Liquid Biopsy: Mounting Evidence Shows Clinical Utility in Tumor Monitoring

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A “blood-first” approach could soon shift the diagnostic paradigm in advanced lung cancer, replacing tissue biopsy with minimally invasive assays. According to Natasha B. Leighl, MD, MMSc, FRCPC, FASCO, there is rapidly mounting evidence that liquid biopsy serves a prognostic function in advanced disease and is an important correlate of relapse. It might also be an early predictor of response and improved outcomes. At the International Association for the Study of Lung Cancer (IASLC) 2020 Lung Cancer Hot Topic: Liquid Biopsy Virtual Conference, Dr. Leighl reviewed several studies aimed at demonstrating the clinical utility of liquid biopsy in tumor monitoring.1

“Currently, we can use liquid biopsy to estimate prognosis, stratify surveillance, and detect recurrence,” said Dr. Leighl, a medical oncologist at Princess Margaret Cancer Centre and Professor of Medicine at the University of Toronto, Canada. “Recent data suggest that liquid biopsy can also be used as a surrogate endpoint that allows us to change treatment intensity or even de-escalate.”

Natasha B. Leighl, MD, MMSc, FRCPC, FASCO

Natasha B. Leighl, MD, MMSc, FRCPC, FASCO

Prognostic Impact in Advanced Lung Cancer

As Dr. Leighl reported, several different soluble mediators have been studied in the setting of both advanced and early-stage lung disease. However, there is considerable evidence supporting circulating tumor DNA (ctDNA), the detection of tumor-derived fragmented DNA in the bloodstream.

The FLAURA trial screened nearly 1,000 patients and found that those who did not have evidence of ctDNA in plasma at baseline had a better prognosis.2 Patients treated with osimertinib who were ctDNA-negative had a median progression-free survival of 23.5 months vs 15.2 months for those with detectable ctDNA. A better prognosis was also associated with no evidence of ctDNA at baseline in the standard-of-care arm, said Dr. Leighl, which is likely due to lower tumor burden.

Clearance of ctDNA has also been associated with better outcomes. The results of a real-world study from China of nearly 1,000 patients with non–small cell lung cancer (NSCLC) showed that higher ctDNA abundance and mutation count at baseline were associated with shorter overall survival.3 The researchers also found that patients with ctDNA clearance, not just driver mutation clearance, at any point during the course of treatment had longer progression-free survival (hazard ratio [HR] = 0.28) and overall survival (HR = 0.19), regardless of the type of treatment or evaluation schedule.

Early ctDNA dynamics can also predict pathologic response to immune checkpoint blockade. Another study of metastatic NSCLC showed that patients receiving immune checkpoint inhibitor therapy who were molecular responders had dramatic responses early on compared with those who were nonresponders.4 This translated to better progression-free survival for patients with undetectable ctDNA on treatment vs those with detectable ctDNA, said Dr. Leighl.

Even without complete clearance, evidence of ctDNA response is still correlated with improved outcomes. A recently published longitudinal analysis of plasma KRAS mutations in NSCLC showed that patients who maintained ctDNA at 3 to 4 weeks had worse outcomes than those with a decrease in overall ctDNA.5 What’s more, noted Dr. Leighl, if levels of ctDNA increased, the odds of progressive disease were sevenfold, with worse progression-free and overall survival.

“Recent data suggest that liquid biopsy can also be used as a surrogate endpoint that allows us to change treatment intensity or even de-escalate.”
— Natasha B. Leighl, MD, MMSc, FRCPC, FASCO

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Predicting Clinical Resistance, Hyperprogression

According to Dr. Leighl, liquid biopsy can also be used to detect clinical resistance. A study of ensartinib in ALK-rearranged lung cancer showed that although baseline levels of ctDNA did not predict response, changes in ctDNA were associated with disease progression.6 An increase in ctDNA level preceded radiographic disease progression by anywhere from 1 to 4 months, Dr. Leighl reported. Similar effects were observed in EGFR-mutant lung cancer, with changes in ctDNA levels preceding the development of clinical resistance to osimertinib by up to 8 or 9 months.7

Liquid biopsy may also be used to predict hyperprogression, said Dr. Leighl. In a longitudinal analysis of plasma KRAS mutations, investigators observed similar ctDNA kinetics as those seen in hyperprogressive disease.5

“We could potentially use ctDNA to identify those patients with rapid disease progression and salvage them with alternative therapies,” Dr. Leighl suggested.

