Analysis Published In New England Journal of Medicine Highlights Discovery Of
New Predictive Biomarkers For Vectibix® (Panitumumab)
Study Links RAS Mutations to Vectibix Clinical Response in Patients With
Metastatic Colorectal Cancer
THOUSAND OAKS, Calif., Sept. 11, 2013
THOUSAND OAKS, Calif., Sept. 11, 2013 /PRNewswire/ --Amgen (NASDAQ:AMGN)
today announced the publication of a biomarker analysis of Vectibix^®
(panitumumab) in combination with FOLFOX, a type of oxaliplatin-based
chemotherapy, for the first-line treatment of patients with metastatic
colorectal cancer (mCRC). Published in the New England Journal of Medicine,
the analysis found that RAS mutations, beyond the known KRAS exon 2 mutations,
predict lack of response to Vectibix in combination with FOLFOX. RASmutations
are mutations occurring in exons 2, 3 and 4 ofKRASandNRAS.
"While the KRAS exon 2 biomarker is well-known and has facilitated selection
of patients more likely to respond to anti-EGFR treatment, we found that there
were still some patients who didn't benefit from treatment," said Jean-Yves
Douillard, M.D., Ph.D., professor of medical oncology, Centre R Gauducheau,
France and PRIME trial lead investigator and study author. "This analysis is
important as it furthers our understanding of tumor genetics and allows
physicians to more accurately match patients to effective treatments."
This predefined retrospective subset analysis of the PRIME ('203) study
assessed the safety and efficacy of Vectibix plus FOLFOX, compared to FOLFOX
alone based on RAS or BRAF mutation status. By more precisely narrowing the
pool of patients treated with Vectibix plus FOLFOX to those with wild-type
RAS, greater improvements in overall survival (OS) and progression-free
survival (PFS) were observed. Specifically, previous data found that OS was
improved by 4.4 months in patients with wild-type KRAS. By further narrowing
to patients with wild-type RAS, an improvement in OS of 5.8 months was
In patients with wild-type RAS, OS was 26.0 months and 20.2 months (HR = 0.78;
95 percent CI, 0.62-0.99) and PFS was 10.1 months and 7.9 months (HR = 0.72,
95 percent CI, 0.58-0.90) in the Vectibix plus FOLFOX arm compared to the
FOLFOX alone arm, respectively. BRAF mutations were not observed to have
Conversely, in the patients with RAS mutations, inferior OS (HR = 1.25, 95
percent CI, 1.02-1.55) and PFS (HR = 1.34, 95 percent CI, 1.07-1.60) were
observed in the Vectibix plus FOLFOX arm compared to the FOLFOX alone arm.
Amgen has informed investigators and physicians of this important new safety
information, and is working with regulatory agencies regarding appropriate
communication of the outcomes of the analysis.
"Amgen is proud of our continuing work to identify and establish predictive
biomarkers, like RAS, that will help better inform therapeutic decisions,"
said Sean E. Harper, M.D., executive vice president of Research and
Development at Amgen. "As a result of this information, the European
Commission has refined the prescribing information for Vectibix to the
treatment of adult patients with wild-type RAS metastatic colorectal cancer."
No new safety signals were identified in this analysis.
PRIME ('203) Study Design
The PRIME (Panitumumab Randomized trial In combination with chemotherapy for
Metastatic colorectal cancer to determine Efficacy) ('203) trial is a global,
multicenter, randomized Phase 3 study designed to evaluate Vectibix (6.0 mg/kg
every two weeks) plus FOLFOX versus FOLFOX alone in patients with wild-type
KRAS exon 2 mCRC. The primary endpoint is PFS.
The primary objective of this predefined retrospective subset analysis was to
determine the effect of Vectibix plus FOLFOX versus FOLFOX alone on OS and PFS
in patients with mCRC based on RAS or BRAF mutation status. The analysis
included 512 patients who were identified with wild-type RAS tumors.
About KRAS and RAS
Results from studies performed over the last 30 years indicate that KRAS plays
an important role in cell growth regulation. In mCRC, EGFR transmits signals
through a set of intracellular proteins. Upon reaching the nucleus, these
signals instruct the cancer cell to reproduce and metastasize, leading to
cancer progression.^1 Anti-EGFR antibody therapies work by inhibiting the
activation of EGFR, thereby inhibiting downstream events that lead to
malignant signaling. However, in patients whose tumors harbor a mutated KRAS
gene, the KRAS protein is always turned "on," regardless of whether the EGFR
has been activated or therapeutically inhibited. Common KRAS mutations
occurring in exon 2 (codons 12/13) are present in approximately 40 to 50
percent of mCRC patients.^2,3 Additional RAS mutations occurred in
approximately 17 percent of patients with wild-type KRAS exon 2 tumors.
