FDA draft guidance issued Monday endorses ctDNA as a biomarker in drug development for early-stage, non-metastatic solid tumors, and lays out the agency’s thinking on its uses and limitations in four broad areas: patient selection based on molecular alteration, risk assessment based molecular residual disease, response measurement, and as an early endpoint for clinical trials.
“ctDNA as a biomarker has a number of potential regulatory and clinical uses in the early-stage setting that may assist and expedite drug development,” FDA wrote in the guidance.
Industry interest in circulating tumor DNA (ctDNA) shed from cancers has been strong, as the sequences are measurable in blood, making them relatively easy to implement and routinely collect in the clinical trials.
Companies have been building the data needed to support several use cases. “We’ve seen that continue to increase over the last several years,” Jeff Allen, president and CEO of Friends of Cancer Research, told BioCentury.
Initially entailing exploratory studies to characterize the role ctDNA may be playing in cancer biology, the work quickly expanded into investigating the roles ctDNA could play as a drug development tool, Allen said.
“From our vantage point, we certainly are thrilled to see this guidance come out,” Allen said. “I think it’s a recognition that FDA is acknowledging that there is promise for using ctDNA as a potential tool in each of these different use cases,” he added.
In its draft guidance, FDA lays out its thinking on four uses of ctDNA, some of which are more mature than others. “In the early stage, cancer setting, ctDNA may be used to detect a certain targetable alteration, to enrich a high- or low-risk population for study in a trial, to reflect a patient’s response to treatment, or potentially as an early marker of efficacy,” the agency wrote.
In the adjuvant setting, FDA proposes using ctDNA to either select or stratify patients based on molecular alteration, so long as the assay’s sensitivity can catch all genetic variants of interest interest. The agency added that “if no variants are detected in ctDNA, tumor testing may need to be performed to confirm the negative result.”
When using ctDNA to select high-risk or low-risk patients based on molecular residual disease (MRD) status after surgery the primary endpoint should be disease-free survival if only adjuvant therapy is given, event-free survival if neoadjuvant therapy is given, or overall survival. While early interim readouts are not appropriate due to low event rates, the agency says later interim analyses “may be considered.”
FDA endorsed use of ctDNA for signal finding in early-phase clinical trials, but said it “encourages sponsors to develop evidence regarding the usefulness of ctDNA response” in supporting pathologic complete response information after neoadjuvant therapy.
Although use of ctDNA as a surrogate endpoint is “not currently validated,” the agency said changes in ctDNA in response to a drug “may have the potential” to be used as an early endpoint to support drug approval in the early-stage cancer setting.
“Further data are required to support the use of ctDNA as an endpoint reasonably likely to predict long term outcome,” FDA said, noting that meta-analyses used to validating the endpoint should include “only randomized trials.”
The nonprofit Friends for Cancer Research (FCR) issued a white paper last November that calls for a collaborative effort to investigate the use of ctDNA as an early endpoint, which regulators could then use when considering certain accelerated cancer approvals.
Several FDA officials, including Oncology Center of Excellence Chief of Medical Oncology Julia Beaver and Molecular Genetics and Pathology Division Director Philip Reena, formed part of the working group that wrote the FCR white paper. Other contributors included AstraZeneca plc (LSE:AZN; NASDAQ:AZN), Bristol Myers Squibb Co. (NYSE:BMY), the Genentech Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY), Johns Hopkins School of Medicine, Natera Inc. and others.
The FCR white paper underscored the need for large amounts of data from multiple prospective clinical trials representing robust clinical outcomes and coming from multiple sources to validate the use of ctDNA as an early endpoint in early-stage cancers.
Allen said the group will be publishing results in lung cancer in the upcoming weeks showing that a reduction in ctDNA levels correlates with overall survival.
There are challenges that remain to be harmonized in the field. FDA recognized this by proposing certain characteristics for assays that could help get drug developers on the same page. The recommendations spanned types of MRD panels, sample considerations and analytical validation. For example, when using a panel of candidate genes the agency called for multiple markers to “help assure that the MRD assay will serve its function, even with the development of additional cytogenetic changes.”
“I think as a research community, we’re all in this together,” Allen said. “FDA has taken helpful steps in articulating some of the questions that they have and some of the recommendations to the research community. But I think this will be an evolving picture.”
Comments on the draft are due July 1st.