Ultrasensitive ctDNA Detection Improves Clinical Sensitivity of MRD in Early-Stage NSCLC

Ultrasensitive circulating tumor DNA (ctDNA) detection “improved the clinical sensitivity” of measurable residual disease (MRD) at “key landmarks” in early-stage non-small cell lung cancer (NSCLC), according to a poster to be presented at the 2024 American Society of Clinical Oncology Annual Meeting.

“Based on these results, we now have another new tool that can help clinicians determine the need for post-operative treatment,” James M. Isbell, MD, MSCI, a thoracic surgeon at Memorial Sloan Kettering Cancer Center and lead poster author, said in a news release about the study results.

Dr. Isbell and colleagues conducted the study because “translation of ctDNA MRD in NSCLC has been hampered by suboptimal sensitivity of first-generation assays,” they explained. In the study presented at the meeting, the researchers explored “how improvements in analytical sensitivity can drive improved clinical sensitivity for MRD after surgery in NSCLC.”

To understand MRD kinetics, Dr. Isbell and colleagues used data from the TRACERx study to analyze longitudinal ctDNA in early-stage NSCLC. They generated patient-specific mathematical models to predict MRD levels at the postsurgical landmark to estimate the impact of an assay’s 95% limit of detection (LOD95) on clinical sensitivity.

The researchers assessed ctDNA MRD dynamics in 23 patients from TRACERx with ≥3 consecutive samples with detectable ctDNA without intervening therapy. The study showed that “MRD kinetics strongly correlated with exponential growth,” with a median ctDNA doubling time of 51 days, according to Dr. Isbell and colleagues. In addition, they found that “extrapolating MRD levels to the postsurgical landmark predicted that improving MRD assay LOD95 from 100 ppm (0.01%) to 1 ppm could increase clinical sensitivity by 2.1-fold.”

To test the predictions, they conducted tumor-informed ctDNA testing with the CAPP-Seq assay and the PhasED-Se assay on 269 samples from 46 patients. The median LOD95 was 1 ppm for PhasED-Seq and 84 ppm for CAPP-Seq. The researchers found that 12 cases were MRD-positive by PhasED-Seq. All these patients experienced recurrent disease, with MRD levels as low as 0.19 ppm. However, only 6 cases were MRD-positive by the CAPP-Seq assay and 83% of these patients experienced recurrent disease, showing that the PhasED-Seq had a higher clinical sensitivity than the CAPP-Seq assay (67% vs 28%; P=.022).

When the researchers conducted a Kaplan-Meier analysis for freedom from recurrence, they found that there were “significantly worse outcomes for patients with detectable MRD regardless of the method used,” but that “outcomes were better stratified using PhasED-Seq,” with a hazard ratio (HR) of 3.1 versus 11.4.

Patients who were MRD-negative after surgery by both assays “had similar outcomes regardless of adjuvant therapy (chemotherapy and/or radiotherapy),” the researchers reported. However, patients who were MRD-positive per PhasED-Seq data who were receiving adjuvant therapy had significantly better outcomes than those who were not (HR, 8.2; P=.00035). The researchers did not find a similar benefit for adjuvant therapy with the CAPP-Seq assay. Using PhasED-Seq, 80% of the patients who were MRD-positive and were receiving adjuvant therapy cleared their MRD, compared with none of those who did not receive adjuvant treatment.

“Ultrasensitive ctDNA detection improved the clinical sensitivity of MRD at key landmarks in early-stage NSCLC,” Dr. Isbell and colleagues concluded. “PhasED-Seq detected MRD at levels below 1 ppm and was associated with significantly better outcomes, revealing potential benefits of adjuvant therapy in MRD-positive patients. This suggests that ultrasensitive MRD detection is promising for use in risk-adapted trials in early-stage NSCLC.”

Reference

Isbell JM, Goldstein JS, Hamilton EG, et al. Ultrasensitive circulating tumor DNA (ctDNA) minimal residual disease (MRD) detection in early stage non-small cell lung cancer (NSCLC). Presented at the 2024 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024; Chicago, Illinois.