Long-term ctDNA reassessment (LTctDNA) in NSCLC immunotherapy responders.

e20539 Background: Immune checkpoint inhibitors (ICI) with or without chemotherapy are standard frontline therapy for metastatic non–small cell lung cancer (mNSCLC). However, the optimal duration of immunotherapy remains undefined. ctDNA monitoring at a long-term timepoint may have the potential to identify patients at risk of progression. Methods: Patients with mNSCLC who started frontline ICI-based treatment and had an ongoing durable response for at least 18 months were included. All patients had ctDNA analysis at diagnosis and at an 18+ month time point (long-term ctDNA reassessment, LTctDNA) utilizing Guardant360 Liquid to assess genomic alterations (single nucleotide variants, indels, fusions, and copy number variants) and Guardant Reveal to evaluate methylation-based tumor fraction (mTF). Demographics, cancer and treatment information, and subsequent progression/death events were collected. Subsequent progression free survival (PFS) was calculated from time of LTctDNA draw. Molecular response was assessed using (1) change in mTF and (2) change in mean variant allele frequency (VAF) of genomic alterations between baseline and LTctDNA timepoints. Associations between ctDNA response metrics and PFS were evaluated using via log-rank analyses. Results: Our cohort included 30 eligible patients with paired samples. Median age was 64.9 years, 27 (90.0%) had a smoking history, and 17 (56.7%) were white. The majority had adenocarcinoma (76.7%); 36.7% were treated with ICI monotherapy vs chemoimmunotherapy; and 53.3% were still on treatment at time of LTctDNA draw. The median time from ICI start to LTctDNA draw was 27.1 months (range, 17.9 to 75.2). The majority of patients (23/30) had LTctDNA clearance by mTF (-100% mTF change), only 1 of whom had subsequent progression of disease (CNS-only, 10.3 months after LTctDNA draw). Of the 7 patients who did not have LTctDNA clearance, 4 experienced progression of their original cancer, and 2 died of their cancer. mPFS from LTctDNA draw was 22.6 months for the overall cohort and was longer in patients with LTctDNA clearance vs. non cleared (NR vs 9.8 months; log rank p<0.001). Compared to the methylation-based assay (mTF change), molecular response by genomic assay (VAF change) was much less reliable in predicting subsequent progression (75% vs 80% sensitivity; 59% vs 88% specificity). Conclusions: In our study, LTctDNA clearance using a commercially available methylation-based assay correlated with improved mPFS and had a 100% negative predictive value for systemic progression. These findings suggest that LTctDNA assessment at a clinically meaningful decision point, such as the 18–24 month landmark when discontinuation of ICI is often considered, could provide valuable prognostic information and guide individualized treatment decisions.