Liquid Biopsies Reliably and Quickly Detect Genomic Biomarkers in Metastatic NSCLC

Vassiliki A.

Papadimitrakopoulou, MD

Liquid biopsies can reliably detect guideline-recommended biomarkers in patients with stage IV non—small cell lung cancer (NSCLC), said Vassiliki A. Papadimitrakopoulou, MD, with a quicker turnaround time compared with that of standard tissue-based assays.

“Liquid biopsies have revolutionized our clinical practice over the last 5 years in NSCLC,” said Papadimitrakopoulou. “With improvements in sensitivity and the expansion of gene panels that are being examined in liquid biopsies, we are capable of profiling patients with NSCLC before they start their treatment relatively fast.”

The number of guideline-recommended biomarkers to assess for in patients with newly diagnosed disease continues to increase. These molecular markers include predictive targets such as EGFR, ALK, ROS1, BRAF, RET, MET, and ERBB2, as well as prognostic targets, such as KRAS. With the Noninvasive versus Invasive Lung Evaluation (NILE) trial, investigators set out to demonstrate the noninferiority of cell-free DNA (cfDNA) analysis compared with the use of tissue genotyping in patients with metastatic NSCLC.

A total of 282 patients with pretreatment cfDNA samples were included in the analysis. Results, which were presented at the 2019 AACR Annual Meeting, showed that Guardant360, a 73-gene next-generation sequencing (NGS) panel, increased the rate of biomarker detection by 48%. Sixty patients were identified with a least 1 guideline-recommended biomarker through the use of tissue-based tests, while 77 patients were identified via liquid biopsy (21.3% vs 27.3%; P <.0001). This included patients whose samples were negative by tissue, not tested, or did not have enough material for tissue genotyping.

“Comparisons between cfDNA testing and tumor tissue testing were done for all of the guideline-recommended biomarkers and the positive predictive value for the cfDNA test compared with a tissue test was 100%,” said Papadimitrakopoulou, a professor of medicine in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center. “Sensitivity was 80% for all of the biomarkers.”

In an interview with OncLive, Papadimitrakopoulou, who is the senior author of the NILE trial, highlighted the implications of the study on clinical practice and shed light on the potential future utility of liquid biopsies in this space.

OncLive: What is the current role of liquid biopsies in lung cancer?

Papadimitrakopoulou: We mainly use liquid biopsies to profile patients with metastatic NSCLC. These liquid biopsies have also found recent utility in monitoring disease after surgical resection. In the future, now only in experimental phase, [we want to use them as a way to] detect disease early.

The basic principle of a liquid biopsy is to obtain a blood sample from the patient from which we extract DNA that is shed from the tumor. We then sequence as we would do with a tissue tumor biopsy.

Could you discuss the NILE trial? What were the key takeaways?

NILE was a prospective clinical trial comparing liquid biopsies—cfDNA tumor profiling—with tumor tissue profiling, in an attempt to demonstrate noninferiority. The patients were prospectively entered in the clinical trial based on predefined criteria. The main finding in the trial is that liquid biopsies are equally effective in detecting guideline-recommended biomarkers, mutations in the tumor, and at a significantly faster rate of detection—9 days versus 15 days—[than what is seen with tissue-based tests].

Could you expand on the benefits of liquid biopsy compared with standard tissue?

The number one benefit is how rapidly the results come back for the patient. Secondly, [compared with] the [current] standard-of-care—tissue genotyping experience in the community—there is the avoidance of depletion of tumor tissue and the avoidance of sequential biomarker testing, which leads to “under-genotyping.” This test is done once, with 1 blood specimen collected at the beginning of treatment. Therefore, this approach offers more complete genotyping for more patients, and faster.

Were there any limitations to this research?

One of the major weaknesses of the clinical trial that we performed is that we didn't dictate the type of standard-of-care testing that would be done on tumor tissue. Therefore, this is not a direct comparison of NGS in the tissue versus NGS in the blood. We actually allowed the physicians to use their local standard of care for genotyping, which, of course, makes the results [have a] real-world effect.

What are the clinical implications of these findings?

The results of the NILE study provide the confidence to clinical practitioners to use liquid biopsy as the first profiling test for patients in their practice. We already knew that liquid biopsies can provide this information, but this represents a prospective validation of what we already knew. Practitioners can have the confidence that this test will reliably detect the alterations in the tumor, and they will be able to guide the therapy for their patients much faster than they could in the case of tissue profiling.

What are the next steps for this research?

The next step in the research is to look at the outcomes of patients who were treated utilizing a blood specimen compared with the patients who were treated using a tissue specimen for genotyping. [We want to] look at whether we improved their outcomes by detecting more alterations; that [goal] is included in the NILE clinical trial as a secondary endpoint.

In the future, the use of liquid biopsies to detect minimal residual disease or to detect early recurrence in tumors is very, very promising. Hopefully, we'll see [promising] results from these studies.

Learn More About the NILE Study.

Leighl N, Page RD, Raymond VM, et al. Clinical utility of comprehensive cell-free DNA (cfDNA) analysis to identify genomic biomarkers in newly diagnosed metastatic non—small cell lung cancer (mNSCLC). Presented at: 2019 AACR Annual Meeting; March 29-April 3, 2019; Atlanta, GA. Abstract 4460.