Multiple research studies are focusing on the use of biomarkers to detect and treat cancers at their earliest stages. The Friends of Cancer Research (Friends) has released a white paper showing the value of circulating tumor DNA (ctDNA) as a biomarker for cancer in solid tumors. While speakers at a webinar to release the paper hailed the promise of this biomarker, they also said much work needs to be done to bring this promise to the clinic.
Circulating tumor DNA is genetic material shed from cancer cells and found in the bloodstream; it is often referred to as liquid biopsy. Researchers are investigating whether measurement of ctDNA could be used as a fast, reliable, noninvasive approach for clinical applications, such as measuring a patient’s response to treatment. They are also investigating whether ctDNA could be used as a tool during the regulatory process of accelerated drug approval at the FDA.
The new Friends white paper is titled Circulating Tumor DNA in Development of Therapies for Cancer: An Evidentiary Roadmap to an Early Endpoint for Regulatory Decision-Making. The term early endpoint signifies measuring ctDNA changes earlier than other endpoints, such as progression-free survival. During the webinar, keynote speaker Patrizia Cavazzoni, MD, Director of the FDA’s Center for Drug Evaluation and Research, noted that accelerated approval is an essential program for oncology and other serious diseases, and it can lead to patient access to effective drugs “in some cases years earlier” than would be the case without accelerated approval. She said accelerated approval is especially important in oncology because “all cancers are serious and life-threatening.”
Cavazzoni acknowledged the FDA is “very interested” in advancing new endpoints that can lead to accelerated approval, noting that there is an opportunity in oncology to develop new validated endpoints such as ctDNA through evidence generation that can reasonably predict clinical outcomes. However, she emphasized the need for embedding consistent upfront planning for confirmatory studies with FDA staff as early as possible when a drug is approved through an accelerated regulatory pathway.
Cavazzoni cited a draft FDA guidance document released in May 2022, “Use of Circulating Tumor DNA for Early Stage Solid Tumor Drug Development Guidance for Industry.” This document, which is being circulated for comments, is intended to help drug sponsors who plan to use plasma-derived ctDNA as a biomarker in cancer clinical trials under an investigational new drug application, and/or to support marketing approvals of drugs and biologicals that treat solid tumors in the early-stage setting.
To date, ctDNA has been used primarily as a selection marker in the metastatic setting for patients in clinical trials, said Julia Beaver, MD, Chief of Medical Oncology at FDA’s Oncology Center of Excellence. But, she noted, there is more interest now in using ctDNA in earlier stage settings, which is why the FDA released the guidance document as a response “to a whole lot of questions we were getting.”
As a biomarker, “ctDNA has so much clinical potential,” said Aadel Chaudhuri, MD, PhD, Assistant Professor of Radiation Oncology at Washington University School of Medicine. He called some of the correlations between ctDNA and clinical outcomes “jaw-dropping.” Chaudhuri, whose laboratory measures ctDNA as a liquid biopsy biomarker for molecular residual disease and correlates it with cancer survival, said he appreciates how much oncogenic information he learns from ctDNA.
The new Friends white paper states that ctDNA has potentially broad application in oncology and could be used to select patients based on molecular alteration; detect molecular residual disease in order to determine the need for adjuvant therapy after surgery, radiation or chemotherapy; measure the response to treatment; and serve as an early endpoint in clinical trials to evaluate treatment efficacy and support regulatory decision-making.
And the primary question for the use of ctDNA, as posed by the white paper, seems to be: Do changes in ctDNA while patients are on treatment predict long-term outcomes? The Friends organization did a recent meta-analysis of trials in non-small cell lung cancer, which suggests that “decreases in ctDNA levels due to therapeutic intervention are associated with improved outcomes.” Chaudhuri noted that this finding is consistent with studies that have shown ctDNA is present in much higher concentrations in metastatic cancers than in earlier-stage settings. He has found that levels of ctDNA are typically low in non-metastatic patients, requiring highly precise methods for detection and quantitation.
In addition to setting forth the potential of ctDNA in clinical practice, the Friends white paper identifies a number of challenges that need to be addressed, including the following.
- There are inconsistencies in how ctDNA is collected, measured, and reported, as well as the variability of the tests measuring ctDNA.
- There is a need for harmonizing assays that measure ctDNA. The FDA guidance document also notes the lack of harmony in ctDNA measurement, stating: “ctDNA assessments can vary among laboratories and technologies to detect ctDNA, which can result in discrepant results.”
- There is a lack of data on baseline ctDNA shed rates in the early-stage setting.
- There is a need for more data on tumor-specific ctDNA dynamics, such as changes in tumor clonality.
- Standards need to be set for ctDNA patient samples.
“We need to do the foundational work” to move ctDNA research forward, said Angela DeMichele, MD, MSCE, Co-Leader of the Breast Cancer Research Program at Abramson Cancer Center at the University of Pennsylvania and Director of the Breast Cancer Clinical Trials Unit at Penn Medicine. This work includes such specifics as determining false positives and false negatives. She advised defining what Phase II trials should look like as a collective, collaborative community, rather than “doing it in a piecemeal fashion.” She also noted the potential value of using ctDNA as a complement to imaging results.
Jeff Allen, PhD, Friends’ President and CEO, emphasized the overall revolutionary potential of ctDNA in oncology for therapy and the acceleration of new treatments. Allen noted that the organization launched the ctDNA MoniTR (ctDNA for Monitoring Treatment Response) Project to assess whether ctDNA can be used as a biomarker to easily and more rapidly validate whether a drug is working. Findings from step 1 of this project have shown that disparate datasets can be harmonized through statistical methods, there is a consistent association between reductions in ctDNA and improved treatment outcomes, and the strength of this association remains after accounting for clinical covariates.
Step 2 of this project will update step 1 methodology for combining data to account for additional treatment settings and tumor types, and validate step 1 findings in a bigger cohort with more treatment classes and cancer types.