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Study Solidifies Confidence in Liquid Biopsies for Faster Biomarker Detection in NSCLC, Expert Says

Kristi Rosa
Published Online:5:50 PM, Wed April 17, 2019

Vassiliki A. Papadimitrakopoulou, MD

In addition to confirming the utility of liquid biopsies to reliably detect guideline-recommended biomarkers in patients with stage IV non–small cell lung cancer (NSCLC), findings from the NILE study also showed liquid biopsies have a quicker turnaround time compared with standard tissue-based assays, said senior study author Vassiliki A. Papadimitrakopoulou, MD.

"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," she said.

The Noninvasive versus Invasive Lung Evaluation (NILE) trial was a prospective multicenter noninferiority study that compared the utility of liquid biopsy using cell-free DNA (cfDNA) tumor profiling versus tumor tissue profiling. The study evaluated whether Guardant360—a 73-gene next-generation sequencing panel—can be used to detect all 7 guideline-recommended predictive biomarker mutations (EGFRALKROS1BRAFRETMET, and ERBB2) and 1 prognostic biomarker mutation (KRAS) at the same rate as traditional tissue genotyping tests in patients with newly diagnosed advanced NSCLC.

The analysis looked at a total of 282 patients with pretreatment cfDNA samples. Results, which were presented at the 2019 AACR Annual Meeting, showed that Guardant360 increased the rate of biomarker detection by 48%.1 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.

"In the largest prospective, multicenter cfDNA study in previously untreated mNSCLC, we demonstrate that cfDNA genotyping utilizing a single, well-validated and highly sensitive comprehensive cfDNA test detects guidelinerecommended biomarkers at a rate similar to tissue genotyping, meeting the primary study objective," Papadimitrakopoulou and co-investigators wrote in a report published in Clinical Cancer Research.2

In an interview with Targeted Oncology, Papadimitrakopoulou highlighted how these findings translate to clinical practice and shed light on the potential future utility of liquid biopsies in this space.

TARGETED ONCOLOGY:  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.

TARGETED ONCOLOGY:  Could you discuss the NILE trial? What were the key takeaways?

Papadimitrakopoulou: 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].

TARGETED ONCOLOGY: Could you expand on the benefits of liquid biopsy compared with standard tissue testing?

Papadimitrakopoulou: 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.

TARGETED ONCOLOGY:  Were there any limitations to this research?

Papadimitrakopoulou: 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.

TARGETED ONCOLOGY:  What are the clinical implications of these findings?

Papadimitrakopoulou: 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.

TARGETED ONCOLOGY:  What are the next steps for this research?

Papadimitrakopoulou: 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.
  1. 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.
  2. Leighl NB, Page RD, Raymond VM, et al.  Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non-small cell lung cancer [published online April 15, 2019]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-19-0624.

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