Upfront Liquid Biopsy Use Expands Reach of Genomic Testing in NSCLC

Hatim Husain, MD

The role of liquid biopsy has grown dramatically in non—small cell lung cancer (NSCLC), said Hatim Husain, MD, adding that implementing this testing modality for genomic markers may optimize treatment for newly diagnosed patients.

"Liquid biopsies are being widely adopted in the upfront setting," said Husain. "It is becoming increasingly important to get genomic test results in an efficient fashion."

While liquid biopsy is associated with certain caveats, including potential false-negative results, its utility with concurrent or subsequent tissue-based testing has transformed the application of targeted therapy for patients with NSCLC whose tumors harbor particular abnormalities.

Moreover, studies are looking to further evaluate the role of liquid biopsy, particularly upon resistance in lung cancer. The phase II APPLE trial (NCT02856893) is a feasibility study evaluating optimal strategies for sequencing gefitinib (Iressa) and osimertinib (Tagrisso) in patients with newly diagnosed, advanced EGFR-mutant NSCLC.

In the study, patients will either receive osimertinib until disease progression (arm A); gefitinib followed by a circulating tumor (ct)DNA assay to test for T790M and, if positive, followed by osimertinib (arm B); or gefitinib until disease progression followed by osimertinib (arm C). The plasmatic ctDNA T790M test will be performed in all arms, but will be applied as a predictive marker for making treatment decisions in arm B. The primary endpoint is the 18-month progression-free survival rate.

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Lung Cancer, Husain, an assistant professor of medicine at Moores Cancer Center at the University of California (UC), San Diego, discussed the current state of liquid biopsy in NSCLC.

OncLive: What difficulties are associated with liquid biopsy?

Husain: Time to test results has been one of the biggest challenges with tissue-based genome sequencing. Liquid biopsies help facilitate a shorter turnaround time.

However, there are certain caveats with liquid biopsy where if a patient has a negative test result, it is critical that tumor sampling be assayed. Largely, this is because there is a false negative rate [associated with liquid biopsy] that is due to the amount of shedding a tumor may have, the location of the tumor, and the sites of metastases a patient has.

Conversely, what benefits have been demonstrated with plasma-based testing in NSCLC diagnosis and treatment?

Circulating tumor (ct)DNA analyses have had positive predictive value in correlation with tumor responses with targeted therapies. They are being explored in concepts of immunotherapy as well.

Right now, in the frontline management of a patient with NSCLC, it is fundamentally important to have data upfront, so that we can guide the best treatment paradigm to manage a patient with NSCLC. Liquid biopsies help facilitate that.

How do liquid biopsies compare with tissue biopsies in this landscape?

In many cases, there is concordance between tissue and liquid biopsies. However, in some cases, there is discordance where a genome aberration may be found in the tissue but not in the plasma, or vice versa.

It is important to better understand what some of these factors may be. The sites of where metastasis may occur can determine the effective detection of plasma-based findings.

Also, it is important to note that when patients are on therapy, there may be lower rates of shedding from their tumors. Lastly, there may be clonal hematopoiesis. Genes that derive from bone marrow cells may also lead to genome findings in plasma that mimic those in the tumor.

How has the use of liquid biopsies evolved in clinical practice?

The role of liquid biopsies has evolved in a dramatic way. There have been proof-of-concept studies. These studies largely took place in the EGFR-positive NSCLC space and have defined testing for EGFR mutations.

Additionally, there has been evolution of the technology itself from digital polymerase chain reaction to next-generation sequencing (NGS) strategies. There have also been improvements in the lower levels of detection for certain genomic alterations.

With the rise of NGS, we now have strategies to look for a diversity of different genes, including somatic mutations, rearrangements, and amplifications. Right now, there has been clinical implementation in the frontline initial genotyping phase of patients to utilize liquid biopsies to get a fast turnaround for the genomic results.

It is important to note that if the results are negative, we still need to perform a tissue-based analysis. In my practice, I try to utilize concurrent testing with plasma and tissue to have the best chance of finding a genome aberration that a patient may derive [benefit] from with a targeted therapy.

What mutations can be detected with liquid biopsies in patients with NSCLC?

Somatic mutations are best detected with liquid biopsy. In the concept of lung cancer, that includes point mutations, fusions, and in some cases, amplifications.

EGFR exon 19 deletion L858R—which is the most common EGFR mutation—as well as other less common EGFR mutations can be detected, as well as BRAF mutations.

There is a lower sensitivity for fusions compared with somatic and point mutations, but they can be identified.

What ongoing trials are looking to further evaluate plasma-based testing?

There are a number of studies incorporating liquid biopsies as new endpoints to better understand [how plasma-based testing impacts] progression-free survival (PFS) and overall survival (OS).

At UC San Diego, we performed a study where we looked at the clearance of ctDNA for specific known oncogenes and how that correlated with PFS and OS on therapy.

There are studies looking at concordance among tissue and plasma. There are additional studies looking at responsiveness based on plasma-based detection. One of these studies is looking at osimertinib in the setting of liquid biopsy for patients who have EGFR-mutated NSCLC. Another is the APPLE study, which is basing treatment decisions upon resistance profile.