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My Thoughts on the Evolving Role of Liquid Biopsies in the Treatment of EGFR Mutation–Positive Advanced NSCLC

Christian Rolfo, MD, PhD, MBA, Dr.hc.

Professor of Medicine
Division of Hematology and Oncology
Icahn School of Medicine at Mount Sinai
Associate Director of Clinical Research
Center for Thoracic Oncology
The Tisch Cancer Institute
Mount Sinai Health System
New York, New York


Christian Rolfo, MD, PhD, MBA, has disclosed that he has received consulting fees from Archer, Boston Pharmaceuticals, Bristol-Myers Squibb, Inivata, MD Serono, and Novartis; fees for non-CME/CE services from AstraZeneca, MSD, and Roche; funds for research support from Lung Cancer Research Foundation-Pfizer; and non-financial research support from Guardant Health and MD Serono.


View ClinicalThoughts from this Author

Released: June 1, 2021

The first biomarker test using liquid biopsy (ie, circulating cell-free DNA in blood or plasma) approved by the FDA was for the detection of common EGFR gene mutations to identify patients with advanced non-small-cell lung cancer (NSCLC) who were candidates for treatment with first-generation EGFR tyrosine kinase inhibitor (TKI) therapy. Its use in the care of patients with advanced NSCLC has expanded considerably in recent years, first to identify mechanisms of resistance to EGFR TKI therapy, most notably the EGFR T790M mutation to identify patients eligible for treatment with the third-generation EGFR TKI osimertinib (which has since become standard-of-care frontline therapy). Biomarker testing by liquid biopsy is now used as a primary approach in newly diagnosed disease for the identification of driver mutations predictive of response to a suite of targeted therapies via next-generation sequencing (NGS).

Validation of Liquid Biopsy for Biomarker Testing in Newly Diagnosed Advanced NSCLC
Historically, liquid biopsy has been used in the detection of driver mutations only if the amount of available biopsy tissue was inadequate or after molecular testing of a tissue biopsy failed. If you obtain a suitable tissue biopsy, you can certainly still test tissue first and use liquid biopsy as needed. However, data from recent prospective studies support the validity of taking a complementary or even blood-first approach to biomarker testing in newly diagnosed advanced NSCLC.

Data from the observational NILE study of 282 patients with previously untreated metastatic NSCLC showed that concomitant molecular analysis with liquid and tissue biopsies increased biomarker detection by 48% compared with tissue-only testing, including in patients with negative, not assessed, or insufficient tissue results. In the phase II/III BFAST trial evaluating blood-based NGS as the sole source for biomarker testing in patients with advanced NSCLC (NCT03178552), the ALK TKI alectinib achieved an objective response rate (ORR) of 87% in 87 patients where an ALK fusion was identified by liquid biopsy, which is comparable to the ORR (83%) observed in the practice-changing phase III ALEX trial of first-line alectinib in ALK fusion–positive disease, even in the absence of a tissue biopsy. More recently, the BFAST trial also showed, for the first time, that blood-based NGS can be used to identify KRAS G12C mutations in patients with advanced NSCLC.

How I Use Liquid Biopsy in Advanced NSCLC: The US Experience
I currently use broad-based NGS testing concomitantly with liquid biopsy and tissue biopsy to identify driver mutations, including those in EGFR, when making treatment decisions for all of my patients with newly diagnosed advanced NSCLC. I am also starting to test my patients with resectable stage II/III disease for EGFR mutations on tumor tissue now that adjuvant osimertinib is approved based on a disease-free survival benefit in these patients as demonstrated by the phase III ADAURA trial. In the near future, liquid biopsy might play an important role in the identification of measurable residual disease to evaluate outcomes after surgical resection in this early-stage setting. 

In the United States, there are currently 2 commercial NGS platforms approved by the FDA for use with liquid biopsy for the genetic profiling of solid tumors. Guardant360 CDx interrogates more than 60 genes and is a companion diagnostic for osimertinib via the identification of the common EGFR mutations ex19del and L858R and the T790M resistance mutation, and more recently for amivantamab and sotorasib through the identification of EGFR exon 20 insertion mutations and KRAS G12C mutations, respectively. FoundationOne Liquid CDx interrogates more than 300 genes along with other genetic features, such as microsatellite instability, and is a companion diagnostic for osimertinib, gefitinib, and erlotinib. Both tests also have good coverage of targetable uncommon EGFR mutations as well as detect comutations that are present at diagnosis that can provide important information about a patient’s prognosis (eg, detection of a TP53 mutation in EGFR-mutant lung cancer is predictive of poor outcomes). Of note, to ensure that a patient receives optimal therapy, care must be taken when interpreting NGS reports, as sometimes targetable variants can be mislabeled as undruggable and vice versa.

