The Role of Liquid Biopsy in NSCLC Continues to Emerge

Bob T. Li, MD, MPH

Liquid biopsy is emerging as an important diagnostic and evaluative tool for oncologists in the treatment of non—small cell lung cancer (NSCLC), especially as a greater understanding of the tumor microenvironment emerges. In addition, multiple molecular biomarkers are undergoing evaluation, particularly circulating tumor DNA (ctDNA). This promising biomarker has demonstrated potential benefit and is currently being explored in guided clinical trials (FIGURE).

In a presentation during the 2nd Annual Precision Medicine Through Plasma: Using Liquid Biopsies in Contemporary Oncology Care symposium hosted by Physicians’ Education Resource®, LLC, in New York, New York, Bob T. Li, MD, MPH, explained ctDNA’s growing importance in lung cancer, given the disease’s challenging prognosis.¹

“Our colleagues in the breast cancer arena talk about improving 5-year survival rates from 96% to 98%,” said Li. “We are nowhere near that in lung cancer.”

Circulating tumor DNA is single- or double-stranded DNA released by tumor cells into the blood. It thus contains the mutations of the original tumor. Through steady advancements in technology, liquid biopsy based on ctDNA analysis will expand its clinical applicability in the near future, according to Li, a medical oncologist and physician ambassador to China and the Asia-Pacific region at the Bobst International Center at Memorial Sloan Kettering Cancer Center in New York.

The use of ctDNA can provide many opportunities to intervene and improve upon the standard of care in lung cancer, continued Li. He cited several characteristics that make ctDNA a biomarker worth considering in the clinical setting, including its short half-life, its presence in the blood that serves as a link to malignancy, and noninvasive means of access.

Li said that the use of ctDNA in lung cancer is quite appropriate and should be encouraged because “we have oncogenes that we can match a drug to that will be highly effective. In addition, actionable drivers are detected in 64% of lung adenocarcinomas.”

Historically, detecting oncogenic drivers and identifying a matched therapy was the rationale for the course of treatment. “This is an old paradigm with EGFR, in which you treat the mutation with a first-generation EGFR tyrosine kinase inhibitor drug, the cancer develops resistance, a biopsy is conducted, and treatment continues with a third-generation drug,” said Li. That paradigm has changed, according to Li, with osimertinib (Tagrisso) now being a frontline option, based on findings of the multicenter, double-blind, randomized FLAURA trial (NCT02296125). He emphasized that this frame-work is still useful, however, as it may lead to the identification of new mutation patterns that could lead to new targeted therapies.

The other advantage of ctDNA is its ability to identify mechanisms of acquired resistance in patients with lung cancer who have been treated with EGFR-targeted therapies.²Offin et al discussed resistance mechanisms to osimertinib and rociletinib, such as EGFR C797S and L798I mutations, and mechanisms such as MET amplification. Activating mutations in PIK3CA have also been identified or character- ized by sequencing ctDNA.

The biomarker has also demonstrated sensitivity to the detection of oncogenic drivers in plasma compared with tissue sequencing as the standard.³Li et al demonstrated that ultra- deep plasma next-generation sequencing (NGS) can detect a wide range of oncogenic drivers in NSCLC and may be more sensitive than establish paired plasma droplet digital polymerase chain reaction assays. Li also noted a difference in detection depending on whether the patient is undergoing treatment with chemotherapy. A patient who just received their diagnosis has a much higher detection rate than a patient who is undergoing treatment, at about 75% versus about 40%, respectively, said Li.

“This corresponds with the effect of chemotherapy and the dynamics of tumor DNA shedding,” he added.

