THOUSAND OAKS, Calif.,
Jan. 23, 2016 /PRNewswire/ -- Amgen
(NASDAQ: AMGN) today announced the presentation of detailed results
of a Phase 3 study with Vectibix® (panitumumab) and best
supportive care (BSC) compared to BSC alone. The study met
its primary endpoint, demonstrating a statistically significant
improvement in overall survival (OS) in patients with
chemorefractory wild-type KRAS (exon 2) metastatic
colorectal cancer (mCRC; n=377 total). This is the first Phase 3
Vectibix study to include an analysis of efficacy of Vectibix by
wild-type KRAS (exon 2) and in wild-type RAS tumor
mutation status in its primary analysis, providing important
information about OS in these populations. These results, in
addition to secondary endpoint data, were presented at the 2016
Gastrointestinal Cancers Symposium (GICS) in San Francisco.
The study (GICS abstract #642) showed that patients with
wild-type KRAS (exon 2) mCRC treated with Vectibix and BSC
achieved a median OS of 10 months compared to 7.4 months for
patients treated with BSC alone (hazard ratio [HR]=0.73, 95 percent
confidence interval [CI]=0.57-0.93, p=0.0096). Data
from a key secondary endpoint showed that patients with wild-type
RAS (absence of mutations in exons 2, 3 and 4
of KRAS and NRAS) mCRC treated with
Vectibix and BSC achieved a median OS of 10 months compared to 6.9
months for patients treated with BSC alone (n=270; HR=0.70, 95
percent CI=0.53-0.93, p=0.0135). Patients with mutant
RAS mCRC did not benefit from Vectibix treatment (n=54; OS
HR=0.99, 95 percent CI=0.49-2.00). The safety profile was
comparable to the known safety profile of Vectibix when
administered as a single agent, with skin, nail, gastrointestinal
and electrolyte disorders being the most frequently reported
adverse events.
"Amgen has played a significant role in the advancement of
personalized medicine, applying cutting-edge science and technology
in our efforts to target therapies to the patients who are most
likely to benefit. Amgen is committed to understanding cancer
biology through studies like this," said Sean E. Harper, M.D., executive vice president
of Research and Development at Amgen. "As well as providing
additional insights into the way Vectibix works in mCRC, these data
support expanding biomarker screening to include wild-type
RAS."
Colorectal cancer is the third most common cancer worldwide,
with approximately 1.2 million cases occurring globally each
year.1,2 Approximately 20 percent of colon cancers are
diagnosed at the metastatic stage, when the disease has already
spread to distant organs, a diagnosis associated with only a 12
percent five-year survival rate.3 Using molecular
approaches to identify unique genetic signatures in mCRC has the
potential to help improve treatment outcomes. Of the few biomarkers
in colorectal cancer, RAS genes (KRAS, NRAS)
have a validated impact on treatment outcomes.4,5
Abstracts are currently available on the GICS
website.
About '0007 Study (NCT01412957)
This Phase 3 global,
multicenter, randomized, open-label study was designed to evaluate
OS with Vectibix and BSC compared to BSC alone in patients with
chemorefractory wild-type KRAS (exon 2) mCRC.
Key secondary endpoints included progression-free survival (PFS)
in patients with wild-type KRAS mCRC, as well as OS and PFS
in patients with wild-type RAS (absence of mutations in
exons 2, 3 and 4 of KRAS and NRAS) mCRC, objective
response rate (ORR) and safety in both wild-type KRAS (exon
2) and wild-type RAS groups.
Patients were randomized 1:1 to receive 6 mg/kg of Vectibix
every 14 days and BSC, or BSC alone (as defined by the
investigator). There were a total of 377 patients enrolled:
- 324 out of 377 subjects with RAS mutation status
determined (86 percent ascertainment rate)
- Out of 324
- 270 had wild-type RAS (83 percent)
- 54 were found to be mutant RAS (17 percent)
- 189 patients for KRAS (exon 2) group for Vectibix and
BSC
Treatment with Vectibix combined with BSC in patients with
wild-type KRAS resulted in median PFS of 3.6 months versus
1.7 months with BSC alone (HR=0.51, 95 percent CI=0.41-0.64,
p=0.0001). In patients with wild-type RAS, the
Vectibix combination resulted in median PFS of 5.2 months versus
1.7 months with BSC alone (HR=0.46, 95 percent CI=0.35-0.59,
p=0.0001).
