Developing Prognostic Tools
Finding prognostic markers and choosing the right therapy once disease has been identified remains one of the main challenges for the clinical development of molecular diagnostics in oncology, according to Walter Koch, Ph.D., vp, global research. “These are unmet clinical needs that we and others are trying to address, and the challenges for prognostic versus predictive biomarkers can be very different.”
Once biomarkers are discovered, they have to be validated in independent cohorts. The resulting data must substantiate that the markers provide clinically useful information that predicts patient outcome. “Challenges with this scenario include the fact that there aren’t many sets of cohorts, and most samples banked over the past decades come from clinical endpoints not designed to answer a diagnostic question but rather safety and efficacy questions,” Dr. Koch reports.
Roche Diagnostics is currently working with Plexxikon on a therapy-selection marker for melanoma. It is a BRAF kinase inhibitor that targets a specific mutated form, V600E, present in 70% of melanomas.
In drug development itself, Roche has established a new organizational structure to include biomarker discovery and validation in all its programs. “We have the right tools in diagnostics to provide clinically important information and can apply them in clinical trials from the beginning to the end,” Dr. Koch states.
“When a companion diagnostic is necessary and helpful in selecting and stratifying patient populations, we can more easily register drug and diagnostic together. This is a fundamental change from the endpoint of how a physician goes about treating a patient, and also for the drug development process. You start with the notion that you may have a smaller potential market.”
The biggest challenge to reaching the goal of personalized medicine, according to Nancy Simonian, M.D., CMO, Millennium Pharmaceuticals: The Takeda Oncology Company, is the science: trying to understand what are the most critical pathways driving cancer cells to proliferate.
This has led to a change in the approach of clinical studies, especially patient selection. “If you knew your drug was only going to work in a subset of patients who had a specific abnormality in cancer that you can detect, you would only enroll those patients.” But, she adds, that the endpoints of clinical trials have remained the same—clinical efficacy and a positive benefit-to-risk ratio. “Ultimately, I think companies will have to develop their drugs with a companion diagnostic.”
Dr. Simonian says there is an increasing role of various biomarkers early in cancer drug development. “Early on, in first-in-human trials, we collect tumor biopsies before and after the drug candidate is given, to measure target pathway inhibition.” The company is using this approach in studies of a small molecule inhibitor of the Aurora-A kinase.
“The reason is to prove early on in development that you are hitting your target and effecting downstream pathways, which is very important for decision making and dose selection.” In drug development, this represents a move away from pushing the drug to toxicity to, instead, show that the compound is hitting its target and effecting pathways. “As a result, there is more assay development early on, which is later translated to the clinic,” concludes Dr. Simonian.