On August 3, 2020 Natera, Inc. (NASDAQ: NTRA), a pioneer and global leader in cell-free DNA testing, reported the publication of a manuscript in Nature Cancer1 that validates the ability of its Signatera personalized circulating tumor DNA (ctDNA) technology to evaluate tumor response to immunotherapy in 25 different types of solid cancer (Press release, Natera, AUG 3, 2020, View Source [SID1234562731]). The full study can be found here.
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"Although immune checkpoint inhibitors are an effective tool for treating many types of cancer, the decision to treat beyond radiological progression can sometimes be challenging due to potential pseudo-progression," explained Lillian Siu, MD, FRCPC, BMO Chair in Precision Cancer Genomics at the Princess Margaret Cancer Centre and lead investigator of the study. "We are delighted to have partnered with Natera on this landmark study, which shows that ctDNA-based surveillance using the Signatera test, in conjunction with imaging, can be used to identify true disease progression and thus help patients receive appropriate immunotherapy treatment."
Pseudo-progression is a phenomenon whereby the tumor appears larger on an initial scan during treatment before shrinking on subsequent scans, and it has been reported in up to 1 in 10 patients treated with immunotherapy.2,3 The ability to distinguish true progression from pseudo-progression, earlier in the course of treatment, has emerged as a significant unmet clinical need.
The prospective phase II INSPIRE study, led by the Princess Margaret Cancer Centre in Toronto, followed patients with advanced solid tumors being treated with the immunotherapy drug, pembrolizumab. Whole exome sequencing was performed using tumor and matched normal DNA, and then bespoke ctDNA assays were designed using Signatera technology. ctDNA assessments were made at baseline in 94 patients, and every three cycles during treatment in 73 patients where serial plasma samples were available.
In the published manuscript, the study’s authors concluded, "The findings from this prospective study suggest broad clinical utility for ctDNA-based surveillance in patients treated with immune checkpoint blockade."
Key findings from the study include:
Signatera technology detected ctDNA before treatment in 98% of cases (92/94), emphasizing its validity as a universal biomarker across tumor types.
ctDNA increase after just 6 weeks of treatment, together with increasing tumor volume on imaging, was identified in 42% of patients (30/73) and predicted treatment non-response with 100% accuracy. These patients received on average 6 extra weeks of treatment that potentially could have been avoided.
ctDNA clearance at any time 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 followup beyond first clearance.
All findings were independent of tumor mutational burden (TMB) and PD-L1 status.
"With over 200,000 patients per year being treated with immunotherapy,4 we see a significant opportunity for serial use of Signatera to help physicians determine treatment response earlier," said Solomon Moshkevich, General Manager of Natera’s oncology business. "We think this novel application could be as significant as Signatera’s use case in early-stage colorectal cancer."
We thank Merck for contributing the drug for this clinical trial.
About Signatera
Signatera is a custom-built circulating tumor DNA (ctDNA) test for treatment monitoring and molecular residual disease (MRD) assessment in patients previously diagnosed with cancer. 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). The Signatera test is personalized and tumor-informed, providing each individual with a customized blood test tailored to fit the unique signature of clonal mutations found in that individual’s tumor. This maximizes accuracy for detecting the presence or absence of residual disease in a blood sample, even at levels down to a single tumor molecule in a tube of blood.
Unlike a standard liquid biopsy, Signatera is not intended to match patients with any particular therapy. Rather, it is intended to detect and quantify how much cancer is left in the body, to detect recurrence earlier, and to help optimize treatment decisions. Signatera test performance has been clinically validated in multiple cancer types including colorectal, non-small cell lung, breast, and bladder cancers. Medicare has proposed insurance coverage for the use of Signatera in patients with Stage II or III colorectal cancer, and it is expected to finalize that coverage decision in 2020. Signatera has been developed and its performance characteristics determined by the CLIA-certified laboratory performing the test. The test has not been cleared or approved by the US Food and Drug Administration (FDA). Although FDA is exercising enforcement discretion of premarket review and other FDA legal requirements for laboratory-developed tests in the US, certification of the laboratory is required under CLIA to ensure the quality and validity of the tests.