
specifically indicated for patients with BRAF-mutant mCRC.11,12,
13
About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating
the efficacy and safety of BRAFTOVI, MEKTOVI and ERBITUX in
patients with BRAFV600E-mutant mCRC whose disease has progressed
after one or two prior regimens.
The randomized portion of the BEACON CRC trial is designed to
assess the efficacy and safety of BRAFTOVI in combination with
ERBITUX with or without MEKTOVI compared to ERBITUX and
irinotecan-based therapy. 665 patients were randomized 1:1:1 to
receive the Triplet combination, the Doublet combination (BRAFTOVI
and ERBITUX) or the control arm (irinotecan-based therapy and
ERBITUX). The study was amended to include an interim analysis of
endpoints including ORR. The primary overall survival endpoint is a
comparison of the Triplet combination to the control arm. Secondary
endpoints address efficacy of the Doublet combination compared to
the control arm, and the Triplet combination compared to the
doublet therapy. Other secondary endpoints include progression-free
survival, duration of response, safety and tolerability. The trial
is being conducted at over 200 investigational sites in North
America, South America, Europe and the Asia Pacific region. The
BEACON CRC trial is being 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 + MEKTOVI
BRAFTOVI is an oral small molecule BRAF kinase inhibitor and
MEKTOVI is an oral small molecule MEK inhibitor which target key
enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK).
Inappropriate activation of proteins in this pathway has been shown
to occur in many cancers including melanoma and colorectal cancer.
In the U.S., BRAFTOVI + MEKTOVI are approved for the treatment of
unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K
mutation, as detected by an FDA-approved test. BRAFTOVI is not
indicated for treatment of patients with wild-type BRAF melanoma.
In Europe, the combination is approved for adult patients with
unresectable or metastatic melanoma with a BRAFV600 mutation, as
detected by a validated test. In Japan, the combination is approved
for unresectable melanoma with a BRAF mutation.
Pfizer has exclusive rights to BRAFTOVI and MEKTOVI in the U.S.
and Canada. Ono Pharmaceutical Co. Ltd. has exclusive rights to
commercialize both products in Japan and South Korea, Medison has
exclusive rights to commercialize both products in Israel and
Pierre Fabre has exclusive rights to commercialize both products in
all other countries, including Europe, Latin America and Asia
(excluding Japan and South Korea).
Indications and Usage
BRAFTOVI® (encorafenib) and MEKTOVI® (binimetinib) are kinase
inhibitors indicated for use in combination for the treatment of
patients with unresectable or metastatic melanoma with a BRAF V600E
or V600K mutation as detected by an FDA-approved test.
Limitations of Use: BRAFTOVI is not
indicated for treatment of patients with wild-type BRAF
melanoma.
BRAFTOVI + MEKTOVI Important Safety Information
The information below applies to the safety of the
combination of BRAFTOVI and MEKTOVI unless otherwise noted. See
full Prescribing Information for BRAFTOVI and for MEKTOVI for dose
modifications for adverse reactions.
WARNINGS AND PRECAUTIONS
New Primary Malignancies, cutaneous and non-cutaneous
malignancies can occur. In the COLUMBUS trial, cutaneous squamous
cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in
2.6% and basal cell carcinoma occurred in 1.6% of patients. Median
time to first occurrence of cuSCC/KA was 5.8 months. 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.
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 prior to initiating BRAFTOVI.
Cardiomyopathy, manifesting as left ventricular
dysfunction associated with symptomatic or asymptomatic decreases
in ejection fraction, has been reported in patients. In the
COLUMBUS trial, evidence of cardiomyopathy occurred in 7% and Grade
3 left ventricular dysfunction occurred in 1.6% of patients. The
median time to first occurrence of left ventricular dysfunction
(any grade) was 3.6 months. Cardiomyopathy resolved in 87% of
patients. Assess LVEF by echocardiogram or 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.
Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE
occurred in 6% of patients, including 3.1% of patients who
developed pulmonary embolism.
Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in
19% of patients and ≥ Grade 3 hemorrhage occurred in 3.2% of
patients. Fatal intracranial hemorrhage in the setting of new or
progressive brain metastases occurred in 1.6% of patients. The most
frequent hemorrhagic events were gastrointestinal, including rectal
hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage
(1%).
