On July 11, 2023, Friends of Cancer Research (Friends) hosted, “Establishing Evidence: New Advancements Using ctDNA”, a public meeting in Washington, DC. The meeting included data readouts for two initiatives: 1) the Baseline circulating tumor DNA (ctDNA) Project, which Friends initiated to address a knowledge gap identified in the Evidentiary Roadmap, included a data readout of baseline ctDNA levels across cancer types, stages, and assays; 2) the second data readout was ctMoniTR Step 2 Module 1 data demonstrating relationships between changes in ctDNA and outcomes in patients with advanced Non-Small Cell Lung Cancer (aNSCLC) treated with Tyrosine Kinase Inhibitors (TKI). Friends will continue to collaborate with stakeholders on these projects to generate meaningful data that aim to advance the understanding and use of ctDNA in oncology drug development.
The meeting began with a keynote conversation moderated by Jeff Allen, Friends of Cancer Research, and featured Patrizia Cavazzoni, U.S. Food and Drug Administration (FDA), and Lee Fleisher, Centers for Medicare & Medicaid Services (CMS). They discussed interactions between the FDA and CMS related to making decisions about the approval and coverage of new treatments. Dr. Cavazzoni described the interagency communication that occurs at the beginning and end of the approval process and the importance of frequent interaction between the FDA and CMS. Fleisher agreed the two agencies communicate often and highlighted differences in how the two agencies evaluate treatments noting the FDA evaluates whether a treatment is safe and effective, and CMS evaluates whether it is reasonable and necessary. He continued that the FDA and CMS have been in communication about the new approvals of Alzheimer’s treatments.
The speakers then discussed the use of novel endpoints. Dr. Cavazzoni spoke about how it is important to use novel endpoints in clinical trials in conjunction with accepted clinical endpoints to determine whether the novel endpoint may be an appropriate surrogate endpoint. Fleisher agreed and said that these endpoints can also help CMS decide if a treatment is reasonable and necessary. Dr. Cavazzoni was then asked about the impact of the new FDA authorities related to accelerated approval provided through the Food and Drug Omnibus Reform Act (FDORA). She spoke about how these provide FDA with important tools to ensure timely completion of confirmatory studies and establish an expedited process for withdrawing therapies that fail to confirm benefit. Fleisher then spoke about the effectiveness of the Transitional Coverage for Emerging Technologies (TCET) pathway and the future of collecting real-world evidence. The keynote speakers concluded the keynote conversation by talking about how they encourage stakeholders to make sure the right data is being collected.
Panel 1: Evaluating ctDNA measurements across cancer types and stages
Brittany McKelvey from Friends presented initial findings from the Friends’ collaborative initiative comparing trends in baseline ctDNA levels between cancer types and stages across assay developers (slides available here). Following her presentation, a panel discussion moderated by Mark Sausen of Personal Genome Diagnostics and including James Chen of Tempus Labs, Greg Jones of NeoGenomics Laboratories, Eric Peters of Genentech, and Anand Pathak of the FDA discussed how initial learnings from Friends’ ctDNA Baseline Project could be applied to inform future prospective studies intended to support the use of ctDNA in various clinical settings.
The panel highlighted that the literature has supported use of ctDNA within the metastatic space, stipulating the great promise ctDNA holds for informing clinical practice. The panel also discussed key technical and biological challenges of measuring ctDNA including sources of variability across assays and disease states that complicate measurement and understanding of the biomarker. To resolve these challenges, panelists discussed the need for harmonization across assays and collection of clinical data to provide more robust understanding around the use of ctDNA for rare cancers and early-stage disease. The group identified potential next steps including harmonization of data elements across clinical trials. Panelists agreed that collaboration will be needed to help reduce heterogeneity around measurement and use of ctDNA. To close the panel, the panelists emphasized the importance of pooling baseline data to generate evidence that can further inform the use of ctDNA assays within various populations.
“It gives me a lot of hope that in the metastatic stage we have a reasonable shot of detecting ctDNA.” – Eric Peters, Genentech
Lunch Keynote with moderator Richard Pazdur, Valerie Jensen, and Harpreet Singh, FDA. During the lunch keynote, representatives from the FDA discussed recent developments at the agency including the new pilot program and guidance, “Oncology Drug Products Used with Certain In Vitro Diagnostics Pilot Program” and strategies to address current shortages of critical cancer drugs. The conversation emphasized the importance of creating a set of standard minimal performance characteristics for locally developed tests to ensure patient safety and clarified requirements for involvement in the pilot program. They then highlighted how the FDA has used its authority to curb the current shortage of cisplatin and carboplatin. The speakers also discussed potential avenues to prevent future shortages in oncology including strategic reserves which would provide a supply of drugs in case of shortages and provide baseline prices to incentivize suppliers to keep these critical drugs on the market.
Panel 2: Changes in ctDNA levels as an early indicator of outcomes in advanced NSCLC treated with TKI (ctMoniTR Module 1)
Hillary Stires of Friends presented an overview of ctMoniTR Step 2 Module 1 findings to provide context for the panel (slides available here). After the presentation, a panel moderated by Nevine Zariffa of NMD Group, LLC, and including Carin Espenschied, Guardant Health, Minakshi Guha of Takeda Pharmaceutical Company, Geoff Oxnard of Foundation Medicine, Inc., Diana Vega of AstraZeneca, and Paz Vellanki of the FDA discussed key learnings from Module 1 and considerations for future work in this space. First, panelists noted it was interesting to see that first RECIST alone did not associate with long-term outcomes but that non-detected ctDNA did associate with improved progression-free survival (PFS) and overall survival (OS). Next, panelists discussed future needs to improve measurement and understanding of ctDNA, including the need for standardized ctDNA analysis techniques to ensure reliable and comparable results across studies. It was also noted that patients with decreasing but still detected ctDNA did not show significant improvements in outcomes, suggesting the involvement of additional factors in treatment response and need for further exploration of these factors. The panel also discussed the practical implications of these findings, such as incorporating ctDNA as a prognostic biomarker and considering its use as a stratification factor in future clinical trials.
Panel 3: Regulatory considerations for using ctDNA as an early endpoint
Panel 3 was moderated by Amy McKee of Parexel, with panelists Ken Billett, a patient advocate, Nicole Gormley of the FDA, Vladimir Jankovic of Regeneron Pharmaceuticals, Inc., Minetta Liu of Natera, Reena Philip of the FDA, and Christian Rolfo of the Ichan School of Medicine at Mount Sinai. First, the panelists discussed the regulatory future of using ctDNA as an early endpoint including the potential of mimicking the process used to establish other novel endpoints to make ctDNA a successful endpoint. They spoke about the importance of identifying the right assays and thresholds to use when analyzing ctDNA and discussed performance characteristics (e.g., specificity and sensitivity) for assays to ensure the measurement of ctDNA is reliable to support its use as an early endpoint. The panel discussed how ongoing trials are using ctDNA as an exploratory endpoint and how ctDNA may be incorporated into future trials. The panelists then discussed how to make ctDNA part of clinical trials without creating additional burden for patients. The panelists spoke about the importance of clearly communicating the potential benefits of ctDNA measurements to patients and discussed challenges in implementing standards and methods in a rapidly evolving field. The panelists then talked about what is required to keep this technology moving forward and emphasized that it will be important to continue to educate patients and others about ctDNA and how it can be used to support research. The panelists concluded by identifying key next steps to support future use of ctDNA, which focused on the need for continued data generation and standardization of ctDNA measurements.
“Anything that makes the lives of patients easier is going to be a huge benefit.” – Ken Billett, Patient Advocate