For patients with wild-type KRAS, ORRs were 27.0 percent
with Vectibix versus 1.6 percent with BSC (HR=24.9, 95 percent
CI=7.5-123.8, p<0.0001). For patients with wild-type
RAS, ORRs were 31.0 percent with Vectibix versus 2.3 percent
for BSC (ODDS Ratio=20.0, 95 percent CI=5.9-101.6,
p<0.0001).
Patients with mutant RAS mCRC did not benefit from
Vectibix treatment (OS HR=0.99, 95 percent CI=0.49-2.00). No new
safety signals were seen in this study. The safety profile was
comparable to the known safety profile of Vectibix when
administered as a single agent, with skin, nail, gastrointestinal
and electrolyte disorders being the most frequently reported
adverse events.
About Vectibix® (panitumumab)
Vectibix is
the first fully human monoclonal anti-epidermal growth factor
receptor (EGFR) antibody approved by the U.S. Food and Drug
Administration (FDA) for the treatment of metastatic colorectal
cancer (mCRC). Vectibix was approved in the U.S. in September 2006
as a monotherapy for the treatment of patients with EGFR-expressing
mCRC after disease progression after prior treatment with
fluoropyrimidine-, oxaliplatin-, and irinotecan-containing
chemotherapy.
In May 2014, the FDA approved Vectibix for use in combination
with FOLFOX, as first-line treatment in patients with wild-type
KRAS (exon 2) mCRC. With this approval, Vectibix became the
first-and-only biologic therapy indicated for use with FOLFOX, one
of the most commonly used chemotherapy regimens, in the first-line
treatment of mCRC for patients with wild-type KRAS mCRC.
Important U.S. Product Information
Vectibix is indicated for the treatment of patients with
wild-type KRAS (exon 2 in codons 12 or 13)
metastatic colorectal cancer (mCRC) as determined by
an FDA-approved test for this use:
- As first-line therapy in combination with FOLFOX
- As monotherapy following disease progression after prior
treatment with fluoropyrimidine-, oxaliplatin-, and
irinotecan-containing chemotherapy
Limitation of Use: Vectibix is not indicated for the treatment
of patients with RAS-mutant mCRC or for
whom RAS mutation status is unknown.
WARNING: DERMATOLOGIC TOXICITY
Dermatologic
Toxicity: Dermatologic toxicities occurred in 90 percent of
patients and were severe (NCI-CTC grade 3 or higher) in 15% of
patients receiving Vectibix monotherapy.
In Study 1, dermatologic toxicities occurred in 90% of patients
and were severe (NCI-CTC grade 3 and higher) in 15% of patients
with mCRC receiving Vectibix. The clinical manifestations included,
but were not limited to, acneiform dermatitis, pruritus, erythema,
rash, skin exfoliation, paronychia, dry skin and skin fissures.
Monitor patients who develop dermatologic or soft tissue
toxicities while receiving Vectibix for the development of
inflammatory or infectious sequelae. Life-threatening and fatal
infectious complications including necrotizing fasciitis, abscesses
and sepsis have been observed in patients treated with
Life-threatening and fatal bullous mucocutaneous disease with
blisters, erosions and skin sloughing has also been observed in
patients treated with Vectibix. It could not be determined whether
these mucocutaneous adverse reactions were directly related to EGFR
inhibition or to idiosyncratic immune-related effects (e.g.,
Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold
or discontinue Vectibix for dermatologic or soft tissue
toxicity associated with severe or life-threatening inflammatory or
infectious complications. Dose modifications for Vectibix
concerning dermatologic toxicity are provided in the product
labeling. Vectibix is not indicated for the treatment of patients
with colorectal cancer that harbor somatic mutations in exon 2
(codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons
117 and 146) of either
KRAS or NRAS and
hereafter is referred to as "RAS."
