Changes to circulating tumor DNA (ctDNA) tumor fraction (TF) provided a numerically superior estimation of overall survival in response to treatment compared to traditional methods in metastatic castration-resistant prostate cancer (mCRPC) patients, according to a study presented at the American Association for Cancer Research (AACR) annual meeting. These results add to evidence for the potential of ctDNA TF as a new monitoring tool that could allow clinical researchers to detect tumor progression and change treatment strategies earlier than through current methods.
In clinical research, it can be challenging to understand treatment response and the depth of that response, information that is key to understanding the efficacy of a new treatment or combination and enabling pipeline strategy and decision making.
This challenge puts more emphasis on monitoring, where imaging is the current standard of care. But imaging has limitations, including potentially unclear results for patients with bone metastases or patients on immunotherapy. With immunotherapy, a phenomenon called “pseudo-progression” can make it appear as if a cancer is stable or growing, but scans reflect inflammation signaling treatment response.
However, advances that allow monitoring for ctDNA using a simple blood sample can provide complementary insights to imaging to help track tumor dynamics and understand more about the evolving mutations that drive tumor progression. Biopharma companies and academic researchers are starting to incorporate ctDNA monitoring in early clinical trials to accelerate their drug discovery and development plans.
Now, Christopher Sweeney and colleagues have shown the value of ctDNA monitoring in their retrospective analysis of the IMbassador250 clinical trial, a prospective Phase III international multicenter trial enrolling 759 men with mCRPC who had prior progression on abiraterone, with or without prior taxane, randomizing to enzalutamide with or without atezolizumab.
Sweeney and team employed a tissue-naive ctDNA clinical trial assay that requires only a blood sample based on FoundationOneLiquid CDx, a test that provides fast and comprehensive insights on treatment response. This test can help in early dose assessment studies or other discovery and translational research work, according to Foundation, by identifying variants across more than 300 genes and by quantifying an estimate of how much tumor DNA is in the blood sample with the proprietary multi-omic signature called ctDNA TF.
The study confirmed the researchers’ hypothesis that decreases in ctDNA TF after six weeks of therapy would reliably predict overall survival (and thereby confirm treatment response), independent of prostate-specific antigen (PSA) testing or radiographic progression. ctDNA TF also showed the ability to independently predict overall survival at an earlier time point compared to radiographic progression.
Beyond ctDNA TF, the clinical trial assay based on FoundationOne Liquid CDx has also shown value in drug discovery research and clinical trials by identifying specific variants before treatment, like EGFR T790M or C797S in non-small cell lung cancer (NSCLC), and tracking those variants on treatment to provide insights into response activity and treatment dose after just 14 days.
A New Path to Earlier Insights on Treatment Response: Personalized ctDNA Monitoring Informed by a Comprehensive Tissue Test
Foundation Medicine also provides a clinical trial assay (CTA) for tissue-informed ctDNA monitoring research for biopharma and academic partners, which enables tracking of patient-specific mutations. The assay is based on FoundationOneTracker, which is now available for investigational use (IUO) and provides insights on treatment response from a tissue baseline and subsequent blood samples.
The CTA based on FoundationOne Tracker combines genomic information derived from FoundationOneCDx, Foundation Medicine’s tissue-based comprehensive genomic profiling (CGP) test, with study-subject-specific assay design and ctDNA analysis from Natera, a leader in cell-free DNA testing, and is now available for investigational use in clinical trials, allowing researchers to use real-time processing of fresh specimens in ongoing prospective studies to gain earlier insights on treatment response. The CTA based on FoundationOne Tracker quantifies an estimate of how much tumor is in the blood by assessing the mean tumor molecules per milliliter (MTM/mL).
Two recent studies have shown the value and clinical validity of the CTA based on FoundationOne Tracker for treatment response and minimal residual disease (MRD) detection. The first is from the OMICO-MoST study, the first advanced pan-cancer solid tumor study to demonstrate FoundationOne Tracker can assess ctDNA dynamics for treatment response for two forms of immunotherapy.
The OMICO-MoST study showed that as early as four weeks after treatment, a decline in ctDNA from baseline predicted improved overall survival. In two patients with complete response, ctDNA clearance, or complete removal of ctDNA, preceded any response by scan and showed a median lead time of 11.5 months, a potential advantage in the use of ctDNA for response assessment.
The second study is an exploratory analysis of the PREDATOR trial that showed the feasibility of ctDNA-based MRD detection for metastatic colorectal cancer patients undergoing surgical resection. In this study, ctDNA detection was shown to be more predictive of disease-free survival than standard-of-care carcinoembryonic antigen (CEA) testing.
Forging the Path Ahead to the Next Frontier
Accurate disease monitoring is a particular area ripe for innovation, wrote Priti Hegde, chief scientific officer at Foundation Medicine in a recent blog post. Foundation’ goals are to understand the appropriate dose of a new treatment, find signal of response faster than imaging, and ultimately improve and extend the lives of the growing number of patients living with chronic cancer. By integrating CGP and ctDNA monitoring more deeply into clinical research, she wrote, there is an opportunity to accomplish these goals and stratify patients faster in clinical trials and to understand more about how those patients respond to treatment in weeks or months instead of in months or years with standard imaging only.
With the introduction of this research portfolio for ctDNA monitoring with tissue-naive and tissue-informed testing, Hedge wrote, Foundation Medicine now has flexible options to drive clinical research forward with the biopharma and academic partners in pursuit of our goal to shape the forefront of cancer care and deliver breakthroughs that help more patients in the future