Circulating tumor DNA (ctDNA) monitoring for minimal residual disease (MRD) is emerging as a valuable tool in lung cancer management, offering insights into treatment planning, efficacy assessment, and recurrence detection. At the 2024 Florida Society of Clinical Oncology (FLASCO) Fall Session, Oleg Gligich, MD, from Mount Sinai Medical Center, highlighted recent advancements and challenges in utilizing ctDNA for MRD monitoring in lung cancer.
Overcoming Detection Challenges
One of the primary hurdles in ctDNA monitoring is the low concentration of ctDNA, particularly in the adjuvant setting after tumor removal. First-generation assays often lacked the sensitivity to detect MRD at a threshold of 0.01% variant allele frequency (VAF). To address this, researchers have developed strategies to enhance assay sensitivity, including whole-genome sequencing (WGS), personalized sequencing, and improvements in managing background errors.
"Low levels of detection were quite complicated," Gligich noted. "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."
Commercially available assays now offer limits of detection (LOD) as low as 0.01% VAF, with new assays in development showing even greater sensitivity, down to 0.0001% TF. Understanding the technology and VAF of these assays is crucial for their effective application.
Clinical Trial Insights: TRACERx and AEGEAN
Two key clinical trials, TRACERx (NCT01888601) and AEGEAN (NCT03800134), are shaping the understanding of MRD monitoring in lung cancer. TRACERx, a longitudinal study tracking early-stage non-small cell lung cancer (NSCLC), demonstrated that pre-operative ctDNA detection predicted worse relapse-free survival (RFS) in adenocarcinomas. Post-operative ctDNA detection was prognostic of worse RFS and overall survival (OS), with high sensitivity (85%) and specificity (96%).
The AEGEAN trial, a phase 3 study, evaluated durvalumab plus chemotherapy before surgery, followed by durvalumab monotherapy after surgery in resectable stage II-III NSCLC. Early ctDNA clearance in the durvalumab arm was associated with longer event-free survival and OS compared to patients without clearance and versus the placebo arm. Specifically, cycle 2 dose 1 ctDNA positivity may be a better predictor of RFS than pathologic complete response.
Implications for Treatment Strategies
These trials underscore that patients with positive ctDNA generally have poorer outcomes compared to those who are ctDNA negative, both in adjuvant and neoadjuvant settings. Furthermore, ctDNA clearance correlates with significantly improved outcomes.
"If we focus drug development on patients who are destined to recur and use these treatments earlier, we will change disease-free survival," Gligich stated, highlighting the potential of MRD monitoring to guide more effective treatment strategies.
