- Results to be presented during a
late-breaking oral session at the 2019 ESMO Congress and
simultaneously published in The New England Journal of Medicine
–
- As previously announced, BRAFTOVI
combinations showed statistically significant improvements in OS
and ORR versus control –
Pfizer Inc. (NYSE: PFE) today announced detailed results from
the interim analysis of the Phase 3 BEACON CRC trial evaluating the
combination of BRAFTOVI® (encorafenib), MEKTOVI® (binimetinib), and
cetuximab (BRAFTOVI Triplet), in patients with advanced
BRAFV600E-mutant metastatic colorectal cancer (mCRC), following one
or two lines of therapy. The results show significant improvements
in overall survival (OS) and objective response rates (ORR) for the
BRAFTOVI Triplet and BRAFTOVI Doublet combination (BRAFTOVI and
cetuximab), compared to cetuximab plus irinotecan-containing
regimens (Control), and provide analysis of the efficacy and safety
of the BRAFTOVI Triplet compared to the BRAFTOVI Doublet. These
data will be presented today during a late-breaking oral session at
the 2019 European Society for Medical Oncology (ESMO) Congress in
Barcelona, Spain, and simultaneously published online in The New
England Journal of Medicine (NEJM). Pfizer intends to submit the
results of the BEACON CRC trial for marketing approval in the U.S.
in the fourth quarter of 2019. The use of BRAFTOVI, MEKTOVI and
cetuximab for the treatment of patients with BRAFV600E-mutant mCRC
is investigational and not approved by the FDA.
As previously announced, the BRAFTOVI Triplet showed a median OS
of 9.0 months for patients treated with the Triplet, compared to
5.4 months for Control ([HR 0.52, (95% CI 0.39-0.70),
p<0.0001]). The BRAFTOVI Triplet also demonstrated a
significantly improved ORR of 26% (95% CI: 18%, 35%) compared to 2%
(95% CI: 0%, 7%) for Control (p<0.0001).
“We are pleased to share these data from the BEACON CRC trial
with the oncology community,” said Chris Boshoff, M.D., Ph.D.,
Chief Development Officer, Oncology, Pfizer Global Product
Development. “With no approved therapies currently indicated
specifically for BRAF-mutant mCRC, we believe that the evidence so
far shows encouraging potential for the BRAFTOVI Triplet to make a
meaningful impact on the lives of those living with this
disease.”
The study also showed improvements in secondary efficacy
endpoints. As previously announced, the BRAFTOVI Doublet showed a
statistically significant improvement in OS (median 8.4 months vs.
5.4 months, [HR 0.60, 95% CI (0.45-0.79), p=0.0003]) compared to
Control. Additional analysis showed depth of responses in favor of
the BRAFTOVI Triplet.
“The BEACON CRC trial results show meaningful improvements
compared to an available standard of care for patients with
BRAFV600E-mutant mCRC," said Scott Kopetz, M.D., Ph.D., FACP,
Associate Professor of Gastrointestinal Medical Oncology at The
University of Texas MD Anderson Cancer Center. “These data
presented at ESMO and published in The NEJM further support the
potential of the BRAFTOVI Triplet to be the first
chemotherapy-free, targeted regimen for this patient population,
who have a poor prognosis and limited treatment options."
Further, the data provide additional details on the primary and
secondary endpoints, including observations of response rates by
number of lines of prior therapy, as well as a descriptive analysis
of OS comparing the BRAFTOVI Triplet to the BRAFTOVI Doublet.
The BEACON CRC study was not powered to compare the two
experimental arms directly and such a comparison is further limited
by the interim nature of the analysis. In the data being presented
at ESMO, results of the descriptive analysis of survival comparing
the BRAFTOVI Triplet to the BRAFTOVI Doublet favored the Triplet
combination.
As previously reported, the BRAFTOVI Triplet and Doublet were
generally well-tolerated with no unexpected toxicities. Grade 3 or
higher adverse events (AEs) were seen in 58%, 50% and 61% of
patients in the BRAFTOVI Triplet, Doublet and Control arms,
respectively. Discontinuation of therapy due to adverse events was
seen in 7%, 8% and 11% of patients in the Triplet, Doublet and
Control arms, respectively. The most common Grade 3 or higher AEs
seen in patients treated with the BRAFTOVI Triplet were diarrhea
(10% vs. 2% in the Doublet arm and 10% in the Control arm),
abdominal pain (6% vs. 2% in the Doublet arm and 5% in the Control
arm) and nausea (5% vs. <1% in the Double arm and 1% in the
Control arm).
Details for the late-breaking oral presentation are below. The
abstract can be accessed through the ESMO website:
https://www.esmo.org/Conferences/ESMO-Congress-2019.
