CERSI Collaborators: Valsamo Anagnostou, MD, PhD; Patrick Forde, MD; Robert Scharpf, PhD; Noushin Niknafs, PhD; Lavanya Sivapalan, PhD; Archana Balan, MS

FDA Collaborators: Paz Vellanki, MD, PhD; Oladimeji Akinboro, MD, MPH; Rama Kamesh Bikkavilli, PhD; Wenming Xiao, PhD

Project Start Date: August 19, 2022

Regulatory Science Challenge

Molecular profiling of blood is gaining momentum in precision oncology; these approaches are collectively described as “liquid biopsy”. Tumors routinely shed free genetic material (or DNA) into the bloodstream, which can be “biopsied” by means of a minimally invasive blood draw. This liquid biopsy can be analyzed to provide valuable information such as changes in the genetic material associated with a patient’s cancer. Cell-free DNA (cfDNA) is released into the bloodstream from dying cells. A small fraction of this cfDNA may come from tumor cells and is called circulating tumor DNA or ctDNA. ctDNA can be extracted from blood and analyzed by next-generation sequencing for the presence of changes in the sequence or structure of DNA, known as mutations.

An important advantage of liquid biopsies is the ability to perform these analyses repeatedly over time during therapy to monitor a cancer’s response to treatment or identify genetic alterations related to resistance to therapy. Liquid biopsies are increasingly applicable in the field of cancer immunotherapy because, in contrast to traditional biopsies which only provide a snapshot of the tumor characteristics at one specific timepoint, liquid biopsy approaches may generate a more complete picture of an individual’s cancer by allowing for the monitoring of tumor burden and therapeutic response in real time.

Use of molecular assays to capture clinical outcomes with cancer immunotherapy is particularly timely, as immunotherapy poses a challenge to the well-established concept of assessing response based on radiographic imaging (e.g., with CT or MRI scans). With immunotherapy, even if patients are benefitting from treatment, tumors may not decrease in size or “shrink” on imaging scans as quickly as has been seen with other cancer therapies such as traditional chemotherapy. Conversely, for the majority of tumors that do not shrink on imaging, this does not necessarily reflect lack of therapeutic benefit. Therefore, conventional radiographic response criteria may underestimate the benefit from immunotherapy and the unique patterns and timing of response. In addition, looking at the landscape of immunotherapy clinical trials, investigators are nearing trial fatigue with thousands of trials, and this truly highlights the urgent unmet clinical need for real-time, molecular biomarkers to guide therapy. To this end, liquid biopsies are emerging as a powerful tool to help navigate through immunotherapy-based treatments that are in clinical trials or that are already FDA-approved.

Despite the growing body of evidence that supports the clinical utility of liquid biopsies in the context of immunotherapy, there are still several open questions. More data are needed to solidify the ctDNA profiles that are predictive of clinical response to therapies alongside the timing of ctDNA response and value in predicting long-term clinical outcomes.

Project Description and Goals

In previous pilot studies, investigators have observed distinct ctDNA dynamic changes during therapy that are reflective of clinical outcomes. Individuals with a significant drop or clearance of ctDNA tend to attain long term clinical benefit, such as increased life expectancy, with immunotherapy. Conversely, for individuals in which ctDNA levels are unchanged or increased despite treatment with immunotherapy, the immunotherapy is unlikely to be effective. With the support of the Food and Drug Administration Oncology Center of Excellence (FDA OCE) and working under the Johns Hopkins Center of Excellence in Regulatory Science and Innovation (CERSI), investigators will focus on serial liquid biopsy analyses from patients with non-small cell lung cancer who received cancer immunotherapy to understand the association of changes in ctDNA profiles with clinical response. This work will broaden our understanding of whether liquid biopsies can be used to assess a patient’s response to immunotherapy and to guide the design of future clinical trials. This is extremely important, as liquid biopsies can change the way patients with cancer will be treated by helping to evaluate therapeutic responses in real-time, and avoid unnecessary toxicity or ineffective treatments. The underlying premise of the proposed research is to increase delivery of the earliest best clinical care with precision for the increasing number of patients receiving cancer immunotherapy.