Understanding Molecular Residual Disease (MRD) in Clinical Trials
What is MRD?
The buzz around molecular residual disease (MRD) has been growing for several years, with several assays now on the market and numerous ongoing trials investigating clinical utility. MRD refers to the presence of a tumor-derived molecular analyte (e.g. cancerous DNA, RNA, or protein) that remains in bodily fluids following cancer treatment. Most MRD tests currently use next-generation sequencing to detect circulating tumor DNA (ctDNA), a biomarker which can be differentiated from non-cancerous circulating DNA by specific mutations and epigenetic modifications such as methylation.
Several MRD tests are currently on the market for a variety of indications and use cases (see this article for more on the state of the field). In general, MRD tests are either tumor-informed or tumor-agnostic, depending on whether the patient’s tissue biopsy sequencing is used to design the assay. Tumor-informed assays test for a relatively small and patient-specific set of mutations, meaning these tests can achieve high sensitivity. However, tumor-informed tests need to be custom-made for each patient, meaning the time to results is longer. In tumor-agnostic liquid biopsy, a broad panel of mutations are tested for, with a resulting lower sensitivity but without the prior requirement of tumor biopsy and sequencing which may not be possible.
When is MRD testing used?
MRD testing can occur at multiple points in the patient journey and has several different applications. In surveillance monitoring, also known as recurrence monitoring, patients undergo repeated longitudinal ctDNA testing to catch the first appearance of MRD, which may signal an impending clinically-detectable relapse. Patients may undergo surveillance monitoring after resection surgery or any other treatment with curative intent, and after successful treatment of metastatic disease.
MRD testing can be used throughout the patient journey to provide actionable information. Following initial treatment, MRD testing could be used to monitor for recurrence and determine if a patient could benefit from additional therapy to lower the risk of relapse. During the course of treatment, ctDNA can be used the monitor patient response over time and inform decisions on whether to continue or change therapy.
In the other major application of MRD testing, therapy response monitoring, longitudinal ctDNA testing is used to assess ctDNA levels during the course of systemic treatment. This could include monitoring during neoadjuvant therapy, adjuvant therapy, and treatment for metastatic disease. Increasing ctDNA levels during treatment may indicate a lack of response, while decreasing levels point to effective treatment. This information could inform decision-making around changing, escalating, or de-escalating therapy.
How can MRD testing be used in clinical trials?
Evidence has been mounting demonstrating that ctDNA kinetics are an accurate reflection of disease status for multiple types of cancers: ctDNA positivity post-treatment has strong predictive value for relapse, while ctDNA negativity is well-correlated with true lack of molecular disease. The FDA has published a draft recommendation on the use of ctDNA analysis for MRD detection in the clinical trial setting, with potential uses including:
Assessing eligibility for a trial (e.g. only MRD-positive patients enrolled)
Stratifying study populations (e.g. MRD-positive and MRD-negative arms)
Using MRD status to determine treatment (e.g. experimental treatment escalation or de-escalation)
In addition to these use cases, the field has begun to work towards incorporating MRD testing in oncology clinical trials as an early endpoint. In regulatory language, an “endpoint” is an event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial. In oncology, overall survival—the time to death of any cause—is the gold-standard endpoint, because the goal of cancer treatment is generally to extend survival. Overall survival is a straightforward metric, but it requires extensive follow-up with the study population, translating to high costs and limited usefulness in slow-progressing cancers. Many alternative surrogate endpoints—substitutes for a direct measure of patient experience and survival—have been validated for clinical trial use.
An example of ctDNA monitoring incorporated into clinical trial design: the ongoing CIRCULATE-Japan study, composed of three parallel clinical trials, evaluates the clinical benefits of ctDNA analysis and precision adjuvant therapy for resectable colorectal cancer. Abbreviations: F/U, follow up; FTD/TPI, trifluridine/tipiracil; mo, month; NAC, neoadjuvant chemotherapy; Op, operative; WES, whole-exome sequencing. Figure from Taniguchi et al. Cancer Science (2021).
Some surrogate endpoints are also early endpoints, meaning that they are predictive of long-term outcome. The value of early endpoints is evident in their name: early endpoints can be measured earlier, thereby potentially reducing the length of a clinical trial and time-to-approval for a given treatment. In the context of liquid biopsy, MRD is a promising surrogate early endpoint candidate, but not currently sufficient to support a drug marketing application. The FDA has determined that additional evidence is needed to establish a strong correlation between ctDNA status and disease outcome or treatment response.
What challenges remain in validating MRD as an early endpoint?
To date, many trials have used ctDNA as exploratory endpoints, but few have incorporated the necessary standards and controls that would allow this data to be used for endpoint validation. Many open questions remain on the ability of ctDNA to predict clinical benefit. For example, does the validity of ctDNA as an early endpoint depend on type of treatment or tumor? When should ctDNA measurements be taken for most effective predictive value? What types of measurements are most useful in different settings, such as adjuvant, neoadjuvant and recurrence monitoring?
In addition to these and other clinical concerns, there are multiple technical considerations in validation of MRD testing as an endpoint given the plethora of different assays available. Technical questions include: how do differences in sample collection and processing affect a test’s ability to accurately detect ctDNA? Can data from trials using different MRD tests be pooled and correlated to long-term outcomes?
Answering these and other questions with confidence and care will require multiple independent clinical trials with careful design correlating ctDNA levels with long-term outcome in different tumor types, cancer stages, and treatment settings. Meta-analyses of the resulting data can then be used as evidence to support MRD testing as an early endpoint. Of course, setting up and running these trials will be expensive and lengthy. In order to maximize success, collaboration between test developers, regulatory agencies, and other stakeholders will be important–this is where BLOODPAC is active. In the words of Dr. Anne-Marie Martin, BLOODPAC member and Global Head of Experimental Medicine at GSK, “BLOODPAC working groups are currently engaged in bringing MRD testing into clinical use and defining standards and validation criteria, and I really think it’s going to have a huge impact on future patients.”
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