Plasma NGS Demonstrating Practice-Changing Potential in NSCLC

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.

“In early-stage lung cancer this gets incredibly exciting because before surgery or radiation you can find the tumor DNA in the blood, cut it out, and get [the DNA count] to zero, [at which point] the patient is cured,” Li said.

With radiation, it can be difficult to tell when the PET scan becomes faint, he added. “You don’t know if the radiation is still working or how well it’s working, but you can do a blood test and if [the DNA count] has gone to zero, the patient is cured.”

On the other hand, if MRD is detected in the blood, “you know the cancer is not finished,” said Li, who also explained that a ctDNA MRD-negative test result forecasts cure, whereas a ctDNA MRD-positive test result forecasts recurrence.

Data from a retrospective study in which investigators sought to measure MRD in 255 blood and tissue samples from 40 patients with stage I to stage III lung cancer who had been treated with curative intent and 54 healthy adults demonstrated that ctDNA analysis identified posttreatment MRD indicative of residual and recurrent disease earlier than standard of care radiologic imaging. Specifically, liquid biopsy detected disease recurrence sooner than imaging in 72% of patients.³

Investigators also assessed patients’ freedom from progression (FFP). At 36 months from the MRD landmark, FFP was 0% in patients with detectable ctDNA MRD and 93% in those with undetectable ctDNA MRD, respectively (P <.001; HR, 43.4; 95% CI, 5.7-341).³

“If you have a blood test that’s negative after surgery or radiation, your cure rate is very, very high, but if it’s positive, you’ll get a relapse with a HR of 43.4. That’s an enormous difference,” Li said.³

Knowledge of whether or not ctDNA MRD remains in a patient’s blood post-therapy can empower oncologists to preemptively intercept the cancer before it embeds in the lung and liver, according to Li.

“Perhaps you could cure some of the patients who are destined to relapse,” he said. “Randomized trials are being designed to keep the cancer out before it takes root, [which could] perhaps elevate the cure rates of early-stage lung cancer.”

There are several ongoing studies of NGS analysis of ctDNA for early detection or MRD assessment of NSCLC, such as CAPP-Seq, TEC-Seq, CancerSEEK, and TRACERx.

Although liquid biopsies have “an emerging role in treatment monitoring and in the MRD setting” in NSCLC, Li emphasized that plasma NGS “is already in the clinic.”

“It’s in the National Comprehensive Cancer Network guidelines and it’s a standard of care in advanced metastatic NSCLC,” Li said.

Notably, the FDA has permitted the clinical use of assays presuming that they are CLIA certified and conducted in a lab, to assess technical validity and reproducibility. To date, the FDA has only approved one liquid biopsy assay, Roche’s Cobas EGFR Mutation Test v2 Plasma ctDNA, for the detection of EGFR mutations including exon 19 del, exon 21 L858R, and exon 20 T790M in advanced stage lung cancers.

Despite this singular approval, ctDNA assays are nevertheless a highly active area of division and some have already obtained clearance from the New York State Department of Health, which imposes different, more stringent requirements for regulatory approval than other states. Guardant Health, GeneStrat, FoundationOne Liquid, Resolution Bioscience ctDx Lung, and MSK-ACCESS are among them.

Many other assays are currently in development exemplifying Li’s statement, “the technology is constantly evolving.”

References

1. Li, BT. The next big thing in lung cancer: liquid-based biopsies. Presented at: 14th Annual New York Lung Cancers Symposium^®; November 9, 2019; New York, New York.
2. Sabari JK, Offin M, Stephens D, et al. A prospective study of circulating tumor DNA to guide matched targeted therapy in lung cancers [published online November 28, 2018]. J Natl Cancer Inst. doi: 10.1093/jnci/djy156.
3. Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov. 2017;7(12):1394-1403. doi: 10.1158/2159-8290.CD-17-0716.

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