About Colorectal Cancer
Colorectal cancer is the third most common cancer found in both men and women
in the U.S., and is the second leading cause of cancer deaths.^4,5
Approximately 1.2 million cases of colorectal cancer are expected to occur
globally. The highest incidence rates are found in Japan, North America, parts
of Europe, New Zealand and Australia, and rates are low in Africa and
Vectibix is the first fully human anti-EGFR antibody approved by the U.S. Food
and Drug Administration (FDA) for the treatment of mCRC. Vectibix was approved
in theU.S. in September 2006 as a single agent for the treatment of patients
with EGFR-expressing mCRC with disease progression on or following
fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy
regimens. The effectiveness of Vectibix as a single agent for the treatment of
EGFR-expressing mCRC is based on PFS. More than half of patients who receive
Vectibix monotherapy respond to treatment with an average six month PFS
benefit. Currently, no data are available that demonstrate an improvement in
disease-related symptoms or increased survival with Vectibix.
Retrospective subset analyses of mCRC trials have not shown a treatment
benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12
or 13. Use of Vectibix is not recommended for the treatment of mCRC with these
Important U.S. Product Information
Vectibix is indicated as a single agent for the treatment of EGFR-expressing
mCRC with disease progression on or following fluoropyrimidine-, oxaliplatin-
and irinotecan-containing chemotherapy regimens. The effectiveness of Vectibix
as a single agent for the treatment of EGFR-expressing mCRC is based on
progression-free survival. Currently, no data demonstrate an improvement in
disease-related symptoms or increased survival with Vectibix.
Vectibix is not indicated for the treatment of patients with KRAS
mutation-positive mCRC or for whom KRAS mCRC status is unknown. Retrospective
subset analyses of metastatic colorectal cancer trials have not shown a
treatment benefit for Vectibix in patients whose tumors had KRAS mutations in
codon 12 or 13. Vectibix in combination with oxaliplatin-based chemotherapy is
not indicated for the treatment of patients with RAS (KRAS or NRAS)
mutation-positive mCRC or for whom RAS status is unknown.
WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS
Dermatologic Toxicity: Dermatologic toxicities occurred in 89 percent of
patients and were severe (NCI-CTC grade 3 or higher) in 12 percent of patients
receiving Vectibix monotherapy. [See Dosage and Administration (2.1), Warnings
and Precautions (5.1), and Adverse Reactions (6.1)].
Infusion Reactions: Severe infusion reactions occurred in approximately one
percent of patients. Fatal infusion reactions occurred in postmarketing
experience [See Dosage and Administration (2.1), Warnings and Precautions
(5.2), and Adverse Reactions (6.1, 6.3)].
The most common adverse events of Vectibix are skin rash with variable
presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea and
diarrhea, including diarrhea resulting in dehydration.
The most serious adverse reactions of Vectibix are pulmonary fibrosis,
pulmonary embolism, severe dermatologic toxicity complicated by infectious
sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia,
nausea, vomiting and constipation.
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 the world's largest independent biotechnology company,
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
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^1 Malumbres, M. and Barbacid, M. RAS oncogenes: the first 30 years. Nature
Reviews Cancer. 3:459-65, 2003.
^2 Karapentis C, S. Snell, L, E. The Laboratory Assessment of KRAS Mutation
Status in Colorectal Cancer. Asia Pacific Journal of Oncology and
^3 Friday BB and Adjei AA. K-ras as a target for cancer therapy. Biochim.
Biophys. Acta 1756: 127-144, 2005.
^4 Cancer Facts and Figures 2013. American Cancer Society website.
Accessed March 25, 2013.
^5 Colorectal Cancer Prevention (PDQ^®). National Cancer Institute. Accessed
March 25, 2013.
^6 Jemal. Global Cancer Statistics. CA Cancer J Clin. 2011;61:69-90.
^7 Vectibix (panitumumab) Prescribing Information. Thousand Oaks, Calif:
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