Over the last decade, molecular residual disease (or minimal residual disease; MRD) has emerged as a powerful dynamic biomarker in oncology. Defined as a very small number of tumor cells remaining after curative-intent intervention, MRD is gaining acceptance as a reliable predictor of cancer relapse1. The recent expansion of our clinical understanding of the role circulating tumor-derived DNA (ctDNA) plays in cancer has driven the need for highly-sensitive MRD detection, while Next Generation Sequencing (NGS) advances have enabled unprecedented genomic characterization of cancer mutations. Today, ctDNA analysis has the potential to fulfill unmet needs in drug development, including patient stratification for trials based on likelihood of relapse, rapidly identifying therapy response and resistance, quantifiably tracking variants, and assessing treatment outcome early. Because of its ability to inform post-resection therapy, assess therapy efficacy, and detect recurrence earlier than standard of care, MRD is rapidly being integrated into clinical trial design and translational research studies2. Using MRD as a biomarker in clinical trials can increase efficiency, reduce overall costs, and demonstrate durability of treatment response.
MRD strategies
MRD assessment using ctDNA can be divided into two approaches. Tumor-naive assays detect residual cancer using a predetermined panel of hotspot tumor mutations and/or epigenetic alterations, which limits the number of markers tracked, but may be necessary when tumor tissue is limited or nonexistent. Conversely, tumor-informed strategies deliver a highly-personalized assay which is well-suited for longitudinal testing. The genomic signature identified by sequencing the primary tumor tissue can be monitored and tracked throughout the individual’s care journey. Tumor-informed ctDNA assessment is associated with higher sensitivity compared to tumor-naive assays, making it preferable to detect the very low disease volumes characteristic of early MRD. Additionally, integrating fixed panels curated to detect resistance-associated mutations can complement MRD to provide crucial insights into the emergence of known clinical and resistance hotspots, advance knowledge of tumor biology, and inform therapy strategy. Today, the field of oncology is leveraging technologies that combine the strengths of the strategies described above, as well as whole genome sequencing, into a single assay that provides unprecedented sensitivity (~10-6)3. This unique combination empowers reliable longitudinal therapy response analysis, including variant tracking and proactive monitoring, resistance mechanisms, and ctDNA clearance assessment.
The proportion of tumor-derived DNA among the large amount of normal DNA is often low, and out of the detection range of many established technologies, leading to false negative results.4,5 Therefore, ultra-sensitive ctDNA measurement plays an important role both in identifying driver mutations to inform therapy, and in enabling long-term outcome prognostication.
Using MRD to inform clinical trial decisions
An integral part of clinical trial design centers on predicting which patients will relapse and potentially benefit from the treatment of interest versus standard of care; yet this remains technically challenging. The biological relevancy and prognostic value of MRD are well understood and have been supported by multiple studies. MRD status addresses the need for risk stratification across solid tumor types by providing detailed information on treatment response and probability of relapse significantly earlier than standard methods3. Moreover, detecting ctDNA from a simple blood draw facilitates patient screening during the recruitment phase and provides valuable insights in retrospective trials looking at progression free survival (PFS) and overall survival (OS) rates. MRD can also help expedite drug development, be it when used for trial patient selection, stratification or enrichment, to guide treatment decisions, or to provide an early estimate of treatment efficacy. By selecting MRD-positive patients, researchers can focus on participants who are highly likely to relapse during the course of the study. This strategy is accepted by the FDA6 and can facilitate regulatory approval by ensuring that the trial can meet its stated objectives – detect clinically meaningful treatment effects or lack thereof – with sufficient statistical power while maintaining smaller sample sizes.
Because it provides an earlier assessment of efficacy and correlates strongly with clinically relevant endpoints such as PFS and OS, MRD evaluation has come to the forefront as a valuable surrogate endpoint. According to recent studies, MRD negativity is strongly associated with long PFS in patients with multiple myeloma (MM) regardless of the treatment received, the disease setting (newly diagnosed or relapsed/refractory) or the depth of clinical response at the time of MRD measurement.1,7 These findings confirm the utility of MRD as a relevant surrogate for PFS and OS in clinical trials for MM and suggest that MRD can be used as a significant trial endpoint for other types of solid tumors. Although the FDA has not yet approved the use of MRD as a primary endpoint in the context of solid tumors, MRD can help avoid over and under treatment and inform de-escalation or termination of a clinical trial.
With cancer therapies becoming increasingly effective, patients are experiencing progressively longer PFS and OS. As a consequence, the time to reach the traditional endpoints is becoming prohibitively long. Non-invasive and rapidly obtainable ctDNA results coupled with the sensitivity to detect changes in tumor burden at infinitesimal levels – only days after surgery3 – give the next generation of liquid biopsy assays the power to dramatically accelerate drug development. The team at Personalis is eager to share more about how our NeXT Personal™ assay can benefit your translational and clinical trial work by personalizing your approach to precision oncology.
References
- Munshi NC et al. A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma. Blood Adv. 2020
- clinicaltrials.gov. Clinical Trials Using MRD as Outcome Measures.
- Personalis, Inc. NeXT Personal
- Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol. 2018
- Mansoori B et al. The Different Mechanisms of Cancer Drug Resistance: A Brief Review. Adv Pharm Bull. 2017
- U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for Industry. Published online May 2022
- Avet-Loiseau H et al. Minimal Residual Disease Status as a Surrogate Endpoint for Progression-Free Survival in Newly Diagnosed Multiple Myeloma Studies: A Meta-analysis. Clin Lymphoma Myeloma Leuk. 2020