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Amgen Reports Mixed Results from Prospective Vectibix Study in mCRC Patients Based on KRAS Status

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By Turna Ray

Preliminary top-line results from a prospective Phase III trial evaluating Amgen's colorectal cancer drug Vectibix (panitumumab) as a second-line therapy for metastatic colorectal cancer showed that when combined with a chemothereapy regimen it improved progression-free survival in patients with wild-type KRAS tumors compared to chemotherapy alone.

However, the improvement in median overall survival in this same population receiving the Vectibix-containing chemotherapy regimen did not reach statistical significance, Amgen reported in a statement.

The so-called "181" trial enrolled nearly 1,200 patients with metastatic colorectal cancer and randomized them to receive either Vectibix and FOLFIRI (folinic acid, fluorouracil, and irinotecan) or just FOLFIRI. The co-primary endpoints of the study, launched in 2006, were PFS and OS.

According to a statement from the company, Vectibix "significantly improved progression-free survival in combination with FOLFIRI, compared to FOLFIRI alone, in patients with KRAS wild-type mCRC." And while the improvement in overall survival was numerically greater for patients in the Vectibix-containing arm, the finding was not statistically significant.

The addition of Vectibix had no positive or negative effect on progression-free or overall survival in patients with tumors harboring activating KRAS mutations, the company also reported in a statement.

"With these data, Vectibix has now demonstrated improved progression-free survival in Phase III trials in patients with KRAS wild-type tumors in both first- and second-line treatment of metastatic colorectal cancer," said Roger Perlmutter, executive vice president of research and development at Amgen, in the statement. "These results add to the growing body of evidence confirming the utility of KRAS as a predictive biomarker."

Earlier this month, Amgen announced Phase III results from the "203" trial, which showed that colorectal cancer patients with KRAS wild-type tumors "significantly improved PFS" when given Vectibix in combination with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) as a first-line treatment, compared to FOLFOX alone.

The US Food and Drug Administration approved Vectibix three years ago. The drug is currently indicated in the US as a single agent for the treatment of metastatic colorectal cancer after patients' disease have progressed despite treatment with fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy regimens. The FDA does not recommend Vectibix for patients whose tumors have KRAS mutations in codon 12 or 13.

An Amgen spokesperson told Pharmacogenomics Reporter that the company would not release any further details from the "181" study until the European Cancer Organisation and the European Society for Medical Oncology joint conference in September in Berlin. Data from the "203" and the "181" studies could help Amgen expand Vectibix's indication into more colorectal cancer patients.

"We plan to share these data with the FDA and other regulatory agencies," the Amgen spokesperson said. "We cannot speculate how those interactions will go."

The FDA recently updated the label for Vectibix and ImClone Systems’ Erbitux (cetuximab) to indicate that colorectal cancer patients with certain KRAS mutations would not respond to these epidermal growth factor receptor-inhibiting monoclonal antibodies. In order to make this change to the label, the FDA, despite its proclivity towards prospective clinical trials, looked at retrospective analyses from Amgen and from Bristol-Myers Squibb/ImClone [see PGx Reporter 07-22-2009].

Despite FDA having accepted retrospective data from Amgen, the company had previously said it was investigating the clinical utility of KRAS testing to predict response to Vectibix in the combination chemotherapy setting in two prospective Phase III clinical trials in mCRC patients.

According to Amgen, the "181" trial was originally designed to compare the treatment effect in the overall colorectal cancer population, but as the study progressed the design was amended to analyze patient outcomes based on KRAS mutation status. KRAS tumor status was ascertained in more than 90 percent of study participants.

The adverse event profile in study "181" was "as anticipated for an anti-EGFR antibody," such as skin toxicity, diarrhea, and hypomagnesemia, Amgen said in a statement.

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