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BMS Identifies Response Biomarkers to Erbitux As It Strives to Expand Population for the Drug

BOSTON — Bristol-Myers Squibb, eager to expand the patient population for its targeted colorectal cancer drug Erbitux, is heavily immersed in genomic biomarkers tied to tumor response, according to a company researcher at the IBC Drug Discovery Technology conference here last week.
Helped by Genomic Health and the drug’s developer, ImClone, the efforts appear to be paying off: The drug maker has recently identified a set of biomarkers that may triple the drug’s response rate through better selection of patients, said Shirin Khambata-Ford, BMS’s senior research investigator for oncology biomarkers.
Khambata-Ford presented her company’s findings during a talk in Boston last week at the Drug Discovery Technology conference. BMS has a program focused on moving Erbitux from third-line therapy to second-line therapy by identifying pharmacogenomic biomarkers of response, she said. And ImClone, the company’s partner, has been trying to broaden the drug’s indication using pharmacogenomics since at least June 2005.
In an interview after her talk, Khambata-Ford declined to disclose development plans for the assay.
BMS prefers to conduct its oncology biomarker programs in parallel with drug discovery and development, Khambata-Ford said during the talk. In some cases, the approach can lead to pharmacogenomic programs, she said. This didn’t occur with Erbitux’s response biomarker, however, because the drug has been approved in the US since early 2004. It received its CE Mark in June 2004.
Still, Khambata-Ford explained the firm’s Erbitux program in the context of BMS’  oncology biomarker discovery and development efforts. If her presentation is an accurate guide, that effort has been largely genomic.
According to the US Food and Drug Administration, Erbitux is the first monoclonal antibody approved to treat metastatic colorectal cancer and is indicated as a combination treatment with irinotecan or as a standalone drug if patients cannot tolerate irinotecan.
To locate the Erbitux response markers, BMS researchers used Affymetrix chips to identify promising genes from 164 colon tumor and 31 colon cell samples in a phase I study known as CA225-045. The study, which began in Sept. 2005, aimed to, according to BMS, “predict response to Erbitux as a single agent in patients with metastatic colon cancer.”
The team is supporting its biomarker focus with biopsy samples, archival tissues, and blood samples in a phase 2 exploratory study of Erbitux monotherapy in refractory metastatic colorectal cancer.
Using pathway analysis to help choose its targets, the group is looking at RNA profiles, EGFR and KRAS mutations, immunohistochemical protein staining, and gene-copy numbers for EGFR, Khambata-Ford explained.

Genomic Health has the right to commercialize any diagnostics resulting from its collaboration with BMS

A mid-stream analysis of the phase 2 study narrowed the list to 39 differentially expressed genes that were split almost evenly between markers of resistance and markers of sensitivity, said Khambata-Ford. Most of these RNA species can be traced back to the EGFR pathway, suggesting that those patients having an active pathway are more likely to respond to Erbitux, she added.
Khambata-Ford reminded the audience that the previous studies had pointed to EGFR gene-copy number as a positive correlate of response to another EGFR inhibitor, AstraZeneca’s doomed lung cancer drug Iressa, as opposed to EGFR mutations, which showed little association. KRAS mutations, on the other hand, correlate to resistance to Iressa and Tarceva, a lung cancer drug marketed by OSI Pharmaceuticals and Genentech that also targets EGFR.
Genomic Health has developed some of BMS’ qPCR gene-expression assays, while the drug giant has developed some of its own along with gene-copy number EGFR assays, said Khambata-Ford.
Genomic Health has the right to commercialize any diagnostics resulting from its collaboration with BMS, a Genomic Health spokesperson told Pharmacogenomics Reporter this week. She did not elaborate on the capabilities of the company’s assays.
BMS is also developing response-predicting markers for its phase 2 compound ixabepilone in breast cancer and pharmacodynamic biomarkers for Sprycel in chronic myelogenous leukemia and for an unnamed VEGFR inhibitor, said Khambata-Ford.

In the section of her talk devoted to ongoing and upcoming research, Khambata-Ford said BMS employs immunohistochemistry, ELISA, and qPCR to investigate its top-candidate biomarkers. The company plans to validate its biomarker findings in formalin-fixed paraffin embedded tissue samples gathered from three phase 3 clinical trials, she said. It was not clear whether any of these investigations were related to the biomarkers that may triple response to Erbitux, however.

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