Plasma NGS Demonstrating Practice-Changing Potential in NSCLC

Rachel Narozniak, MA
Published: Monday, Nov 11, 2019

Bob T. Li, MD, MPH, an expert in lung cancers at Memorial Sloan Kettering Cancer Center

Bob T. Li, MD, MPH

Plasma genotyping is the next big thing in non–small cell lung cancer (NSCLC), and it’s already impacting clinical practice, Bob T. Li, MD, MPH, said in a presentation that canvassed the utility of circulating tumor (ctDNA) liquid biopsy assays during the 14th Annual New York Lung Cancers Symposium®.1

“ctDNA is probably at the forefront in terms of its potential to transform clinical practice,” said Li, an expert in lung cancers at Memorial Sloan Kettering Cancer Center (MSK).

The potential benefits of ctDNA liquid biopsy assays are manifold and start with the noninvasive, nonsurgical nature of this evolving approach. ctDNA liquid biopsies measure the small amounts of DNA that tumor cells shed into a patient’s bloodstream. Although “finding these tiny fragments of ctDNA is not a simple exercise,” according to Li, the blood tests can identify the actionable mutations that can guide precision therapy faster than tissue next-generation sequencing (NGS) assays, which constitute the standard biopsy in NSCLC.

ctDNA NGS was superior to tissue NGS in finding oncogenic drivers in a recent study of 210 patients with advanced lung cancers. All patients underwent plasma NGS and a subset (n = 106) also had concurrent tissue NGS using the MSK-IMPACT 468-gene panel.

Findings showed that plasma ctDNA NGS detected a variety of mutations with a shorter turnaround time (TAT) compared with tissue NGS: the median TAT from the time of blood draw to the time of the primary investigator receipt of the report was 9 days with liquid biopsy versus 20 days with tissue biopsy (P < .001).2

Moreover, findings on plasma NGS were highly concordant with those on tissue NGS. Patients who were positive for oncogenic drivers via plasma NGS testing had tissue NGS concordance of 96.1% (49 of 51 patients; 95% CI = 86.5% to 99.5%).2

Investigators of the study, conducted by MSK in collaboration with Resolution Bioscience, were able to immediately treat those who tested positive for an oncogenic driver based on the oncogenic driver uncovered by plasma NGS.

“We rendered a clinical response in 22% of [these] patients,” Li said. “This was without waiting for the tissue [result] to take action.”

The quicker TAT with plasma NGS and the ability that the liquid biopsy afforded investigators to specify the appropriate targeted therapy and initiate treatment would be of greatest benefit to patients with advanced NSCLC due to the lethality of late-stage disease, Li said.

Li cited 2 patients he treated at MSK as examples of ctDNA liquid biopsy’s ability to enhance care. Both patients had lung cancer, but how the diagnosis came into focus differed for each of them. Li’s first patient came to MSK in search of a second opinion. He’d been diagnosed with stage IV colorectal (CRC) cancer and had been advised to begin chemotherapy.

Li didn’t think the patient’s disease resembled CRC on a CT scan and ordered a liquid biopsy. What the blood test returned: a diagnosis of lung cancer with an ALK gene fusion. The discovery enabled Li to promptly treat the patient with the second-generation ALK inhibitor alectinib (Alecensa).

The other patient had been correctly diagnosed with stage IV lung cancer that had spread to her lungs, bone, brain, liver, and leptomeninges. Again, a liquid biopsy found a mutation present that could be attacked with an agent indicated for the treatment of the oncogenic driver.

“These patients were on their deathbeds,” Li said. “There [had been] insufficient tissue analysis and indeterminate results, but liquid biopsy found the driver, got them to the therapy, and resurrected them from their deathbeds.”

Emerging data suggests that ctDNA can be used to monitor patients for treatment response; this information can be gleaned “much earlier” via liquid biopsy than via a CT scan, according to Li.

“You can do it perhaps just one week into treatment to discern whether or not the treatment is working, so this is an adjunct to all symptom reporting and tracks very nicely with RESIST measurements,” Li said. His caveat: this specific application of plasma NGS is in a nascent stage.

Questions such as, “What is considered a partial molecular response? What is a complete molecular response? and What do either really mean for the patient?” remain and require additional prospective research. If these questions can be answered in the future, then ctDNA liquid biopsy could emerge as an effective means of treatment monitoring in NSCLC, Li said.

Furthering the value of plasma NGS in the field is liquid biopsy’s potential to guide precision therapy in the adjuvant setting through the detection of minimum residual disease (MRD) in early-stage lung cancers.

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