Retrospective subset analyses across several randomized clinical
trials were conducted to investigate the role
of RAS mutations on the clinical effects of
anti-EGFR-directed monoclonal antibodies (panitumumab or
cetuximab). Anti-EGFR antibodies in patients with tumors
containing RAS mutations resulted in
exposing those patients to anti-EGFR related adverse reactions
without clinical benefit from these agents.
Additionally, in Study 3, 272 patients
with RAS-mutant mCRC tumors received Vectibix in
combination with FOLFOX and 276 patients received FOLFOX alone. In
an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI
1.01-1.45) in patients with RAS-mutant mCRC who
received Vectibix and FOLFOX versus FOLFOX alone.
Progressively decreasing serum magnesium levels leading to
severe (Grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2)
of patients across clinical trials. Monitor patients for
hypomagnesemia and hypocalcemia prior to initiating Vectibix
treatment, periodically during Vectibix treatment, and for up to 8
weeks after the completion of treatment. Other electrolyte
disturbances, including hypokalemia, have also been observed.
Replete magnesium and other electrolytes as appropriate.
In Study 1, 4% of patients experienced infusion reactions and 1%
of patients experienced severe infusion reactions (NCI-CTC grade
3-4). Infusion reactions, manifesting as fever, chills, dyspnea,
bronchospasm, and hypotension, can occur following Vectibix
administration. Fatal infusion reactions occurred in postmarketing
experience. Terminate the infusion for severe infusion
reactions.
Severe diarrhea and dehydration, leading to acute renal failure
and other complications, have been observed in patients treated
with Vectibix in combination with chemotherapy.
Fatal and non-fatal cases of interstitial lung disease (ILD)
(1%) and pulmonary fibrosis have been observed in patients treated
with Vectibix. Pulmonary fibrosis occurred in less than 1% (2/1467)
of patients enrolled in clinical studies of Vectibix. In the event
of acute onset or worsening of pulmonary symptoms, interrupt
Vectibix therapy. Discontinue Vectibix therapy if ILD is
confirmed.
In patients with a history of interstitial pneumonitis or
pulmonary fibrosis, or evidence of interstitial pneumonitis or
pulmonary fibrosis, the benefits of therapy with
Vectibix versus the risk of pulmonary complications must be
carefully considered.
Exposure to sunlight can exacerbate dermatologic toxicity.
Advise patients to wear sunscreen and hats and limit sun exposure
while receiving Vectibix.
Keratitis and ulcerative keratitis, known risk factors for
corneal perforation, have been reported with Vectibix use.
Monitor for evidence of keratitis or ulcerative keratitis.
Interrupt or discontinue Vectibix for acute or worsening
keratitis.
In an interim analysis of an open-label, multicenter, randomized
clinical trial in the first-line setting in patients with mCRC, the
addition of Vectibix to the combination of bevacizumab and
chemotherapy resulted in decreased OS and increased incidence of
NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4
adverse reactions occurring at a higher rate in Vectibix-treated
patients included rash/acneiform dermatitis (26% vs 1%), diarrhea
(23% vs 12%), dehydration (16% vs 5%; primarily occurring in
patients with diarrhea), hypokalemia (10% vs 4%),
stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs
0).
NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate
in Vectibix-treated patients (7% vs 3%) and included fatal events
in three (< 1%) Vectibix-treated patients.
As a result of the toxicities experienced, patients randomized
to Vectibix, bevacizumab and chemotherapy received a lower mean
relative dose intensity of each chemotherapeutic agent
(oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over
the first 24 weeks on study, compared with those randomized to
bevacizumab and chemotherapy.
Advise patients of the need for adequate contraception in both
males and females while receiving Vectibix and for 6 months
after the last dose of Vectibix therapy.
Vectibix may be transmitted from the mother to the developing
fetus, and has the potential to cause fetal harm when administered
to pregnant women.