Ocular Toxicities: In the COLUMBUS trial, serous
retinopathy occurred in 20% of patients; 8% were retinal detachment
and 6% were macular edema. Symptomatic serous retinopathy occurred
in 8% of patients with no cases of blindness. The median time to
onset of the first event of serous retinopathy (all grades) was 1.2
months. RVO is a known class-related adverse reaction of MEK
inhibitors and may occur in patients treated with MEKTOVI in
combination with encorafenib. In patients with BRAF
mutation-positive melanoma across multiple clinical trials, 0.1% of
patients experienced retinal vein occlusion (RVO). The safety of
MEKTOVI has not been established in patients with a history of RVO
or current risk factors for RVO including uncontrolled glaucoma or
a history of hyperviscosity or hypercoagulability syndromes.
Perform ophthalmological evaluation for patient-reported acute
vision loss or other visual disturbance within 24 hours.
Permanently discontinue MEKTOVI in patients with documented RVO. In
COLUMBUS, uveitis, including iritis and iridocyclitis was reported
in 4% of patients treated with MEKTOVI in combination 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.
Interstitial Lung Disease (ILD): ILD, including
pneumonitis occurred in 0.3% of patients with BRAF
mutation-positive melanoma across multiple clinical trials. Assess
new or progressive unexplained pulmonary symptoms or findings for
possible ILD.
Hepatotoxicity: In the COLUMBUS trial, the incidence of
Grade 3 or 4 increases in liver function laboratory tests was 6%
for alanine aminotransferase (ALT), 2.6% for aspartate
aminotransferase (AST), and 0.5% for alkaline phosphatase. No
patient experienced Grade 3 or 4 serum bilirubin elevation. Monitor
liver laboratory tests before initiation of MEKTOVI, monthly during
treatment, and as clinically indicated.
Rhabdomyolysis: In the COLUMBUS trial, elevation of
laboratory values of serum CPK occurred in 58% of patients.
Rhabdomyolysis was reported in 0.1% of patients with BRAF
mutation-positive melanoma receiving MEKTOVI with encorafenib
across multiple clinical trials. Monitor CPK and creatinine levels
prior to initiating MEKTOVI, periodically during treatment, and as
clinically indicated.
QTc Prolongation: BRAFTOVI is associated with
dose-dependent QTc interval prolongation in some patients. In the
COLUMBUS trial, an increase in QTcF to > 500 ms was measured in
0.5% (1/192) of 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 or MEKTOVI can cause
fetal harm when administered to pregnant women. BRAFTOVI can render
hormonal contraceptives ineffective. Nonhormonal contraceptives
should be used during treatment and for at least 30 days after the
final dose for patients taking BRAFTOVI + MEKTOVI.
Risks Associated with BRAFTOVI as a Single Agent: There
is an increased risk of certain adverse reactions compared to when
BRAFTOVI is used in combination with MEKTOVI. Grades 3 or 4
dermatologic reactions occurred in 21% of BRAFTOVI single agent
compared to 2% in patients treated with BRAFTOVI in combination
with MEKTOVI. If MEKTOVI is temporarily interrupted or permanently
discontinued, reduce the dose of BRAFTOVI as recommended.
ADVERSE REACTIONS
The most common adverse reactions (≥20%, all Grades, in the
COLUMBUS trial): were fatigue (43%), nausea (41%), diarrhea (36%),
vomiting (30%), abdominal pain (28%), arthralgia (26%), myopathy
(23%), hyperkeratosis (23%), rash (22%), headache (22%),
constipation (22%), visual impairment (20%), serous retinopathy
(20%). Other clinically important adverse reactions occurring in
<10% of patients in the COLUMBUS Trial were facial paresis,
pancreatitis, panniculitis, drug hypersensitivity and colitis.
In the COLUMBUS Trial, the most common laboratory abnormalities
(all grades) (≥ 20%) included increased creatinine (93%), increased
creatine phosphokinase (58%), increased gamma glutamyl transferase
(GGT) (45%), anemia (36%), increased ALT (29%), hyperglycemia
(28%), increased AST (27%), and increased alkaline phosphatase
(21%).
DRUG INTERACTIONS
Avoid concomitant use of strong or moderate CYP3A4 inhibitors or
inducers and sensitive CYP3A4 substrates with BRAFTOVI. Modify
BRAFTOVI dose if concomitant use of strong or moderate CYP3A4
inhibitors cannot be avoided. Avoid coadministration of BRAFTOVI
with medicinal products with a known potential to prolong QT/QTc
interval.
Please see full Prescribing Information for BRAFTOVI
and full Prescribing Information for MEKTOVI for additional
information.14,15
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 Oncology is striving to change the trajectory of
cancer.
