Longitudinal circulating tumor DNA surveillance as predictor of progression in advanced non-small-cell lung cancer with long-term benefit to immunotherapy.

8540 Background: Radiographic assessments often lag behind biological progression, and reliable biomarkers to stratify the post-treatment progression risk remain lacking in advanced non-small-cell lung cancer (NSCLC). The clinical utility of minimal residual disease in advanced solid tumors also requires further evaluation. We investigated ctDNA-based post-immunotherapy molecular residual disease (ctDNA-iMRD) in advanced NSCLC with long-term benefit from immunotherapy and assessed its predictive value for subsequent progression. Methods: This prospective, observational, multicenter CR1STAL study, is designed to evaluate whether longitudinal ctDNA-iMRD surveillance can can stratify progression risk in advanced NSCLC patients with long-term benefit from immunotherapy (defined as non-PD at 12 months after treatment initiation). The primary endpoint was progression-free survival (PFS), defined as the time from enrollment to radiographic progression or death. For ctDNA detection, tumor-informed and tumor-agnostic approaches were selected according to tumor tissue availability. ctDNA-iMRD positive was defined as detectable ctDNA at at any surveillance timepoint. Results: A total of 97 advanced NSCLC patients were included, comprising 46 in the tumor-informed cohort and 51 in the tumor-agnostic cohort. At median follow-up of 36.4 months and a median ctDNA-iMRD surveillance duration of 10.5 months, 49 patients (50.5%) were classified as ctDNA-iMRD positive during longitudinal monitoring. Patients who were ctDNA-iMRD positive had a significantly shorter median PFS than those who remained ctDNA-iMRD negative (10.1 months vs not reached; HR = 4.85; 95% CI, 2.66 to 8.82; p < 0.001). ctDNA-iMRD detectable preceded radiographic progression by a median of 5.9 months. The positive and negative predictive values of longitudinal ctDNA-iMRD surveillance were 85.1% and 72.7%, respectively. Between ctDNA detection approachs, ctDNA-iMRD positive was strongly associated with increased progression risk in both the tumor-informed (HR = 6.29; p < 0.001) and tumor-agnostic (HR = 3.67; p < 0.001) cohorts. In addition, longitudinal ctDNA-iMRD negative was associated with long-term overall survival (HR = 0.22, 95% CI, 0.09 to 0.55; p < 0.001), with 2-year and 3-year OS rates of 97.2% and 89.8%, respectively. Furthermore, ctDNA clonal status and high ctDNA growth rates were correlated with early progression. Conclusions: Both tumor-informed and tumor-agnostic ctDNA-iMRD approaches showed strong predictive performance. Longitudinal ctDNA-iMRD surveillance effectively stratified advanced NSCLC patients at high risk of progression after achieving long-term benefit from immunotherapy, supporting its potential role in enabling earlier, risk-adapted intervention in future prospective studies. ClinicalTrials.gov Identifier: NCT05198154.