Circulating tumor DNA Test Predicts Immunotherapy Response

Although some cancer patients derive dramatic and sustained benefit from immunotherapy, most cancer patients do not.

Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer. These checkpoints help keep immune responses from being too strong and sometimes can keep T cells from killing cancer cells. However, existing biomarkers do not reliably predict treatment response across diverse cancer types.

A large team of medical scientists at the Princess Margaret Cancer Center (Toronto, ON, Canada) enrolled 106 patients with advanced cancer and stratified them into five cohorts based on tumor type. These cohorts included patients with squamous cell head and neck cancer, triple-negative breast cancer, high-grade serous ovarian cancer, and malignant melanoma; the fifth cohort included patients with other solid tumor types. Patients with advanced solid tumors treated with pembrolizumab.

The team applied bespoke circulating tumor DNA (ctDNA) assays to 316 serial plasma samples obtained at baseline and every three cycles from 94 patients. Tumor specimens were prospectively collected from patients at baseline, and 94 patients' samples were sufficient for whole-exome sequencing required to design customized assays that could detect ctDNA in accordance with the unique genetic signature of each patient's tumor. Investigators selected up to 16 clonal somatic mutations to include in the customized ctDNA assay for each patient. The customized Signatera assays were designed by Natera Inc., (San Carlos, CA, USA).

The investigators found that change in ctDNA levels early in the course of immunotherapy, after six weeks of treatment, could predict whether patients would benefit from immunotherapy across the five cohorts. Thirty-three patients had lower ctDNA levels at week six compared to baseline, and 14 patients (42%) saw their tumors shrink on pembrolizumab. In comparison, only one of the 40 patients whose ctDNA levels increased from baseline at week six responded to immunotherapy. Change in ctDNA levels at six weeks was also associated with a higher clinical benefit rate and favorable overall and progression-free survival in the five cohorts. Testing detected ctDNA increases in 30 patients who had the shortest survival in the study.

Lower ctDNA levels after two pembrolizumab cycles and on-treatment ctDNA clearance appeared to identify subsets of patients with good prognosis, independent of tumor type, TMB, or PD-L1 status. All 12 patients with ctDNA clearance during treatment were alive with median 25 months follow up.

Solomon Moshkevich, MBA, general manager of the oncology division at Natera, said, “This is, to our knowledge, the largest prospective study that has evaluated the value of serial ctDNA analysis in patients prior to and during immune checkpoint blockade therapy. The study demonstrates the potential for broad clinical utility of Signatera in patients with advanced solid tumors treated with immune checkpoint blockade.” The study was published on August 3, 2020 in the journal Nature Cance.

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Princess Margaret Cancer Center
Natera Inc.