FLASCO Fall Session: Advancements in MRD Monitoring Using ctDNA in Lung Cancer

The term minimal residual disease (MRD) is used to describe a very small number of cancer cells that remain in the body during or after treatment. MRD can be detected using highly sensitive laboratory methods that are able to find 1 cancer cell per million normal cells. Currently, MRD is understood in oncology to be helpful in planning treatment, assessing the efficacy of treatment, detecting recurrence, or making a prognosis.¹ Although MRD testing is primarily used for blood cancers such as lymphoma and leukemia, it can also be used for lung, breast, and colon cancers.^1,2

Since MRD is closely associated with disease recurrence, identifying specific genetic and molecular alterations as novel MRD detection targets using circulating tumor DNA (ctDNA) has been a research focus for the past several years. ctDNA, which is a cell-free DNA fragment in the bloodstream originating from malignant tumors or circulating tumor cells, is a non-invasive biomarker in clinical oncology. Using liquid biopsy, which is defined as the analysis of cancer biomarkers in tumor-derived material extracted from patients’ bloodstream, urine, pleural effusion, cerebrospinal fluid, saliva, or bile, ctDNA can be identified using biomarkers such as somatic point mutations, deletions, amplifications, gene fusions, DNA methylation markers, MicroRNAs, proteins, or metabolites.³

During a presentation at the 2024 Florida Society of Clinical Oncology (FLASCO) Fall Session in Orlando, Oleg Gligich, MD, an oncologist at Mount Sinai Medical Center, discussed the role of MRD monitoring using ctDNA in lung cancer treatment. Gligich explained that the use of ctDNA in MRD monitoring has not been without its challenges, including low ctDNA concentrations, especially in the adjuvant setting when the tumor is removed; limits of detection (LOD) in the advanced state are 10% ctDNA, locally advanced disease is 1%, and early stage or curative intent is less than 0.1%; and first-generation assays lack sensitivity to detect minimum MRD at a threshold of 0.01% variant allele frequency (VAF). Gligich explained further that for these reasons, a few strategies were established to increase the sensitivity of assays, including whole-genome sequencing (WGS), personalized sequencing, and improvements on background errors and clonal hematopoiesis of indeterminate potential.³

“Low levels of detection were quite complicated,” Gligich said during the FLASCO session. “The first-generation assays were unable to pick up less than 0.01% VAF, hence novel technologies implemented WGS, enriched tumors, personalized assays, and improvements on background noise. [This] brings us to a few assays today that are currently available.”³

Among commercially available assays that can be used for lung cancer, LOD is 0.01% VAF, 0.01% ThermoFisher (TF), 0.001% VAF, and 0.02% TF. However, new assays in development are showing LOD of 0.005% VAF and 0.0001% TF.³

“When looking through some of these assays, it's important to know how it works,” Gligich said. “It's important to know what type of technology is being used, what the VAF is, and what types of cancers it's approved for.”³

According to Gligich, there are 2 clinical trials addressing MRD monitoring that may be practice changing: TRACERx (NCT01888601) and AEGEAN (NCT03800134).^3-5

TRACERx is a longitudinal study tracking the evolution of early-stage non–small cell lung cancer. Image Credit: © iDoPixBox - stock.adobe.com

TRACERx, a longitudinal study tracking the evolution of early-stage non–small cell lung cancer (NSCLC), pre-operative ctDNA detection predicted worse relapse-free survival (RFS) in adenocarcinomas. Single-timepoint detection within a landmark analysis window of 10 to 120 days post-operation showed negative ctDNA with a 5-years RFS of 70.8% and a 5-year overall survival (OS) of 84.8%; for positive ctDNA of less than 80 parts per million (PPM), 5-year RFS was 15.5% and 5-year OS was 38.5%; and positive ctDNA at 80 PPM or greater showed a 5-year RFS at 4.7% and 5-year OS at 11.1%. Gligich noted that any post-operative ctDNA detection was prognostic of worse RFS and OS for patients, with longitudinal 5-year sensitivity at 85% and 5-year specificity at 96%.^3,4

The AEGEAN trial, which is a phase 3, double-blind, placebo-controlled, international study, assessed pathological and clinical outcomes of durvalumab (Imfinzi; AstraZeneca) plus chemotherapy prior to surgery, followed by durvalumab monotherapy after surgery in adults with resectable, stage II to III NSCLC. For this trial, as early as neoadjuvant cycle 2 dose 1, patients in the durvalumab arm with ctDNA clearance had longer event-free survival and OS compared to patients without clearance and versus the placebo arm.^3,5

According to Gligich, these trials help to show that patients with positive ctDNA have a worse outcome than patients who are ctDNA negative in both the adjuvant and neoadjuvant settings. Additionally, Gligich noted that patients who had ctDNA clearance performed significantly better than those who did not. Further, Gligich explained that cycle 2 dose 1 ctDNA positivity may be a better predictor of RFS than pathologic complete response.³

“If we focus drug development on patients who are destined to recur and use these treatments earlier, we will change disease-free survival,” Gligich said.³

REFERENCES

1. Minimal residual disease. National Cancer Institute. Accessed November 2, 2024. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/minimal-residual-disease
2. Peng Y, Mei W, Ma K, Zeng C. Circulating Tumor DNA and Minimal Residual Disease (MRD) in Solid Tumors: Current Horizons and Future Perspectives. Front Oncol. 2021;11:763790. doi:10.3389/fonc.2021.763790
3. Gligich O, Sandoval-Sus JD, Heldermon C, Kim R, Kzandjian D. Minimal residual disease monitoring. Presented at: 2024 FLASCO Fall Session; Orlando, Florida; November 1-2, 2024.
4. Jamal-Hanjani M, Wilson GA, McGranahan N, et al; TRACERx Consortium. Tracking the Evolution of Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Jun 1;376(22):2109-2121. doi: 10.1056/NEJMoa1616288
5. Heymach JV, Mitsudomi T, Harpole D, Aperghis M, Jones S, Mann H, Fouad TM, Reck M. Design and Rationale for a Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab for the Treatment of Patients With Resectable Stages II and III non-small-cell Lung Cancer: The AEGEAN Trial. Clin Lung Cancer. 2022 May;23(3):e247-e251. doi:10.1016/j.cllc.2021.09.010