Title/Abstract Number
Date/Time (CEST)
Location
(LBA32) Encorafenib plus cetuximab with or
without binimetinib for BRAF V600E– mutant metastatic colorectal
cancer: expanded results from a randomized, 3-arm, phase 3 study
vs. the choice of either irinotecan or FOLFIRI plus cetuximab
(BEACON CRC) Tabernero J
Monday, September 30 8:30-8:45 AM
Barcelona Auditorium
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 2018.1,2 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.3 BRAF mutations are estimated to
occur in up to 15% of patients with mCRC and represent a poor
prognosis for these patients.4,5,6,7,8,9 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.10,[11],11
About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating
the efficacy and safety of BRAFTOVI, MEKTOVI and cetuximab in
patients with BRAFV600E-mutant mCRC whose disease has progressed
after one or two prior regimens. BEACON CRC is the first and only
Phase 3 trial designed to test a BRAF/MEK combo targeted therapy in
BRAFV600E-mutant mCRC.
Thirty patients were treated in a safety lead-in conducted prior
to initiation of the randomized part of the trial and received the
Triplet combination (BRAFTOVI 300 mg daily, MEKTOVI 45 mg twice
daily and cetuximab per label). Of the 30 patients, 29 had a
BRAFV600 mutation. As previously announced, the Triplet combination
showed an acceptable safety profile that supported initiation of
the randomized portion of the trial.
The randomized portion of the BEACON CRC trial is designed to
assess the efficacy of BRAFTOVI in combination with cetuximab with
or without MEKTOVI compared to cetuximab and irinotecan-based
therapy. 665 patients were randomized 1:1:1 to receive the Triplet
combination, the Doublet combination (BRAFTOVI and cetuximab) or
the control arm (irinotecan-based therapy and cetuximab). 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. Health related quality of life
data will also be assessed. 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, colorectal cancer,
non-small cell lung cancer and others. 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. BRAFTOVI + MEKTOVI have
received regulatory approval in Australia and the Swiss Medicines
Agency (Swissmedic) is currently reviewing the Marketing
Authorization Applications for BRAFTOVI and MEKTOVI submitted by
Pierre Fabre.
Pfizer has exclusive rights to BRAFTOVI and MEKTOVI in the U.S.
and Canada. Pfizer has granted Ono Pharmaceutical Co. Ltd.
exclusive rights to commercialize both products in Japan and South
Korea, Medison exclusive rights to commercialize both products in
Israel and Pierre Fabre 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 BRAFV600E
or BRAFV600K mutation, as detected by an FDA-approved test.
Limitations of Use: BRAFTOVI is not
indicated for the 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, including keratoacanthoma, occurred in 2.6% and
basal cell carcinoma occurred in 1.6% of patients. 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: Confirm
evidence of BRAFV600E 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, cardiomyopathy occurred in 7% and Grade 3 left
ventricular dysfunction occurred in 1.6% of patients.
Cardiomyopathy resolved in 87% of patients. Assess left ventricular
ejection fraction by echocardiogram or MUGA scan prior to
initiating treatment, 1 month after initiating treatment, and then
every 2 to 3 months during treatment. 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.
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. 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. Assess for visual
symptoms at each visit. Perform ophthalmological evaluation at
regular intervals and for any 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) and 2.6% for aspartate
aminotransferase (AST), and 0.5% for alkaline phosphatase. Monitor
liver laboratory tests before and during treatment and as
clinically indicated.
Rhabdomyolysis: In the COLUMBUS trial, elevation of
laboratory values of serum creatine phosphokinase (CPK) occurred in
58% of patients. Rhabdomyolysis was reported in 0.1% of patients
with BRAF mutation-positive melanoma 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. 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. Non-hormonal contraceptives
should be used during treatment and for at least 30 days after the
final dose for patients taking BRAFTOVI + MEKTOVI.
Adverse Reactions
The most common adverse reactions (≥20%, all Grades, in the
COLUMBUS trial): were fatigue, nausea, diarrhea, vomiting,
abdominal pain, arthralgia, myopathy, hyperkeratosis, rash,
headache, constipation, visual impairment, serous retinopathy.
In the COLUMBUS trial, the most common laboratory abnormalities
(≥20%, all Grades): included increased creatinine, increased CPK,
increased gamma glutamyl transferase, anemia, increased ALT,
hyperglycemia, increased AST, and increased alkaline
phosphatase.
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 co-administration 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.12,13
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
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
Twitter 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 September 30, 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), MEKTOVI® (binimetinib), and cetuximab
(BRAFTOVI Triplet) combination as well as the BRAFTOVI Doublet
combination (BRAFTOVI and cetuximab) 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 and the expected timing of a potential
regulatory submission in the U.S., 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® and MEKTOVI®; 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 Triplet Combination for the potential new
indication may be filed with regulatory authorities in any
jurisdictions; whether and when regulatory authorities in any
jurisdictions 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 the Triplet
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 Triplet 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.
1 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
2 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
3 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.
4 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
5 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
6 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
7 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
8 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
9 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
10 Referenced with permission from the NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer.
V.2.2019.
[11] 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
11 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
12 BRAFTOVI® (encorafenib) Prescribing Information. Array
BioPharma Inc., June 2018
13 MEKTOVI® (binimetinib) Prescribing Information. Array
BioPharma Inc., June 2018
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