Circulating tumor DNA minimal residual disease predicts the risk of progression after long-term response to first-line immunotherapy in advanced NSCLC

BackgroundImmunotherapy has achieved breakthrough progress in non-small-cell lung cancer (NSCLC), with some patients experiencing long-term benefits. However, reliable tools for predicting the risk of disease progression (PD) in these patients are lacking. Circulating tumor DNA minimal residual disease (ctDNA MRD) has demonstrated predictive values in early-stage and locally advanced NSCLC, but its role in advanced NSCLC remains unclear.MethodsThe CR1STAL study (NCT05198154) is a multicenter prospective cohort study utilizing ctDNA MRD to monitor the risk of PD in advanced NSCLC. Patients with stage IIIB-IV NSCLC receiving first-line immunotherapy who had progression-free survival of 1 year were screened. Peripheral blood samples were collected every 2-3 months, synchronized with radiographic efficacy evaluations. The personalized target-capture panels for ctDNA detection were tailored based on individual tumor variants identified through the ultra-depth sequencing of a 1021-gene panel. A plasma sample with at least one detected variant was defined as ctDNA MRD positive.Results30 NSCLC patients were included, with a median age of 63.5 years. 86.7% were male with median follow-up time of 30.2 months (95% CI 28.4 to 32.0 months). Patients underwent ctDNA MRD monitoring with a median frequency of 4 assessments (range: 3 to 8). 50% of patients tested positive of ctDNA MRD. Compare with the negative group, the ctDNA MRD positive group exhibited an increased risk of PD (hazard ratio: 20.73, 95% CI 2.67 to 161.08, p=0.004), offering a median lead time of 6.2 months (95% CI 5.4 to 7.8 months) than radiographic progression. Furthermore, among the 13 patients who experienced PD, 12 were detected as ctDNA MRD positive, demonstrating a sensitivity of 92.3% and a positive predictive value of 80%. Among the 17 patients with non-PD, 14 were confirmed as ctDNA MRD negative, exhibiting a specificity of 82.4% and negative predictive value of 93.3%.ConclusionsctDNA MRD emerges a promising biomarker to predict the risk of PD in advanced NSCLC patients with long-term response to immunotherapy. The surveillance of ctDNA MRD enables earlier detection of PD and facilitates prompt intervention in high-risk patients.Clinical trial identificationNCT05198154: ctDNA Analysis to Monitor the Risk of Progression after First-line lmmunotherapy in Patients with Advanced NSCLC (CR1STAL).Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureAll authors have declared no conflicts of interest.