1. Gallagher, Amy

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On Day 2 of the San Antonio Breast Cancer Symposium (SABCS) held in December, Justin Balko, PharmD, PhD, Associate Professor of Medicine at Vanderbilt University Medical Center, presented an educational workshop on "how to build biomarkers and correlatives into clinical trial design."

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"The purpose of this workshop was to help clinicians, trialists, and translational scientists organize strategies to incorporate biomarkers and correlative studies seamlessly into newly developed clinical trial concepts," said Balko, who opened his session by defining biomarkers as biological indicators of early disease detection with respect to diagnostic indicators.


Based on the National Institute of Health's (NIH) definition of biomarkers referenced by Balko, he further stated that biomarkers also represent "prognostic indicators of disease progression, as well as predictive indicators of response to therapy." He referred to human epidermal growth factor receptor 2 (HER2) and programmed death ligand-1 (PD-L1) that serve as examples of these indicators and the overwhelming successes of immune checkpoint inhibitors (ICI) as addressed in his ongoing research study.


"While HER2 amplification for prediction of HER2-targeted therapy benefit is a great example of a biomarker which has truly changed practice, many biomarkers, such as PD-L1, display poor utility and predictive capacity for a variety of both technological and biological reasons," Balko noted. "Thus, a current focus of research is to find better biomarkers that can help refine how and who we treat with ICIs. These endeavors require a carefully thought out biomarker plan in new trials. A solid biomarker plan influences the outcome of productivity and impact regarding the logistics and considerations in (clinical trial) design."


Purpose of Biomarker Plan

Early in a clinical trial with a new agent, biomarkers are used to provide evidence for the pharmacodynamic activity of a drug. In early-phase clinical trials where an optimal dosing regimen is being studied, Balko explained that one may use a downstream marker to ensure the drug and dose are having the intended effect, which could be a marker of PI3K activity (phospho-AKT or phospho-S6) with a novel PI3K inhibitor, as an example.


"Biomarkers can also help prognosticate a patient," he said. For example, the number of tumor-infiltrating lymphocytes is a well-established marker in triple-negative breast cancer of patients who are less likely to recur or die of their disease.


"Through prediction, we can identify a sub-population of patients-such as those who experience immune-related adverse events (irAEs)-who could be treated with a particular agent with the ultimate goal of knowing how to better manage patients at risk for severe adverse sequelae from ICIs," he said.


Biomarkers highlight the biology of a patient and the disease, Balko noted. "Taking a translational approach when we go back to the lab, we can begin to understand the mechanisms of sensitivity or resistance, as an example."


He stated that the National Cancer Institute (NCI) has organized biomarkers in three formal classifications: integral, integrated, and exploratory.


"When the exploratory process is a multi datapoint analysis, we might consider looking at what is going on with the new drug and how it is affecting the tumor," he said. "We can see how a drug targeting a certain pathway may change the tumor microenvironment, for instance, or how treatment influences the amount of immune cells and their activity in the tumor."


Novel Technologies

Technologically novel platforms and how they work were also addressed during Balko's SABCS session.


"Many of these new technologies allow us to use tissue more sparingly and look at many different parameters, where years ago this would be impossible," he explained. "We can now visualize, for example, many proteins or gene transcripts spatially across a section of a tumor to better understand what is happening, and where in the tumor it is occurring.


"The output of a well-designed biomarker plan leads to scientific discoveries, opportunities for grant funding, producing high-impact (research) papers, and [it] ultimately impacts patients and their care," stated Balko, who also serves as Associate Professor for Cancer Research; co-lead of the Breast Cancer Research Program; and Associate Professor of Pathology, Microbiology, and Immunology at the Vanderbilt-Ingram Cancer Center (VICC).


In April 2019, Balko and co-principal investigator Douglas B. Johnson, MD, MSCI, who leads the VICC melanoma clinical research program, received a grant from the NIH-NCI to study clinically translatable predictive and early-response biomarkers for the development of irAEs caused by ICI therapy in cancer patients, while making new discoveries that identify the pathogenic mechanism of irAEs.


Using these data, Balko and Johnson will address three specific aims in this ongoing research: 1) prospectively characterize on-treatment cell-mediated mechanisms of irAEs; 2) determine whether irAE-associated autoantibodies or T-cell receptors (TCR) can be identified prior to treatment with ICIs; and 3) identify the antigen targets of pathogenic TCRs and profile their expression across tumor and diseased tissue.


"While the numbers of patients at risk for irAEs will continue to rise, this proposal will address the growing unmet need within the subpopulation of patients," Balko noted. "Ultimately, these treatments will be used in increasing numbers of patients and moved to earlier lines of therapy based on the positive outcomes of ICIs and continued scientific discoveries that ultimately impact patients through high-impact research."


Amy Gallagher is a contributing writer.