Foresight Diagnostics in collaboration with the National Cancer Institute (NCI) announced results from an ongoing phase 2 clinical trial of the lymphoma drug acalabrutinib that included Foresight’s proprietary circulating tumor DNA (ctDNA) detection and minimum residual disease (MRD) monitoring assay, Phased variant Enrichment and Detection Sequencing (PhasED-Seq).  

Detection of ctDNA levels with PhasED-Seq was highly correlated with CT imaging and rapidly detected changes in tumor burden in newly diagnosed aggressive B-cell lymphoma patients treated with the drug. The study (abstract #524) was described recently in a podium presentation at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition.

“Despite significant advances in how we treat patients with B-cell lymphomas, we still monitor disease burden and response to therapy primarily through CT imaging,” says Mark Roschewski, MD, Lymphoid Malignancies Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD., and principal investigator of the study. “This study found that changes in MRD levels may predict response to acalabrutinib treatment in as few as seven days and also suggested that ctDNA quantification by PhasED-Seq may demonstrate clinical response prior to CT scans in some cases. In routine clinical care, using a tool like PhasED-Seq to study treatment response in real-time could enable physicians to direct management decisions earlier in the treatment process.”

The open label trial is evaluating patients with newly diagnosed aggressive B-cell lymphoma and is designed such that patients first received the BTK inhibitor acalabrutinib for up to 14 days. Responders, as assessed by CT imaging, continued on acalabrutinib plus chemotherapy.

Non-responders received chemotherapy only. Patients’ tumor burden was evaluated by both CT imaging and ctDNA quantification via Foresight’s MRD assay from the start of the trial to the end of therapy.

The study includes early results from 39 patients, 18 of which (46%) responded to acalabrutinib while 21 (54%) did not based on CT imaging. MRD measurements assessed using PhasED-Seq were strongly predictive of CT response as the log-fold change in ctDNA at the end of the acalabrutinib window correlated with change on CT.

PhasED-Seq results at only seven days, earlier than planned CT imaging, were also highly correlated with the change in tumor burden on CT. One patient with improved symptoms showed a 20-fold drop in ctDNA even with no corresponding CT changes, suggesting that PhasED-Seq may measure response earlier and with greater sensitivity than CT.

“Response to Acalabrutinib in this window study was much better predicted by very early ctDNA dynamics than by the tumor molecular profile, including cell-of-origin subtype,” says Ash Alizadeh, MD, PhD, scientific advisor and co-founder of Foresight Diagnostics and a contributor to the study. “This stands in contrast to other BTK inhibitors where cell-of-origin and tumor genotype can be a strong biomarker. This observation seems to suggest the utility of sensitive MRD methods to quickly test activity of novel agents in the frontline setting in similar window studies, including with other BTK inhibitors.” 

In addition to this study showcasing Foresight’s MRD technology, several other recent presentations highlight the utility of ctDNA in diverse lymphoma types. These include the use of PhasED-Seq in Primary Central Nervous System Lymphomas to be presented in the Plenary Session (abstract #6), in frontline immunochemotherapy of Hodgkin Lymphomas (abstract #233), and for DLBCL subtype classification using EPIC-Seq (abstract #37).

“Our PhasED-Seq ctDNA liquid biopsy platform is designed to produce actionable results sooner by detecting MRD with higher sensitivity than other ctDNA assays. The un-matched sensitivity and accuracy of PhasED-Seq for MRD measurement during treatment demonstrated in this study adds to the accumulating data on the platform’s performance,” says David Kurtz, MD, PhD, scientific advisor and co-founder of Foresight Diagnostics and a contributor to the study. “This includes our recent peer reviewed publication in Nature Biotechnology in which PhasED-Seq demonstrated superior minimal residual disease detection in B-cell lymphoma patients compared to other liquid biopsy approaches. We believe that Foresight’s PhasED-Seq MRD platform holds great promise to offer clinicians a better, more individualized approach to managing B-cell lymphoma patients.”