Sabari and colleagues identified 210 patients who underwent plasma NGS with no known oncogenic driver or who developed resistance to targeted therapy. The panel targeted 21 genes. This group was compared with a subset of patients (n = 106) who underwent concurrent tissue NGS testing that consisted of a 468- gene panel.⁴

When comparing the concordance between plasma NGS and tissue NGS, Li noted that the overall concordance was 57% (95% CI, 47%-66%). Among patients with plasma that tested NGS-positive, concordance was 90% (95% CI, 80%-96%) for positive-tissue NGS. Among patients who tested plasma NGS positive, 89.6% (60/67; 95% CI, 79.7%-95.7%) were also concor- dant on tissue NGS and 60.6% (60/99; 95% CI, 50.3%-70.3%) vice versa. Patients who tested plasma NGS positive for oncogenic drivers had tissue NGS concordance of 96.1% (49/51; 95% CI, 86.5%-99.5%), and directly led to matched targeted therapy in 21.9% (46/210) with clinical response. Among patients with NGS-positive tissue, 61% (95% CI, 50%-70%) were also positive on plasma NGS.

Li cited the case of a 57-year-old man who was a former smoker. The patient had a BRAF mutation, which indicates high kinase activity. “This might respond to downstream inhibition such as a MEK inhibitor,” said Li. “As a result of the liquid biopsy, he was matched with a clini- cal trial investigating the phase I, first-in-class ERK inhibitor ulixertinib,” he said. The patient had a dramatic response, resulting in a —45% RECIST partial response.

“This is an illustration of the clinical utility of liquid biopsy,” said Li. “Not only was it noninvasive, but the quick response was significant.”

Li also highlighted the findings of Newman et al, whose research detected ctDNA in 100% of stage II to IV and 50% of stage I patients with NSCLC, with 96% specificity for mutant allele fractions down to about 0.02%. The investigators found that ctDNA levels significantly correlated with tumor volume, served as a measure to distinguish between residual disease and treatment- related imaging changes, and provided earlier response assessment compared with radiographic examination.⁵

Turning to minimal residual disease (MRD), Li discussed the research of Chaudhuri et al who found that ctDNA is a promising biomarker for early-detection of MRD in patients with localized lung cancer. These findings could help identify patients who are susceptible to recurrence. By following multiple mutations, the sensitivity of MRD can be improved, and both driver and passenger mutations are useful for tracking and monitoring disease.⁶

Liquid biopsies are answering many clinical questions, concluded Li. Although questions about treatment monitoring, detection of MRD in early-stage NSCLC to guide precision adjuvant therapy, early detection, screening, and prevention remain, Li is confident that emerging technology will provide the answers. “ctDNA offers many promises to the oncologist in the future,” he concluded.

References:

1. Li BT. Translating liquid biopsy technology into clinical practice. Pre- sented at: Physicians’ Education Resource®, LLC, 2nd Annual Precision Medicine in Plasma: Using Liquid Biopsies in Contemporary Oncology Care. December 9, 2018. New York, NY. gotoper.com/conferences/ pmlb/meetings/2nd-annual-precision-medicine-through-plasma-us- ing-liquid-biopsies-in-contemporary-oncology-care/agenda.
2. Offin M, Chabon JJ, Razavi P, et al. Capturing genomic evolution of lung cancers through liquid biopsy for circulating tumor DNA. J Oncol. 2017;2017:4517834. doi: 10.1155/2017/4517834.
3. Li BT, Janku F, Janne PA, et al. Ultra-deep next generation sequencing (NGS) of plasma cell-free DNA (cfDNA) from patients with advanced lung cancers: results from the Actionable Genome Consortium. In: Proceed- ings of the 107th Annual Meeting of the American Association for Cancer Research; April 16-20, 2016; New Orleans, LA. Abstract 4342. cancerres. aacrjournals.org/content/76/14_Supplement/4342.
4. Sabari JK, Offin M, Stephens D, et al. A prospective study of circulating tumor DNA to guide matched targeted therapy in lung cancers. J Natl Cancer Inst. 2018;111(6):1-9. doi: 10.1093/jnci/djy156.
5. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548-554. doi: 10.1038/nm.3519.
6. Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA pro- filing. Cancer Discov. 2017;7(12):1394-1403. doi: 10.1158/2159-8290. CD-17-0716.