Hunting for More Biomarkers
Finding reliable biomarkers to predict drug responses requires a tremendous commitment of resources on the part of drug developers. “Head and neck cancer is an area where there is a major need for biomarkers,” David Reese, M.D., executive medical director in medical sciences and therapeutic head for oncology early development at Amgen, told GEN.
“Amgen has a strong commitment to biomarker development. We incorporate it very early in the drug development process in oncology and other areas. The biomarker team is formed well before the drug is administered to humans and remains in existence throughout the development life cycle of the drug.
“Amgen’s biggest biomarker program success has been in colorectal cancer with some of the work we did with Vectibix. We had performed the first analysis of a Phase III trial, the 408 study, the original monotherapy registration trial for Vectibix. We found only patients with KRAS wild-type tumors appeared to respond to the drug. That led to conditional approval of the drug in Europe and to updates to labels in the United States.”
In Amgen’s most recent work tumor samples from 288 patients were analyzed for mutations in nine genes: KRAS (exon 3), NRAS, BRAF, PIK3CA, PTEN, AKT1, EGFR, beta-catenin (CINN1B), and TP53. All nine genes were either direct or indirect components of the EGFR-signaling pathway.
“Using next-gen sequencing technology, we could simultaneously analyze multiple genes, about a dozen, in the tumor samples from the 408 registration study. The use of the new technology was, to our knowledge, the first time it has been employed in a set of tumor samples from a Phase III trial and allowed a rapid analysis of multiple biomarkers.
“We found another RAS gene, NRAS, which when mutated also seemed to predict resistance to Vectibix,” Dr. Reese told GEN. A higher than expected rate of simultaneous mutation of KRAS and either BRAF or NRAS was observed.
“None of the genes that we analyzed were clear predictors of response or resistance. We viewed this work as a proof of principle that you could employ this technology in this setting and are doing additional work to confirm the associations we found in the study. We believe these technologies will become incorporated into clinical medicine rapidly.” But, Dr. Reese cautioned, “The identification of appropriate biomarkers remains one of the core challenges in the field.”