On Wednesday, July 20, Friends of Cancer Research (Friends) hosted a meeting titled “Expediting Drug Development: Use of ctDNA as an Early Endpoint.” Welcoming everyone, Jeff Allen, President & CEO of Friends, provided updates regarding Friends’ ctDNA for Monitoring Treatment Response (ctMoniTR) project , a unique collaboration exploring whether changes in ctDNA levels can indicate clinical benefit in oncology clinical trials. Results from Step 1 of ctMoniTR will be published shortly and Step 2 is underway with initial results projected for the beginning of 2023. Allen then introduced Ellen Sigal, Chair & Founder of Friends, and Patrizia Cavazzoni, CDER Director at FDA, who discussed the importance of the accelerated approval pathway and its use in supporting drug development. Specifically, over 160 oncology therapies have been approved under accelerated approval, enabling earlier patient access to life-saving therapies. To support accelerated approval, reliable early endpoints that predict long-term outcomes are necessary. Cavazzoni mentioned FDA’s recently issued draft guidance which details multiple uses of ctDNA, including the potential use of ctDNA as an early endpoint which could be used to support an accelerated approval.

“Accelerated approval is an essential program for oncology and other disease areas. As such, we need to nurture it, protect it, and expand its use. Some examples of how we can do so include advancing our understanding of the biological underpinnings of diseases and surrogate markers that may serve as endpoints for accelerated approvals.” – Patrizia Cavazzoni

Panel 1:

The first panel was moderated by Chris Abbosh from AstraZeneca and included Angela DeMichele from the University of Pennsylvania, Geoff Oxnard from Foundation Medicine Inc., and Nicole Gormley and Lelah Amiri-Kordestani from the FDA. The panel discussed learnings from establishing other oncology early endpoints to set the stage for success for establishing the use of ctDNA as an early endpoint.

Geoff Oxnard highlighted the value of the accelerated approval pathway by emphasizing how targeted therapies for a variety of advanced cancers receive accelerated approval sometimes years before the full approval, allowing patients with cancer to gain access to life-saving drugs sooner. The panel discussed other early endpoints including pathological complete response (pCR) in breast cancer and minimal residual disease (MRD) in hematologic cancers. Angela DeMichele noted some of the challenges and key learnings that occurred during the process of establishing pCR as an endpoint, including the value of a collective approach by the research community, with Geoff Oxnard agreeing that evidence needs to be built collaboratively.

“Scientific enthusiasm isn’t enough; we need to get organized.” – Geoff Oxnard

Nicole Gormley underscored that when clinical validation studies are conducted, it is paramount that they are harmonized when possible so data can be pooled and adequately evaluated.

Panel 2: 

The second panel was moderated by Gary Pestano from Biodesix and included Julia Beaver and Erik Bloomquist from FDA, Aadel Chaudhuri from Washington University in St. Louis, Mary Savage from GSK, and Alain Silk from Tempus Labs, Inc. The panel helped lay out evidentiary needs and strategies to validate the use of ctDNA as an early endpoint in oncology drug development. Julia Beaver noted ctDNA is currently most often used as a selection marker for clinical trials in the metastatic setting. However, further evidence generation will be required to support the use of ctDNA as an endpoint to predict clinical benefit and support drug approval. Aadel Chaudhuri noted that harmonizing efforts for data capture across assay types in metastatic disease will provide a useful framework for conducting similar analyses in earlier stages. Erik Bloomquist then provided insight on the statistical aspects of evaluating ctDNA as a surrogate endpoint in early-stage disease, highlighting that ctDNA data and more traditional clinical data, such as data on recurrence, should be collected. He discussed the need to pre-specify meta-analyses to ensure the best quality of data is produced moving forward. Panelists then discussed other key items to consider when developing a framework for gathering evidence from trials including ctDNA.

“There is tremendous promise from ctDNA, but there are still a lot of open questions. We must set up evidence generation to first identify those questions and then answer them…The framework [for further evidence generation] should be portable in the sense that it should apply to and account for evidence coming from a broad diversity of trials, tumor types, and assay technologies.” – Alain Silk

Alain Silk stated that researchers will need to be reasonably comprehensive when collecting information for analyses. While some evidence will be prospectively identified as impactful for the evaluation of ctDNA, other factors may be hard to predict in advance. Additionally, evidentiary needs may change over time, with varying levels of evidence needed depending on the use case for ctDNA as an early endpoint to support regulatory decision–making. This speaks to the value of ongoing engagement with and input from the FDA. Julia Beaver added that since the early-stage setting is potentially curative, the overall risk-benefit considerations of using a novel endpoint must be factored in with the potential harm resulting from a premature approval. Thus, it is critical to have strong evidence for the use of a novel endpoint like ctDNA. Nonetheless, Julia Beaver went on to emphasize that expediting access to novel therapies in this setting is imperative due to the potential to reach more patients and have a larger impact on cancer mortality than in later stages of disease.

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