Analysis of Vectibix(R) Study Using New Gene Technology Helps to Advance Prospects for Personalized Medicine

Nine Genes Beyond KRAS Investigated As Potential Predictive Biomarkers For Metastatic Colorectal Cancer Therapy

ABSTRACT NUMBER: LBA 8791

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Apr 18, 2010, 03:30 ET

THOUSAND OAKS, Calif., April 18 /PRNewswire-FirstCall/ -- 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 (N=153; hazard ratio [HR]=0.39; 95 percent CI=0.28,0.56) and had no effect on PFS in patients with KRAS mutant tumors (N=124; HR=1.03; 95 percent CI=0.71,1.50).

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 (HR=0.39, 95 percent CI=0.27, 0.56) compared with those receiving BSC, whereas those with NRAS mutant tumors did not appear to benefit from Vectibix (HR=1.94, 95 percent CI=0.44, 8.44).

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.

About Next-Generation Sequencing Technology

Massively parallel, next-generation sequencing technologies have helped to revolutionize genomic biology as these techniques allow millions of DNA sequences to be read simultaneously in a single experiment. This represents a quantum leap beyond the methods that were used to sequence the first human genomes in the 1990s. The fact that each DNA sequence produced in this way represents a single molecule in the original biological specimen being studied means that "deep resequencing" studies such as the "408" analysis can achieve unprecedented sensitivity and quantitative accuracy for tumor mutation detection.

About KRAS

Results from studies performed over the last twenty-five 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 blocking the activation of EGFR, thereby inhibiting downstream events that lead to malignant signaling. However, it is hypothesized that 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. KRAS mutations occur in approximately 40 – 50 percent of mCRC patients.

About Vectibix

Vectibix is the first fully human anti-EGFR antibody approved by the United States (U.S.) Food and Drug Administration (FDA) for the treatment of mCRC. Vectibix was approved in the U. S. in September 2006 as monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal carcinoma 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, metastatic colorectal carcinoma is based on progression-free survival. Currently no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. Retrospective subset analyses of metastatic colorectal cancer 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.

In December 2007, the European Medicines Agency (EMA) granted a conditional marketing authorization for Vectibix as monotherapy for the treatment of patients with EGFR expressing metastatic colorectal carcinoma with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Vectibix has been launched in over 20 EU countries, Russia, Israel, Switzerland, Australia and Canada. Applications in the rest of the world are pending.

Important Product Safety Information

Dermatologic Toxicity: Dermatologic toxicities occurred in 89 percent of patients and were severe (NCI-CTC grade 3 or higher) in 12 percent of patients receiving Vectibix monotherapy.

Infusion Reactions: Severe infusion reactions occurred in approximately 1 percent of patients. Although not reported with Vectibix, fatal infusion reactions have occurred with other monoclonal antibody products.

The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

About Amgen

Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science's promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives. To learn more about our pioneering science and our vital medicines, visit http://www.amgen.com.

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