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Amgen’s Vectibix® (Panitumumab) shows improved survival benefit in patients with wild-type RAS (KRAS and NRAS) metastatic colorectal cancer versus Bevacizumab phase 2 PEAK study results published in journal of clinical oncology

THOUSAND OAKS, Calif. (April 29, 2014) – Amgen (NASDAQ:AMGN) today announced the publication of results from PEAK, a randomized multicenter phase 2 study evaluating the efficacy of Vectibix® (panitumumab) in combination with FOLFOX, an oxaliplatin-based chemotherapy regimen, compared to a treatment regimen of bevacizumab plus FOLFOX as a first-line treatment in patients with wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC).

A prespecified secondary objective of the study was to assess treatment effects in an extended RAS mutational analysis that included exons 2, 3, and 4 of KRAS and NRAS. Published in the Journal of Clinical Oncology, the study found that patients with wild-type RAS tumour status treated in the panitumumab in combination with FOLFOX arm show extended overall survival (OS) and improved progression-free survival (PFS) versus patients treated in the bevacizumab in combination with FOLFOX arm.

Of the 285 patients with KRAS exon 2 wild-type tumors initially included in the study, the median
OS was 34.2 months for patients treated with panitumumab plus FOLFOX compared to 24.3
months for patients treated with bevacizumab plus FOLFOX (HR = 0.62, 95 percent CI, 0.44 to
0.89; P=.009). PFS (primary endpoint) was similar between both treatment arms (HR = 0.87, 95
percent CI, 0.65-1.17 p= .353).

Recent studies have indicated that activating mutations in KRAS (beyond exon 2) and mutations in NRAS, collectively referred to as RAS (exons 2, 3 and 4 of KRAS and NRAS), are negative predictive biomarkers of clinical response to panitumumab. A secondary objective of the PEAK study was to determine patient outcomes by RAS tumour status. In a predefined analysis of banked patient tumor specimens with wild-type RAS mCRC, it was shown that panitumumab in combination with FOLFOX had a median OS of 41.3 months compared to 28.9 months in patients treated with bevacizumab in combination with FOLFOX (HR = 0.63, 95 percent CI, 0.39-1.02 p=.058). PFS favored the panitumumab arm (HR = 0.65, 95 percent CI, 0.44-0.96 p=
.029). However, in patients with wild-type KRAS exon 2/mutant other RAS exons, PFS was worse in the panitumumab plus FOLFOX arm compared to bevacizumab plus FOLFOX. These results are consistent with reports that the combination of anti- EGFR antibodies with oxaliplatin containing regimens may be predictive of negative outcomes for patients with mutant RAS mCRC.

  • This was a large Phase 2 study
  • PEAK data seems to be the first randomized trial data to our knowledge to estimate the treatment effect of an anti- EGFR antibody relative to an anti-VEGF antibody in combination with an oxaliplatin-containing regimen for first-line treatment of WT RAS mCRC
  • The data suggest that patients with wild-type RAS tumors may receive clinical benefit from treatment with EGFR inhibitors.

The most commonly reported adverse events for the panitumumab treatment arm included rash,
hypomagnesemia and nausea. No new toxicities were identified for panitumumab. The most commonly reported adverse events for the bevacizumab arm included nausea, fatigue and rash.

Approximately 1.2 million cases of colorectal cancer are expected to occur globally.1

PEAK (‘509) Study Design

The PEAK (Panitumumab Efficacy in Combination with mFOLFOX6 Against bevacizumab plus mFOLFOX6 in mCRC subjects with wild-type KRAS tumors) (‘509) trial is a global, multicenter, randomized Phase 2 study designed to compare the efficacy of panitumumab in combination with FOLFOX, an oxaliplatin-based chemotherapy regimen, to the efficacy of bevacizumab in combination with FOLFOX in patients with previously untreated, unresectable, wild-type KRAS exon 2 mCRC. A prespecified secondary objective of PEAK was to assess the effect of panitumumab + mFOLFOX6 or bevacizumab + mFOLFOX6 on PFS (primary endpoint) and OS and safety in the subset of patients with WT RAS (exons 2, 3, 4 of KRAS and NRAS).

About KRAS and RAS

Results from studies performed over the last 25 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.2 Anti- EGFR antibody therapies work by inhibiting the activation of EGFR , thereby inhibiting downstream events that lead to malignant signalling. 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.3,4 RAS mutations are mutations occurring in exons 2, 3 and 4 of KRAS and NRAS and based on study data, appear to occur in approximately 16 percent of patients with wild-type KRAS exon 2.5 When RAS is mutated, panitumumab has no effect, because either the KRAS or NRAS genes produce a dysfunctional protein. The dysfunctional protein remains activated, downstream of EGFR , transmitting signals even when EGFR is inhibited.

About Vectibix

Vectibix is the first fully human 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 single agent for the treatment of metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine, oxaliplatin and irinotecan chemotherapy regimens. Approval is based on progression-free survival; no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix.

Important EU Product Information

For full prescribing information please see the Summary of Product Characteristics.

Vectibix is indicated for the treatment of adult patients with wild-type RAS metastatic colorectal cancer (mCRC):

  • in first-line in combination with FOLFOX.
  • 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.

Vectibix is contraindicated in patients with a history of severe or life-threatening hypersensitivity reactions to the product and in patients with interstitial pneumonitis or pulmonary fibrosis.

The combination of Vectibix with oxaliplatin-containing chemotherapy is contraindicated for patients with mutant RAS mCRC or for whom RAS mCRC status is unknown.

Other adverse events of special importance associated with Vectibix and/or EGFR monoclonal antibody therapies include dermatologic-related reactions, pulmonary complications, electrolyte disturbances, infusion-related reactions (including rare reports with fatal outcome) and ocular toxicities. These events should be monitored carefully, see Summary of Product Characteristics for information on appropriate management of these adverse events. Acute renal failure has been observed in patients who develop severe diarrhoea and dehydration. For patients with ECOG 2 performance status, assessment of benefit-risk is recommended prior to initiation of Vectibix in combination with chemotherapy for treatment of mCRC.

Vectibix should not be used in combination with IFL [bolus 5-fluorouracil (500 mg/m2), leucovorin (20 mg/m2) and irinotecan (125 mg/m2)] or in combination with bevacizumab containing chemotherapy.

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 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 www.twitter.com/amgen.

Forward-Looking Statements

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Kristen Davis, 805-447-3008 (media)

Arvind Sood, 805-447-1060 (investors)

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2 Malumbres, M. and Barbacid, M. RAS oncogenes: the first 30 years. Nature Reviews Cancer. 3:459-65, 2003.
3 Karapentis C, S. Snell, L, E. The Laboratory Assessment of KRAS Mutation Status in Colorectal Cancer. Asia Pacific Journal of Oncology and Hematology. 2010.
4Friday BB and Adjei AA. K-ras as a target for cancer therapy. Biochem. Biophys. Acta 1756: 127-144, 2005.
5 Douillard JY, Oliner K, Siena S, et al. Panitumumab-FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer. N Engl J Med. 2013; 369: 1023–1034.