The future of cancer diagnosis and treatment lies in characterising oncology patients by their biomarker profiles. ICON Central Laboratories helps pharmaceutical companies develop cutting-edge biomarker-based techniques for guiding clinical trial recruitment and assessing the performance and value of oncologics.

We spoke with Dr. Chengsen Xue, Ph.D., one of ICON Central Laboratories’ leading scientists, about the latest biomarker-based methods and how they can be leveraged to add value to oncology trials.

(1) Biomarker choice in an immuno-oncology trial is complex, particularly for a number of trials enrolling patients with advanced metastatic cancers. What do developers need to anticipate to ensure the right biomarker strategy is in place?

The selection of the right biomarker profile for an immune-oncology trial is an art as much as it is a science. As drug development becomes increasingly expensive, sponsors are interested in accruing the best available advice during this stage of trial planning. ICON’s biomarker experts, who have extensive experience in molecular biology and a long CRO service history, can provide developers with valuable insights throughout the duration of immune-oncology trials.

Researchers have developed three biomarkers strategies for the development of a new drug candidate. These strategies include:

1. Measuring host immune responses through lymphocyte immunophenotyping.  A medication can alter the concentration of regulatory T-cells in a patient’s blood, and this can have devastating effects on his or her health. A flow cytometric assay consisting of a panel of fluorochrome-conjugated monoclonal antibodies directed against CD4, CD25 and Foxp3 can monitor this critical cell population in patients’ peripheral blood.
2. Receptor occupancy assays. A receptor occupancy assay estimates the amount of drug that is bound to a particular surface marker in a target cell population, and this assay could potential serve as an index of drug efficacy. This test can help elucidate the dose-response relationship.
3. Circulating tumour (CTC) assays. This assay is a powerful tool for directly measuring the concentration CTCs, which improves tumour sample accessibility and helps reveal a molecular profile of a tumour for more informed targeting and prognosis.

All of these strategies provide an unprecedented and detailed understanding of clinical biomarkers in oncology.

(2) How can bioanalytical methods be leveraged to add value in early phase studies?

Biomarkers are key to success in modern drug development. By developing a molecular profile of a tumour in early phase studies, we can use the aforementioned strategies to predict the chance that a drug might fail in development.

Since immunophenotyping is sensitive to T-cell markers, it can detect whether a drug is harming a patient’s immune system. With this information, a developer can choose to end a trial early to prevent patients from experiencing adverse reactions to the drug being tested. Receptor occupancy assays could also play a vital role in dose-finding studies. If receptor occupancy is tested early, developers can determine what dose achieves the optimal receptor occupancy level and relate this to the clinical efficacy of the drug.

Also, since we developed the CTC assay five years ago, for example, many developers have reported this assay’s value in predicting survival rates in oncology clinical trials. In an adaptive clinical trial, CTC information could be used as an early indicator for drug candidate efficacy, especially when this information has coalesced into a full mutation profile for the tumour. By measuring CTCs early, a developer can cease a trial as soon as it is revealed that a drug is not efficacious, and this could save millions of dollars in trial costs.

(3) What is the potential for liquid biopsies in immuno-oncology trials?

As whole genomic sequencing becomes more readily available, it can be greatly beneficial to integrate CTC information into clinical decisions. It is reasonable to predict that a CTC test will be included in all future oncology clinical trials because of its value in generating prognoses based on the effectiveness of a drug.

ICON started CTC testing services in 2008. Over the last eight years, the ICON team has accumulated rich experience in integrating this increasingly important biomarker analysis into multiple clinical trials. Using only a simple blood test, ICON directly monitors the presence of CTCs and its relation to survival rate. As the technique continues to evolve and is integrated further with next generation sequencing and big data analytics, the potential of liquid biopsies is being realised.

In 2017 ICON added to our liquid biopsy capability through the validation and implementation of the RareCyte, AccuCyte sample collection and slide preparation for nucleated cells. Utilizing globally standardized equipment and a single operational procedure ICON can quickly, efficiently and with high reproducibility, separate nucleated cells from whole blood and generate uniform slide smears. The major advantage of this technique of is the ability to process samples at our regional labs, and store the prepared slides in -80 C for up to 3 months prior to analysis.

(4) High variability among patient samples and assays can prove challenging for immuno-oncology trials. How do you mitigate that variability?

Since CTC analysis is designed to detect rare events, CTC readout may vary for any given test. It is important, therefore, to look for trends in the data. Developers can minimise this variability by performing CTC assays more frequently during the trial and implementing a strict quality control system. Since ICON developed its CTC assay, the assay has consistent passed quality control tests. One advantage of utilising a central laboratory, such as ICON’s Clinical Laboratories, is that we can ensure that all of our testing processes are standardised, and therefore will generate high quality, consistent data. 

(5) For sponsors currently developing an upcoming trial’s protocol and bioanalytical testing methods, what advice would you share?

CROs are a critical player in the modern clinical trial process. Over the years, ICON has given developers access to a variety of experts in every aspect of clinical trials. However, many sponsors still only perceive CROs as “helpful hands,” as they are only brought in later in the development process, after the trial design has been finalised. Once a design reaches the validation stage, it is often too late for a CRO to make any meaningful corrections. I would advise developers to welcome CROs into design process so they can provide their expertise and help design more successful trials.