Because it is approved by the FDA, NGS testing by liquid biopsy is readily reimbursed by insurance in the United States, at least when used in the outpatient setting. However, in some states, it is not reimbursed if done while the patient is admitted to the hospital, which can delay critical biomarker testing by a couple of weeks to a month. Considering the critical and time-sensitive nature of molecular testing to first-line treatment decisions for advanced NSCLC, this is a hurdle I hope to see eliminated in the not-too-distant future.

Advantages of Liquid Biopsy vs Tissue Biopsy
The most obvious advantage of liquid biopsy is that it is minimally invasive. It is simply a blood draw. Being minimally invasive also shortens the amount of time required to obtain critical molecular testing results, which allows us to abbreviate the time from molecular testing to the start of treatment for our patients with newly diagnosed advanced NSCLC. We need to remember that some of our patients have already spent weeks to months from the time they presented to their primary care physician with symptoms to when they arrive to our consultation with an established lung cancer diagnosis, including seeing several providers for a biopsy in between. Finally, one of the major advantages is that liquid biopsy also captures a more complete picture of the disease by catching intratumoral and intrapatient heterogeneity that otherwise would be missed by only testing tissue. That said, some tumors do not shed a detectable amount of DNA, so if molecular testing results are negative with liquid biopsy, the results must be confirmed by tissue biopsy. However, this is becoming less of an issue as the sensitivity and specificity of our NGS technologies improve. 

The Future of Liquid Biopsy in Lung Cancer
There are also numerous other applications of liquid biopsy being explored in the treatment of lung cancer. Most notably is its use in monitoring for disease response to therapy in real time, in part to predict patient outcomes. For example, in a subanalysis of the phase III FLAURA trial evaluating first-line osimertinib vs first-generation EGFR TKI therapy in patients with EGFR-mutated NSCLC, plasma EGFR mutation analysis demonstrated a clearance of the EGFR driver mutation after 3-6 weeks of EGFR TKI therapy that was associated with improved survival. Liquid biopsy is also being used to understand emerging resistance mechanisms to first-line osimertinib, including development of indirect indicators to identify transformation to small-cell lung cancer, which is currently confirmed by tissue biopsy. These applications will allow for treatment customization for patients during the progression. 

There is also a potential to use liquid biopsy for lung cancer screening in the near future, either in combination with low-dose CT scans or alone. In this way, liquid biopsy shows promise in the detection of early-stage lung cancer, which will improve patient survival rates and reduce costs on the healthcare system.

Liquid Biopsy in Advanced NSCLC: Global Considerations
It is important to recognize that, unfortunately, other regions of the world are not so lucky as we are here in the United States to have access to 2 commercially available NGS platforms for use with liquid biopsy—or even with tissue biopsy—for biomarker detection in lung cancer. Many regions must rely on in-house platforms, or even on single-gene testing, because they cannot afford to pay for a $4000 test. To make broad-based NGS testing universally available for every patient around the world, we still have some socioeconomic hurdles to overcome.

Call to Action: Need for Healthcare Professional Education on Liquid Biopsy
There is a clear need to educate healthcare professionals about the importance of liquid biopsy in the care of our patients with lung cancer. The FDA recently approved several amazing targeted therapies in a short period of time, but the rate of biomarker testing in our newly diagnosed patients isn’t where we want it to be—and liquid biopsy can be part of the solution. In fact, there is a movement behind better positioning liquid biopsy for future applications, including efforts by the International Society of Liquid Biopsy, of which I am Vice President, and the NIH’s International Standardization Alliance for Liquid Biopsy.

Your Thoughts
What challenges have you encountered when using liquid biopsy for NGS-based molecular biomarker testing for your patients with EGFR mutation–positive advanced NSCLC? I encourage you to answer the polling question and join the conversation by posting in the discussion section below.

Provided by Clinical Care Options, LLC.

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Supported by an educational grant from
AstraZeneca

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