Amgen announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending that Vectibix (panitumumab) be approved for use in the European Union (EU) in first-line in combination with Folfox and in second-line in combination with Folfiri in patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan) for patients with wild-type KRAS metastatic colorectal cancer (mCRC), following a successful re-examination procedure by Amgen.

"This opinion, for which a final European Commission decision is pending, is a welcome step forward and one that may lead to additional treatment options for patients facing an aggressive disease with limited treatment options," said Willard H. Dere, M.D., senior vice president and international chief medical officer at Amgen. "Studies have shown that patients taking Vectibix in combination with chemotherapy have a greater chance of living longer without their disease getting worse, in a landscape where few targeted agents have been shown to be effective when used with chemotherapy."

Data from studies 20050203 (PRIME) and 20050181 ('181) showed that adding Vectibix to either Folfox or Folfiri chemotherapy improved progression-free survival (PFS) versus chemotherapy alone for patients with wild-type KRAS mCRC. Additionally, the overall response rate (ORR) of Vectibix plus chemotherapy was higher than chemotherapy alone. Although numerically greater, the improvement in median overall survival (OS) did not achieve statistical significance in the Vectibix arm of either trial.

The PRIME study evaluated Vectibix (6.0 mg/kg every two weeks) plus Folfox versus Folfox alone in patients with wild-type KRAS mCRC and found that Vectibix plus Folfox significantly improved PFS versus Folfox alone (median 9.6 months versus 8.0 months, hazard ratio (HR) 0.80; 95 per cent confidence interval (CI): 0.66-0.97; p=0.02). Additionally, combining Vectibix with Folfox resulted in numerically greater OS versus Folfox alone (median 23.9 months versus 19.7 months, HR 0.83; 95 per cent CI: 0.67-1.02), although this was not statistically significant (p=0.072). The ORR achieved with Vectibix plus Folfox was higher than Folfox alone (55 per cent versus 48 per cent).

The '181 study showed that adding Vectibix (6.0 mg/kg every two weeks) to Folfiri chemotherapy improved median PFS by two months in patients with wild-type KRAS mCRC compared to Folfiri alone (median 5.9 months versus 3.9 months; HR 0.73, 95 per cent CI: 0.59-0.90; p=0.004). Additionally, the Vectibix combination more than tripled the ORR compared to Folfiri  alone (35 per cent versus 10 per cent). Though quantitatively greater (14.5 months versus 12.5 months, HR 0.85), the improvement in median OS (co-primary endpoint) did not achieve statistical significance in the Vectibix arm of the trial (p=0.12).

Adverse event rates included known toxicities associated with anti-epidermal growth factor receptor (EGFR) therapy, such as rash, diarrhea, and hypomagnesemia. Vectibix-related grade 3/4 infusion reactions were reported in less than one percent of patients. In patients with mutated KRAS tumours, outcomes were inferior for those receiving Vectibix plus Folfox versus Folfox alone. Vectibix should only be used in those patients in whom wild-type KRAS status has been confirmed, because of the worse outcomes in patients with mutated KRAS tumours treated with Folfox.

The Amgen PRIME and '181 studies were the first phase 3 studies to prospectively analyze the effect of an EGFR inhibitor based on KRAS status in patients with mCRC.

Vectibix is already approved and established in 40 countries as a monotherapy treatment for patients with wild-type KRAS mCRC, when standard chemotherapy is no longer effective. In the United States (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. The 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.

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 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 tumours had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of mCRC with these mutations.

In December 2007, the European Commission 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 countries, Russia, Israel, Australia, Canada and Japan. Applications in the rest of the world are pending.

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