Long-term ctDNA reassessment in NSCLC immunotherapy responders

The optimal duration of immunotherapy for mNSCLC remains undefined; ctDNA reassessment at a long-term timepoint may identify patients at risk of progression. Patients with mNSCLC who started immunotherapy, had baseline ctDNA analysis, and an ongoing response for ≥18 months, underwent repeat ctDNA testing (long-term ctDNA reassessment, LTctDNA). Molecular response was assessed using both (1) change in methylated Tumor Fraction (mTF) and (2) change in mean genomic variant allele frequency (VAF) of genomic alterations, between baseline and LTctDNA timepoints. Association with subsequent PFS measured from LTctDNA was evaluated. In our cohort of 30 patients, median age was 65 years; LTctDNA was drawn a median of 27 months (range,18-75) from immunotherapy initiation. The majority of patients (22/29 with quantifiable mTF change) had LTctDNA mTF clearance, only 1 of whom had subsequent progression of their original cancer (CNS-only, 10.3 months after LTctDNA). Of the 7 patients who did not have LTctDNA clearance, 4 experienced progression. mPFS from LTctDNA draw was longer in patients with mTF clearance vs. non cleared (NR vs 9.7 months; log rank p < 0.001). Compared to mTF change, molecular response by genomic assay (VAF change) was less reliable in predicting subsequent progression (75% vs 80% sensitivity; 59% vs 88% specificity). LTctDNA clearance using a commercially available epigenomic methylation-based assay correlated with improved mPFS. LTctDNA assessment at a clinically meaningful decision point, such as the 18–24 month landmark when discontinuation of ICI is often considered, could help guide individualized treatment decisions. This study investigated whether a blood test performed after 18–24 months of immunotherapy could help identify people with metastatic non-small cell lung cancer who remain at low risk of their cancer returning. Blood samples from 30 patients who had responded well to immunotherapy-based treatment for at least 18 months were analyzed, measuring circulating tumor DNA (ctDNA) using a methylation-based test and comparing results with samples collected before treatment. Patients whose ctDNA became undetectable were much less likely to experience cancer progression than those with persistent ctDNA. These findings suggest that long-term ctDNA testing could help doctors make more personalised decisions about whether immunotherapy can be safely stopped, potentially reducing unnecessary treatment while maintaining good outcomes for patients.