In December 2024, the National Comprehensive Cancer Network updated its clinical practice guidelines to recommend circulating tumor DNA testing for minimal residual disease in patients who have a positive PET scan following frontline therapy in diffuse large B-cell lymphoma (DLBCL). This marks the first time such testing has been included in the B-cell lymphoma treatment guidelines.
In this GenomeWeb Executive Q&A, Foresight Diagnostics’ chief operating and compliance officer Sandra Close and chief business officer John Truesdell discuss the new guidelines, how they may change the treatment journey for DLBCL patients, and Foresight's approach to establishing the clinical utility of its tests.
This transcript has been lightly edited for readability.
Colin O'Connor
What does the patient journey look like currently for a patient with this disease, and how might this recommendation change that?
Sandra Close
For 20 years, the standard of care following a diagnosis with diffuse B-cell lymphoma has been a treatment regimen called R-CHOP. It cures approximately 60 percent of patients with diffuse B-cell lymphoma. However, there's another 10 to 15 percent that don't respond, and another 20 to 30 percent on top of that who relapse within a year or so.
So, the patient comes in, they're diagnosed, and they receive six cycles of traditional R-CHOP treatment. Then they receive a PET scan or an image, and that imaging result says, ‘Your disease is gone,’ or, ‘Your disease is still present.’ PET scans, however, are an indirect measure of disease, and therefore imaging often has false positive and false negative results.
John Truesdell
Currently, the only way to adjudicate that PET-CT scan is either with PET itself or with a biopsy. And biopsy has negative implications for patients: it’s invasive, and it’s expensive for the healthcare system. So being able to do that with a simple liquid biopsy test like the Foresight Clarity* ctDNA MRD test is really important. The NCCN Guidelines Committee agreed that this would be a really helpful tool to avoid those biopsies and the additional PET-CT scans.
*[stylized as Foresight CLARITY]
O'Connor
Can you tell us a little bit more about the evidence that was used to support this new recommendation?
Truesdell
The big pieces of evidence we've generated with a number of partners looked at complete responders after first-line R-CHOP therapy in large B-cell lymphoma. And the thing that we see in the Kaplan-Meier curves separating those patients that have events or relapse and have disease and those that do not have events is that separation is much greater and much more profound than you would see with a PET-CT scan. And then, when we look at those cases where PET and our ctDNA MRD assay disagree, by and large, our assay is correct because in the instances where they're MRD negative but PET-CT positive, those patients do not have events. Whereas when patients are MRD positive and PET-CT negative, those patients generally have events and go on to relapse.
O'Connor
The NCCN guidelines specify using a ctDNA MRD test in this setting with a limit of detection of less than one part per million. Can you explain the significance of that number and how Foresight achieves that?
Truesdell
The one part per million — which is the limit of detection, the analytical sensitivity — is really critical for generating the correct clinical sensitivity that you need in order to determine whether a patient truly has disease or does not have disease. And this is enabled by a technology called phased variant enrichment and detection sequencing (PhasED-seq). We look at the genome for phased variants to really drive down the background noise.
Close
Previous assays have struggled with detecting enough patients accurately and have been rife with false positives and false negatives. So, this paradigm shift to clinical utility of ctDNA from a blood sample is because of technological advances which lead to a more accurate detection of patients and identifying those patients more likely to clinically relapse.
O'Connor
This test is not actually on the market yet. When will patients have access to it?
Truesdell
This is something that we are actively planning for in order to offer the test at the end of 2025 to patients and clinicians, at least in a more limited context as we ensure that we are ready for a full launch sometime in 2026. The test is available in certain circumstances, but only in the context of a clinical trial such as ALPHA3, which is the Allogene CAR T therapy clinical trial.
O'Connor
Tell us about the ALPHA3 drug trial.
Close
Following standard first-line therapy for lymphoma, patients who have obvious progressive disease or progress within a certain period of time, like a year or so, are approved to go on to an additional therapy, such as a CAR T therapy. those patients who maybe have disease or have a complete response on imaging but are still positive for circulating tumor DNA are in a watch-and-wait scenario. So the ALPHA3 trial being run by Allogene Therapeutics is testing that question. If on imaging, you have a complete response, and you look like you do not have any residual disease, but you have residual circulating tumor DNA, you can go either into the treatment arm with the CAR T therapy, or into the standard-of-care arm, which would be a watch-and-wait scenario, to see if those patients who receive CAR T sooner have a better survival outcome.
O'Connor
What are the regulatory considerations that your pharma partners need to manage when using an MRD test like this as a companion diagnostic?
Close
The direct-to-patient test is very often performed in the CLIA- or CAP-accredited laboratory in the United States. When partnering with biopharma, there are additional regulations required when you want to register a diagnostic as a companion diagnostic. Those quality and regulatory considerations include complying with the Code of Federal Regulations in the US and a variety of ISO standards across the world. Very early on, Foresight recognized the opportunity to change the patient treatment landscape by partnering with biopharma in this therapeutic selection field. So, the quality and regulatory infrastructure to support diagnostic development in compliance with the regulations was part of the initial development at the company. So, the quality and regulatory infrastructure is robust to support not only clinical trials and direct patient testing, but also to partner with biopharma meeting the US Food and Drug Administration regulations, but also regulations across the world.
Truesdell
There are two things that differentiate Foresight: the technology and the business approach. On the business approach, we really believe clinical utility evidence is critical to advancing ctDNA MRD in the space because this data is what provides the necessary use of ctDNA MRD, like Foresight Clarity, to determine next steps in a patient journey for treatment. And this is really what's going to not only make the test useful from a clinician’s standpoint, but also ensure that the test is covered and paid for by insurers, because they really gravitate to this kind of evidence as being real determiners of the necessity of this test. And we think it's necessary, and we're producing the evidence to demonstrate so.