There has always been a desire among oncology physicians and their patients to more precisely match treatments to the specific demands of each tumor. Over time that desire has moved closer to reality thanks to the use of biomarkers in the classification and development of treatments for different types of cancer.
A biomarker is a biological molecule found in blood, tissue or body fluids that can be used to identify the presence of an abnormal process or disease. For example, a biomarker may be secreted by a certain type of tumor, or it could be a physical response by the body’s immune system to the presence of a tumor. By identifying biomarkers, researchers and physicians can determine whether a specific treatment is appropriate for a specific tumor type and track their ongoing presence or absence as a measure of how well the body responds to a treatment. Biomarkers can also help indicate drug efficacy, toxicity or resistance, and they may be useful in pharmacodynamics-based therapeutic drug monitoring as surrogate and non-surrogate endpoints.
These are all developments that regulatory agencies, including the U.S. Food and Drug Administration and European Medicines Agency, are significantly interested in because they provide information that can help vastly improve the way we treat cancer.
Better results, better matching
Biomarkers offer two types of information that can support clinical study objectives and endpoints: predictive, identifying patients who are susceptible to a particular drug effect, which may involve benefit or harm; and pharmacodynamic, revealing target engagement and the magnitude of biological response post therapeutic intervention. These results can be used to support drug development and patient care to improve outcomes and reduce the risk that patients will be subjected to ineffective or inappropriate treatments, which may cause harm or discomfort while delaying their ability to secure more effective treatment options.
In patient care, biomarkers may be diagnostic, indicating the presence or absence of pathogenic processes, or prognostic, providing information on the likely future clinical course in the absence of a therapeutic intervention. Used in companion diagnostics, biomarkers help predict responses to therapy. They may also be used in multiplex or multi-analytic diagnostic panels, in next generation-sequencing (NGS) genomic panels, or in whole exon sequencing (WES) or whole genome sequencing (WGS).
The complexity of the immune system and tumor biology also results in a wealth of biomarkers and potential targeted indications and patient populations. New diagnostic tools such as more powerful standardized flow cytometry and NGS can better profile immune response and utilize the immune repertoire for patient selection in clinical trials.
Pitfalls slow progress
The promise of biomarkers as a vital tool to fight cancer is without question, but it’s far from a mature science. Application of these tools in clinical development and patient care has only just begun, and there are many opportunities to better utilize them to benefit patients. Yet there are also many obstacles in the way. Physicians and researchers now must figure out how to identify which biomarkers are relevant, how to use them effectively, and how to figure out what role they will play in the future of immunotherapy treatments. Here are just a few of the challenges that stand in their way.
More data means more complexity. Recent advances that allow for broad spectrum biomarker measures are already enabling researchers to simultaneously identify multiple flaws and abnormalities that aren’t otherwise obvious. This is a great step forward in the ability to accumulate more data more quickly, but it also adds an extra layer of complexity as researchers and physicians are left to determine which abnormality or flaw is relevant and warrants targeted treatment.
Every patient (and tumor) is different. Physicians and researchers must address the fact that each patient has a unique genetic make-up and response rate, which will impact the successful use of biomarkers in their treatment. According to research available today, targeted small molecule therapy can yield high response rates, but it is often prone to resistance. Treatment of patients with immune checkpoint inhibitors can also differ from use of conventional therapies in the need to identify unconventional responses, and to understand and manage immune-related adverse events. And current assays for patient selection may not always have adequate specificity and sensitivity. That can force researchers to raise the threshold to meet specificity goals, which may result in excluding some potential responders.
We don’t what we don’t know. Another major risk in the development of products in this area is failure to anticipate unique properties of the response to the immunomodulator. For example, the mechanism-of-action (MOA) model may be unrepresentative, leading to targeting of unresponsive subpopulations; patient selection assays may be weak; and combinations of immunomodulators may lead to unexpected autoimmune syndromes, and may interfere with desired immunomodulatory effects in ways not seen in animal models.
Small populations make verification difficult. If researchers cannot secure a large enough group of patients in the target subpopulation, due to requirements for a novel screening or limited number of potential candidates, it can be difficult to accumulate enough data to validate results. Monitoring of pharmacodynamic (PD) responses can also pose challenges related to sample handling, lack of availability of clear surrogates of desired bioactivity, or the fact that relevant samples may only be obtainable from repeated tumor biopsies.
More work needs to be done
As the science behind the development of immunotherapy advances, these issues will only become more complex, requiring the industry at large to work together to advance the field. That means investing in more research focused on biomarker technology and assays, and collaborating to identify the best ways to get the most information out of every trials.
It is still early days, and the best approach is a collaborative one. If we work together as an industry and are willing to share our successes and failures, we will drive this research forward faster and more effectively than if we work alone.
As the old saying goes, ‘a rising tide lifts all boats.’ If we can raise the tide on biomarker research for immunotherapy, biopharma, payers, and patients will all benefit.