Amgen announces results from pivotal Phase 3 "408" trial of Vectibix

Amgen (Nasdaq: AMGN) today announced detailed results from a new biomarker analysis of the pivotal Phase 3 "408" trial of Vectibix® (panitumumab) plus best supportive care (BSC) compared to BSC alone. The analysis used massively parallel, next-generation sequencing technology to investigate whether mutations in nine genes known to be mutated in colorectal cancer, including the previously unanalyzed exon 3 mutation of the KRAS gene, are predictive of response to Vectibix in metastatic colorectal cancer (mCRC). Highlighted results were presented at the opening press conference at the American Association for Cancer Research (AACR) 101st Annual Meeting 2010 in Washington, D.C.

"To our knowledge, this is the first time next-generation sequencing has been used to analyze tumor samples from a Phase 3 clinical trial and demonstrates how advancing technologies can be quickly applied to ongoing clinical research," said Marc Peeters, M.D., Ph.D., Department of Oncology, Antwerp University Hospital and the study's principal investigator. "The KRAS gene mutation is a well-established biomarker for a lack of response to anti-EGFR treatment and has played a pivotal role in the advancement of personalized medicine. We are excited to be taking another step forward in the advancement of additional biomarkers with the study results presented today."

The analysis used banked patient tumor samples from the "408" trial, a randomized, Phase 3 study of Vectibix. Tumor samples from 288 patients, which had previously been analyzed for KRAS exon 2 mutations, were analyzed in this study for mutations in nine genes: KRAS (exon 3), NRAS, BRAF, PIK3CA, PTEN, AKT1, EGFR, beta-catenin (CINN1B) and TP53. All nine genes are either direct or indirect components of the EGFR signaling pathway.

In this retrospective analysis of Phase 3 data, which included evaluation of KRAS exon 3 (codon 61) mutations in addition to the initial KRAS exon 2 analysis, Vectibix significantly improved progression-free survival (PFS) in the patients with KRAS wild-type (WT) tumors>KRAS mutant tumors>

In addition to KRAS, mutations in NRAS, another member of the RAS gene family, were also associated with lack of response to Vectibix. Patients with KRAS WT and NRAS WT tumors receiving Vectibix had improved PFS>NRAS mutant tumors did not appear to benefit from Vectibix>

Observed mutation rates in this study were consistent with previous reports in colorectal cancer; however a higher than expected rate of simultaneous mutation of KRAS and either BRAF or NRAS was observed. Further investigation in larger studies is required to determine the predictive value of BRAF mutations.

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 colorectal cancer with these mutations.

For the 288 patient samples, which were balanced between the two treatment arms, the analysis yielded data for an average of 7.85 genes per patient and the data completeness for each gene ranged from 84 percent to 99 percent. One hundred nine tumors had more than one mutant gene, and 20 had more than one mutation in a single gene.  

"In addition to the excitement of this being among the first times this technology has been used in Phase 3 research, the superior sensitivity of next-generation sequencing revealed unexpected genotypic complexity in many patient tumors," said Peeters.

The full data will be presented during an oral session on Monday, April 19 at 3:30 p.m. ET.

SOURCE Amgen