Because many drugs are excreted into human milk and because of
the potential for serious adverse reactions in nursing infants from
Vectibix, a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the importance of
the drug to the mother. If nursing is interrupted, it should not be
resumed earlier than 2 months following the last dose of
Vectibix.
Women who become pregnant during Vectibix treatment are
encouraged to enroll in Amgen's Pregnancy Surveillance Program.
Women who are nursing during Vectibix treatment are encouraged
to enroll in Amgen's Lactation Surveillance Program. Patients or
their physicians should call 1-800-77-AMGEN (1-800-772-6436) to
enroll.
In Study 1, the most common adverse reactions (> 20%) with
Vectibix were skin rash with variable presentations,
paronychia, fatigue, nausea, and diarrhea. The most common (>
5%) serious adverse reactions in the Vectibix arm were general
physical health deterioration and intestinal obstruction.
In Study 3, the most commonly reported adverse reactions (>
20%) in patients with wild-type KRAS mCRC
receiving Vectibix (6 mg/kg every 2 weeks) and FOLFOX therapy
(N = 322) were diarrhea, stomatitis, mucosal inflammation,
asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash,
acneiform dermatitis, pruritus and dry skin. Serious adverse
reactions (> 2% difference between treatment arms) in
Vectibix-treated patients with
wild-type KRAS mCRC were diarrhea and
dehydration.
To see the Vectibix Prescribing Information, including Boxed
Warning visit www.vectibix.com.
In the EU, Vectibix is currently indicated for the treatment of
adult patients with wild-type RAS mCRC:
- in first-line in combination with FOLFOX and FOLFIRI.
- in second-line in combination with FOLFIRI for patients who
have received first-line fluoropyrimidine-based chemotherapy
(excluding irinotecan).
- as monotherapy after failure of fluoropyrimidine-,
oxaliplatin-, and irinotecan-containing chemotherapy regimens.
About Amgen's Commitment to Oncology
Amgen Oncology is
committed to helping patients take on some of the toughest cancers,
such as those that have been resistant to drugs, those that
progress rapidly through the body and those where limited treatment
options exist. Amgen's supportive care treatments help patients
combat certain side effects of strong chemotherapy, and our
targeted medicines and immunotherapies focus on more than a dozen
different malignancies, ranging from blood cancers to solid tumors.
With decades of experience providing therapies for cancer patients,
Amgen continues to grow its portfolio of innovative and biosimilar
oncology medicines.
About Amgen
Amgen is committed to unlocking the
potential of biology for patients suffering from serious illnesses
by discovering, developing, manufacturing and delivering innovative
human therapeutics. This approach begins by using tools like
advanced human genetics to unravel the complexities of disease and
understand the fundamentals of human biology.
Amgen focuses on areas of high unmet medical need and leverages
its biologics manufacturing expertise to strive for solutions that
improve health outcomes and dramatically improve people's lives. A
biotechnology pioneer since 1980, Amgen has grown to be one of the
world's leading independent biotechnology companies, has reached
millions of patients around the world and is developing a pipeline
of medicines with breakaway potential.
For more information, visit www.amgen.com and follow us on
www.twitter.com/amgen.
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CONTACT: Amgen, Thousand
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Kristen Davis, 805-447-3008
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Cancer Incidence and Mortality Worldwide: IARC CancerBase No.
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- Jemal. Global Cancer Statistics. CA Cancer J Clin.
2011;61:69-90.
- Colon Cancer Alliance. Get Information: What is Colon Cancer:
Statistics. Accessed Dec. 3, 2015.
Available at:
http://www.ccalliance.org/get-information/what-is-colon-cancer/statistics/
- Fight Colorectal Cancer. Biomarker Testing for Colorectal
Cancer: Common Biomarker Tests for Colon Cancer. Accessed
Dec. 3, 2015. Available at:
http://fightcolorectalcancer.org/fightcrc-fightit/biomarker-testing-for-colorectal-cancer/
- Colon Cancer Alliance. Get Information: Treatment: Biomarkers.
Know Your Biomarker. Accessed Dec. 3,
2015. Available at:
http://www.ccalliance.org/get-information/treatment/biomarkers/
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