Amgen announced that it has submitted a request to the European Medicines Agency (EMA) for a re-examination of the negative opinion issued in March by the Committee For Medicinal Products for Human Use (CHMP)for the use of Vectibix in combination with chemotherapy for patients with wild-type KRAS metastatic Colo-Rectal Cancer (mCRC).

Amgen believes that Vectibix in combination with chemotherapy provides an important treatment option for patients with wild-type KRAS mCRC. Amgen remains committed to patients with this aggressive disease, for whom there are limited treatment options.

Data from studies 20050203 (PRIME) and 20050181 ('181') showed that adding Vectibix to Folfox and Folfiri chemotherapy, respectively, improved Progression-Free Survival (PFS) versus chemotherapy alone in patients with wild-type KRAS mCRC. Patients taking this combination have a greater chance of living longer without their disease getting worse. Additionally, the response rate of Vectibix plus chemotherapy was higher than chemotherapy alone. Though quantitatively greater, the improvement in median overall survival did not achieve statistical significance in the Vectibix arm of either trial.

In general, adverse event rates were comparable across arms in both studies, with the exception of known toxicities associated with anti-EGFR therapy, such as rash, diarrhoea, and hypomagnesemia. Vectibix-related grade 3/4 infusion reactions were reported in less than one percent of patients. In patients with mutant KRAS tumours, outcomes were inferior for those receiving Vectibix plus Folfox versus Folfox alone.

Vectibix is already approved and established in more than 30 countries outside of the United States (US) as a monotherapy treatment for patients with wild-type KRAS mCRC, when standard chemotherapy is no longer effective. In the US, Vectibix received accelerated approval in September 2006 as a monotherapy for the treatment of patients with EGFR-expressing mCRC after disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Furthermore, use of Vectibix is not recommended in patients whose tumours have KRAS mutations in codon 12 or 13. In Japan and Israel, Vectibix is also approved for use in combination with chemotherapy for patients with wild-type KRAS mCRC.

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. Anti-EGFR antibody therapies work by inhibiting the activation of EGFR, thereby inhibiting downstream events that lead to malignant signaling. However, in patients whose tumours harbour a mutated KRAS gene, the KRAS protein is always turned "on," regardless of whether the EGFR has been activated or therapeutically inhibited. KRAS mutations occur in approximately 40-50 percent of mCRC patients.

Colorectal cancer is the third most common cancer worldwide in men and the second most common in women. In 2008, approximately 1.23 million cases of colorectal cancer were diagnosed globally. In 2008, there were an estimated 333,330 new cases of colorectal cancer in the EU.

Vectibix is the first fully human anti-EGFR antibody approved by the US Food and Drug Administration (FDA) for the treatment of mCRC. Vectibix was approved in the US in September 2006 as a monotherapy for the treatment of patients with EGFR-expressing mCRC after 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 (PFS). 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 tumours had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations.

In December 2007, the European Medicine Agency (EMA) granted a conditional marketing authorization for Vectibix as a monotherapy for the treatment of patients with EGFR-expressing mCRC with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Vectibix has been launched in more than 30 European Union countries, Russia, Israel, Switzerland, Australia, Canada and Japan. Applications in the rest of the world are pending.

Vectibix is indicated as monotherapy for the treatment of patients with EGFR-expressing, metastatic Colo-Rectal Carcinoma (mCRC) with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

It 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.

Other common adverse events of special importance associated with Vectibix and/or EGFR monoclonal antibody therapies include dermatologic-related reactions, pulmonary complications, electrolyte disturbances and infusion-related reactions (including rare reports with fatal outcome) and should be monitored carefully. Acute renal failure has been observed in patients who develop severe diarrhoea and dehydration.

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.

It should not be administered in combination with oxaliplatin-containing chemotherapy to mCRC patients with mutant KRAS tumours or for whom KRAS tumour status is unknown.

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