Using Liquid Biopsy to Improve Outcomes

In fact, recent publications have shown ways that liquid biopsy could be used to improve outcomes. Using capture-based ­“ultradeep” sequencing, 87% of patients with NSCLC who responded to PD-L1 blockade were found to have undetectable ctDNA, and the overwhelming majority remained progression-free.8 Conversely, all four patients with detectable ctDNA eventually experienced disease progression.

“In the future, liquid biopsy could even be used to stop treatment safely in patients who are on long-term immune checkpoint inhibitors,” said Dr. Leighl. “Or it could be used to intensify therapy for patients with evidence of residual ctDNA who may be in need of additional treatment.”

Another study of patients with stage III NSCLC who had either received chemoradiation or chemoradiation followed by immune checkpoint inhibitors found that patients who experienced disease progression were more likely to have ­ctDNA ­detected early on or after chemoradiation.9 Patients who were progression-free, on the other hand, had no evidence of ctDNA. Although some patients with ctDNA detected after chemoradiation appeared to benefit from subsequent checkpoint inhibitors, said Dr. Leighl, other patients had levels of ctDNA that continued to increase, even after checkpoint inhibition, and these patients had poor outcomes.

“Liquid biopsy could even be used to intensify therapy for patients with evidence of ctDNA who may be in need of additional treatment.”
— Natasha B. Leighl, MD, MMSc, FRCPC, FASCO

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“Perhaps we should be thinking of additional ways to intensify therapy in that group,” she said.

Future Research and Clinical Design

According to Dr. Leighl, adaptive randomization could guide treatment based on ctDNA levels either to start with immune-based therapy or to add chemotherapy in patients with no evidence of ctDNA response. And this approach could be extended to other treatment regimens as well.

“In patients with EGFR-mutant lung cancer, for example, there are ongoing studies looking at osimertinib therapy or VEGF inhibition,” said Dr. Leighl. “For patients who do not clear their ctDNA, we should have an arm that allows them to continue on a single tyrosine kinase inhibitor or to add chemotherapy, to establish the benefit of this approach.”

Despite the mounting clinical evidence supporting the role of liquid biopsy in advanced disease, however, Dr. Leighl underscored the importance of designing trials that demonstrate clinical utility. “This will require better understanding of the definition and validation of cutoffs as well as optimal standards for processing, analysis, reporting, and timing of sampling,” she concluded. “Finally, we need more clinical trials with endpoints that matter to our patients.” 

DISCLOSURE: Dr. Leighl reported financial relationships with Amgen, Array Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Xcovery, Guardant Health, Lilly, MSD, Pfizer, Roche, Takeda, and Teva.


1. Leighl NB: Liquid biopsy for tumor monitoring. IASLC 2020 Hot Topic Meeting: Liquid Biopsy. Abstract OA07.05. Presented October 3, 2020.

2. Gray JE, Okamoto I, Sriuranpong V, et al: Tissue and plasma EGFR mutation analysis in the FLAURA trial: Osimertinib versus comparator EGFR tyrosine kinase inhibitor as first-line treatment in patients with EGFR-mutated advanced non-small cell lung cancer. Clin Cancer Res 25:6644-6652, 2019.

3. Song Y, Hu C, Xie Z, et al: Circulating tumor DNA clearance predicts prognosis across treatment regimen in a large real-world longitudinally monitored advanced non-small cell lung cancer cohort. Transl Lung Cancer Res 9:269-279, 2020.

4. Anagnostou V, Forde PM, White JR, et al: Dynamics of tumor and immune responses during immune checkpoint blockade in non-small cell lung cancer. Cancer Res 79:1214-1225, 2019.

5. Zulato E, Attili I, Pavan A, et al: Early assessment of KRAS mutation in cfDNA correlates with risk of progression and death in advanced non-small-cell lung cancer. Br J Cancer 123:81-91, 2020.

6. Horn L, Whisenant JG, Wakelee H, et al: Monitoring therapeutic response and resistance: Analysis of circulating tumor DNA in patients with ALK+ lung cancer. J Thorac Oncol 14:1901-1911, 2019.

7. Romero A, Serna-Blasco R, Alfaro C, et al: ctDNA analysis reveals different molecular patterns upon disease progression in patients treated with osimertinib. Transl Lung Cancer Res 9:532-540, 2020.

8. Hellmann MD, Nabet BY, Rizvi H, et al: Circulating tumor DNA analysis to assess risk of progression after long-term response to PD-(L)1 blockade in NSCLC. Clin Cancer Res 26:2849-2858, 2020.

9. Chabon JJ, Hamilton EG, Kurtz DM, et al: Integrating genomic features for non-invasive early lung cancer detection. Nature 580:245-251, 2020.