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 Dec. 18, 2019. 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 ERBITUX® (cetuximab) combination
(BRAFTOVI Doublet)and a potential new indication for the treatment
of advanced BRAFV600E-mutant metastatic colorectal cancer,
following one or two lines of 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 the BRAFTOVI Doublet; 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; risks associated with interim 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 drug applications for the
Doublet combination for the potential new indication may be filed
with regulatory authorities in any other jurisdictions; whether and
when the FDA and the European Medicines Agency will approve the
pending applications for the potential new indication and whether
and when regulatory authorities in any other jurisdictions may
approve any such other applications that may be pending or filed,
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 the Doublet combination for the potential new
indication 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®, MEKTOVI® or the Doublet
Combination; 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, 2018 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.
1 Kopetz, S., Grothey, A., Yaeger, R., et al. (2019).
Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated
Colorectal Cancer. New England Journal of Medicine, 381(17),
1632-1643. doi: 10.1056/NEJMoa1908075
2 Global Cancer Facts & Figures 3rd Edition. American Cancer
Society. 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-3rd-edition.pdf.
Accessed January 2018
3 Bray, F., Ferlay, J., Soerjomataram, I., et al. (2018). Global
cancer statistics 2018: GLOBOCAN estimates of incidence and
mortality worldwide for 36 cancers in 185 countries. CA: A Cancer
Journal for Clinicians, 68(6), 394-424. doi:10.3322/caac.21492
4 Cancer Facts & Figures 2018. American Cancer Society.
Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-factsand-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf.
Accessed January 2018.
5 Saridaki, Z., Tzardi, M., Sfakianaki, M., et al. (2013).
BRAFV600E Mutation Analysis in Patients with Metastatic Colorectal
Cancer (mCRC) in Daily Clinical Practice: Correlations with
Clinical Characteristics, and Its Impact on Patients’ Outcome. PLoS
ONE, 8(12). doi:10.1371/journal.pone.0084604
6 Loupakis, F., Ruzzo, A., Cremolini, C., et al. (2009). KRAS
codon 61, 146 and BRAF mutations predict resistance to cetuximab
plus irinotecan in KRAS codon 12 and 13 wild-type metastatic
colorectal cancer. British journal of cancer, 101(4), 715–721.
doi:10.1038/sj.bjc.6605177
7 Corcoran, R. B., Ebi, H., Turke, A. B., Coffee, et al. (2012).
EGFR-mediated re-activation of MAPK signaling contributes to
insensitivity of BRAF mutant colorectal cancers to RAF inhibition
with vemurafenib. Cancer discovery, 2(3), 227–235.
doi:10.1158/2159-8290.CD-11-0341
8 Sorbye, H., Dragomir, A., Sundstr�m, M., et al. (2015). High
BRAF Mutation Frequency and Marked Survival Differences in
Subgroups According to KRAS/BRAF Mutation Status and Tumor Tissue
Availability in a Prospective Population-Based Metastatic
Colorectal Cancer Cohort. PLoS ONE, 10(6), e0131046.
doi:10.1371/journal.pone.0131046
9 Safaee Ardekani, G., Jafarnejad, S. M., Tan, L., et al.
(2012). The prognostic value of BRAF mutation in colorectal cancer
and melanoma: a systematic review and meta-analysis. PLoS ONE,
7(10), e47054. doi:10.1371/journal.pone.0047054
10 Vecchione, L., Gambino, V., Raaijmakers, J., et al. (2016). A
Vulnerability of a Subset of Colon Cancers with Potential Clinical
Utility. Cell,165(2), 317-330. doi:10.1016/j.cell.2016.02.059
11 Referenced with permission from the NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer.
V.2.2019.
12 Van Cutsem, E., Cervantes, A., Adam, R., et al. (2016). ESMO
consensus guidelines for the management of patients with metastatic
colorectal cancer. Ann Oncol. 27(8):1386-422. doi:
10.1093/annonc/mdw235
13 Ursem, C., Atreya, C. E., & Van Loon, K. (2018). Emerging
treatment options for BRAF-mutant colorectal cancer.
Gastrointestinal cancer : targets and therapy, 8, 13–23.
doi:10.2147/GICTT.S125940
14 BRAFTOVI® (encorafenib) Prescribing Information. Array
BioPharma Inc., June 2018
15 MEKTOVI® (binimetinib) Prescribing Information. Array
BioPharma Inc., June 2018
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Pfizer Media Contact: Jessica Smith (212) 733-6213
Jessica.M.Smith@pfizer.com
Pfizer Investor Contact: Ryan Crowe (212) 733-8160
Ryan.Crowe@pfizer.com
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