Longitudinal circulating tumor DNA kinetics and correlation with patient outcomes in metastatic melanoma.

e21538 Background: Previous studies have shown circulating tumor DNA (ctDNA) to be an accurate noninvasive method for detecting minimal residual disease and predicting therapeutic response. This study aims to investigate if positive ctDNA and subsequent clearance kinetics may be used as a predictive and prognostic tool in patients with stage IV metastatic melanoma. Non-clearance of ctDNA may be associated with poorer outcomes for progression-free survival (PFS) and overall survival (OS). Methods: In this retrospective analysis of preexisting data from a cohort of 27 patients with stage IV melanoma treated at Rush University, longitudinal ctDNA plasma samples collected between 05/01/2020 and 01/01/2024 were analyzed. A tumor-informed ctDNA assay (SignateraTM, reported in mean tumor molecules per mL (MTM/ml), low limit of detection of 0.01% variant allele frequency) was used for detection and quantification of ctDNA in plasma samples. Progression was determined based off of radiographic studies, overall survival was determined by time from stage IV diagnosis to patient death. Results: A total of 192 ctDNA timepoints were analyzed. The median number of ctDNA timepoints per patient was 5 (range 1-26). 8 patients were identified whose initial ctDNA result was negative and remained negative throughout their treatment course; 5/8 of these patients had baseline negative values available prior to the initiation of treatment. 19 patients had at least 1 positive ctDNA result at any given time; 1/19 of these patients was ctDNA-negative at baseline, 7/19 were positive at baseline, and 11/19 did not have baseline values available. The PFS rate was higher for ctDNA-negative patients compared to ctDNA-positive patients (62.5% vs. 57.9%). The OS rate was also higher for ctDNA-negative patients compared to ctDNA-positive patients (75% vs. 52.6%). Of the ctDNA-positive patients, those who achieved persistent clearance or had decreasing values of ctDNA had higher PFS rates when compared to ctDNA-positive patients who neither downtrended nor achieved clearance (71.4% and 66.7% vs. 22.9%). Patients who achieved persistent clearance or had decreasing values of ctDNA also had higher OS rates when compared to ctDNA-positive patients who neither downtrended nor achieved clearance (71.4% and 100% vs. 33.3%). Conclusions: Within the limitations of a small sample size, our data suggests that for patients with stage IV melanoma, a positive ctDNA result is associated with poorer outcomes for PFS and OS, when compared to patients with negative ctDNA results. Additionally, ctDNA-positive patients who achieved persistent clearance or downtrending ctDNA values showed more favorable outcomes for PFS and OS than ctDNA-positive patients who did not. [Table: see text]