Dr. Alexey Aleshin, M.D., MBA Senior Medical Director Natera

Tumor-Informed ctDNA Test Signatera Evaluates Immunotherapy Response Across Different Solid Tumors

MedicalResearch.com Interview with:

Dr. Alexey Aleshin, M.D., MBA Senior Medical Director Natera

Dr. Aleshin

Dr. Alexey Aleshin, M.D., MBA
Senior Medical Director

MedicalResearch.com: What is the background for this study?

Response: Checkpoint inhibitor-based immunotherapies (ICI)  have changed the management of a range of cancers of diverse histologies. While these therapies are well tolerated and efficacious, only a minority (<20%) of patients respond to treatment or derive durable clinical benefit from them, highlighting the need for a pan-cancer biomarker that can predict response prior to, or shortly after, treatment initiation. With immune checkpoint inhibitors (ICIs) rapidly becoming a cornerstone of cancer therapy, early determination of response to ICI treatment can optimize patient benefit and minimize the risk of toxicities, while potentially reducing unnecessary treatment and costs to patients and payers.

Additionally, due to the nature of immune checkpoint inhibition, atypical patterns of response have emerged. For instance, tumor pseudoprogression — a transient increase in tumor size due to the infiltration of immune cells, followed by delayed shrinkage — has been reported in as much as 10% of patients receiving ICI therapy. Distinguishing pseudoprogression from true progression is clinically important to avoid premature discontinuation of a treatment that may have future benefit, or delay the initiation of an alternative line of therapy. However, they are hard to differentiate using current imaging techniques.

Our study published in Nature Cancer earlier this month, demonstrates that bespoke circulating tumor DNA (ctDNA) testing may be a valuable tool that sheds light on both of these issues.

MedicalResearch.com: Would you describe the bespoke ctDNA assays?

https://www.natera.com/press-releases/new-publication-nature-cancer-demonstrates-signateras-ability-evaluate-tumor-responseResponse: The bespoke ctDNA test used in our study, Signatera, is customized to the unique genetic signature of a patient’s cancer. The assay starts with whole exome sequencing of the patient’s tumor (and matched normal) to identify multiple high-quality, clonal mutations to track. A personalized multiplexed PCR-sequencing assay is custom-built for that patient. This “tumor-informed” approach translates to improved sensitivity (VAF 0.01% or lower) and specificity of detection (99.7%), including the ability to filter out artifacts caused by clonal hematopoiesis of indeterminate potential (CHIP).

MedicalResearch.com: Would you briefly describe the study design?

 Response: This prospective phase II study monitors 94 patients with advanced solid tumors (in distinct cohorts) receiving treatment with the anti-PD-1 monoclonal antibody, pembrolizumab (INSPIRE; NCT02644369). Five parallel cohorts were followed: squamous cell cancer of head and neck, triple negative breast cancer, high-grade serous ovarian cancer, malignant melanoma, and mixed solid tumors. Prior to pembrolizumab treatment, patients received a median of 2 lines of cancer treatment (range 0-6). The median number of treatment cycles was 3 (range 1-35) and median follow-up was 13.8 months (range 0.6-35.4).

MedicalResearch.com: What are the main findings? 

Response: We applied bespoke ctDNA assays to a total of 316 serial plasma samples obtained at baseline and every 3 cycles during treatment from 94 patients.

  • Tumor-informed ctDNA assays performed at baseline are sensitive and prognostic: Signatera technology detected ctDNA before treatment in 98% of cases (92/94), emphasizing its validity as a universal biomarker across tumor types. Baseline ctDNA concentration correlated with progression-free survival, overall survival, clinical response, and clinical benefit, highlighting its prognostic value.
  • Changes in ctDNA levels from baseline are predictive of benefit to ICI across cancer types: Early ctDNA kinetics after initiation of treatment (from baseline to cycle 3) was predictive of clinical benefit across all cohorts. 42% (30/73) of the patients with a decrease in ctDNA levels achieved an objective response, compared to 2% (1/40) of patients with an increase in ctDNA levels.
  • On-treatment changes in ctDNA levels can complement imaging to refine risk grouping: Early increases in ctDNA amounts, when combined with standard imaging, predicted treatment non-response with 100% accuracy after just 6 weeks of treatment. These patients received, on average, an extra 6 weeks of treatment that could have been avoided.
  • Clearance of ctDNA during treatment identifies a highly favorable risk group: ctDNA clearance at any point during treatment was achieved by 16% of patients (12/73) and was associated with 100% overall survival with a median of 25.4 months of follow-up beyond first clearance.
  • Decrease in ctDNA during treatment is a reliable marker of pseudoprogression: Signatera, in conjunction with imaging, can differentiate pseudoprogression from true progression, preventing unnecessary overtreatment or premature withdrawal of treatment.
  • All findings were independent of tumor mutational burden (TMB) and PD-L1 status. 

MedicalResearch.com: What should readers take away from your report? 

Response: To our knowledge, this is the largest published study to prospectively evaluate the value of ctDNA kinetics as a therapeutic biomarker during ICI treatment. Due to the size and mature follow-up of our study, we are able to generalize our findings across different histologies. Our study suggests the broad clinical utility for ctDNA-based surveillance in patients treated with immune checkpoint inhibitors. 

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: Future prospective clinical trials need to rigorously test the potential clinical utility of ctDNA testing as a monitoring tool for patients undergoing ICI treatment, and, eventually, this could open the door to the use of ctDNA as a prognostic and predictive biomarker for ICI treatment benefit.

MedicalResearch.com: Is there anything else you would like to add?

Response: Signatera is the only commercially available, tumor-informed ctDNA test with treatment monitoring applications in both early-stage and advanced stage cancers. The test is available for clinical and research use, and, in 2019, it was granted Breakthrough Device Designation by the U.S. Food and Drug Administration (FDA).


Bratman, S.V., Yang, S.Y.C., Iafolla, M.A.J. et al. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nat Cancer (2020). https://doi.org/10.1038/s43018-020-0096-5


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Last Updated on August 20, 2020 by Marie Benz MD FAAD