THOUSAND OAKS, Calif.,
June 18, 2015 /PRNewswire/
-- Amgen (NASDAQ: AMGN) today announced that a Phase 3
study evaluating Vectibix® (panitumumab) and best
supportive care (BSC) 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) compared to those patients
treated with BSC alone.
The Vectibix treatment arm further showed statistical
significance for all key secondary endpoints including OS in
patients with wild-type RAS (absence of mutations in exons
2, 3 and 4 of KRAS and NRAS) mCRC.
In the Vectibix treatment arm, the observed adverse events were
consistent with the known Vectibix safety profile.
Full results will be submitted to a future medical congress and
for publication.
"Amgen has been at the forefront of researching personalized
approaches to treating cancer, and the Vectibix clinical program
continues to underscore the importance of identifying options for
patients based on their cancer's genetic makeup," said Sean E. Harper, M.D., executive vice president
of Research and Development at Amgen. "These positive overall
survival results for Vectibix reinforce the importance of
KRAS and RAS biomarkers in making treatment decisions
in metastatic colorectal cancer."
Colorectal cancer is the third most common cancer worldwide,
with approximately 1.2 million cases occuring globally each
year.1,2 In the U.S., colorectal cancer is the second
leading cause of cancer-related deaths, with an estimated 132,700
new cases diagnosed in 2015.3,4 In Europe, colorectal cancer is the second most
common cancer, with approximately 470,000 new cases each
year.5
About Study '0007 (NCT01412957)
This
Phase 3 global, multicenter, randomized, open-label study was
designed to evaluate the survival benefit of Vectibix and best
supportive care (BSC) compared to BSC alone in patients with
chemorefractory wild-type KRAS (exon 2) metastatic
colorectal cancer (mCRC). The primary endpoint was overall survival
(OS). 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.
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).
About Vectibix® (panitumumab)
Vectibix is the first fully human anti-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.
Important EU Product Safety Information
Dermatologic related reactions, a pharmacologic effect observed
with epidermal growth factor receptor (EGFr) inhibitors, are
experienced with nearly all patients (approximately 90 percent)
treated with Vectibix®. The majority of dermatological
reactions are mild to moderate in nature. In clinical studies,
subsequent to the development of severe dermatological reactions
(including stomatitis), infectious complications including sepsis,
in rare cases leading to death, and local abscesses requiring
incisions and drainage were reported. Patients who have severe
dermatologic reactions or who develop worsening reactions whilst
receiving Vectibix® should be monitored for the
development of inflammatory or infectious sequelae, and appropriate
treatment promptly initiated.
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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References
- Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0,
Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11.
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed
June 9, 2015.
- Jemal. Global Cancer Statistics. CA Cancer J Clin.
2011;61:69-90.
- U.S. Centers for Disease Control and Prevention.
http://www.cdc.gov/cancer/colorectal/statistics. Accessed
June 9, 2015.
- American Cancer Society. Key Statistics about Colorectal
Cancer.
http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-key-statistics.
Accessed June 17, 2015.
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http://www.europacolon.com/crcstatistics.php?Action=Crcstatistics.
Accessed June 9, 2015.
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