Regulatory Focus - White paper bolsters ctDNA as potential 'early endpoint' in cancer approvals

Mary Ellen Schneider | November 09, 2021

A newly released white paper from the Friends of Cancer Research calls for a collaborative effort to investigate the use of circulating tumor DNA (ctDNA) as an “early endpoint” to predict long-term cancer survival outcomes in early-stage cancers.
This type of early endpoint could be used by regulators when considering certain accelerated cancer approvals. But the group acknowledged that more robust data is needed, as well as harmonization around definitions and standards. As a first step, the group called for a “landscape assessment” of currently available data from previously conducted randomized controlled trials in early-stage solid tumors.
“From a regulatory perspective, if we were confident that a change in ctDNA levels could identify patients that are going to experience long-term benefit from an early-stage intervention, then that could give us the confidence to have patients get access to novel therapeutics earlier when we can see that those therapeutics are efficacious based on this early endpoint, rather than having to wait for gold-standard endpoints such as [overall survival] to mature,” Chris Abbosh, of AstraZeneca, said at the Friends of Cancer Research annual meeting. Abbosh was part of the working group that wrote the white paper.
The white paper builds on the group’s existing research efforts around ctDNA, which include the ctMoniTR Project. In step 1 of the ctMoniTR research initiative, researchers sought to harmonize the use of ctDNA to monitor treatment response and determine if changes in ctDNA levels reflect the therapeutic effect of immunotherapy in lung cancer. They demonstrated that reductions in ctDNA were strongly associated with better clinical outcomes, including overall survival. In step 2 of the project, they are looking across more than 20 clinical trials and 16 different therapies to characterize whether changes in ctDNA are a prognostic indicator and examine ctDNA as a potential drug development tool or early endpoint (RELATED: Friends of Cancer Research project tracks early cancer therapy response, Regulatory Focus 09 June 2021)
The white paper summarizes recommendations from a working group of experts in ctDNA and early-stage cancer including representatives from the US Food and Drug Administration (FDA), drug sponsors, ctDNA assay developments, and academic clinicians. While there are several opportunities to use ctDNA in early-stage cancer, including for risk stratification and treatment selection, patient selection, and monitoring and predicting treatment responses in the neoadjuvant and adjuvant setting, the paper focuses on the potential for using ctDNA changes in response to therapy as an early endpoint that could support regulatory approval.
The working group used the term “early endpoint” to indicate that ctDNA changes may be measurable earlier than endpoints like disease-free survival, event-free survival, or overall survival.
“In order for ctDNA to support an Accelerated Approval as a primary efficacy endpoint, ctDNA changes would need to be proven to be reasonably likely to predict clinical benefit,” the working group wrote in the white paper. “This utility may have therapeutic class specific (e.g., chemotherapy, immunotherapy, targeted therapy, etc.) and tumor type specific considerations, however more data and evidence are needed to delineate these factors. Many clinical and technical questions exist regarding use of ctDNA as an early endpoint and robust evidence generation will be necessary to support its use for regulatory decision-making.”
There are several sources of variability in early-stage disease ctDNA clinical studies, including clinical variables (tumor and treatment type), collection and methodologies, captured endpoints, and diagnostic assay and analysis. There are also key clinical and technical questions that need to be resolved before ctDNA could be a useful endpoint in regulatory decision-making. For instance, are there different minimum analytical performance requirements based on whether the treatment setting is neoadjuvant or adjuvant or based on the type of tumor? On the clinical side there are also several questions, such as at what time point does ctDNA response correlate with a long-term survival benefit?
“This is really just an initial starting point,” said Mark Sausen of Personal Genome Diagnostics, who was part of the white paper working group. “A lot of the existing datasets that are available and have been published today, you use that to establish the minimum analytical, technical, and clinical data requirements to expand into prospective studies to evaluate ctDNA as an early endpoint.”  
Friends of Cancer Research white paper