Circulating tumor DNA-based molecular residual disease detection for treatment monitoring in advanced melanoma patients.

Abstract

Immune checkpoint inhibitors (ICIs) have substantially improved overall survival in patients with advanced melanoma; however, the lack of biomarkers to monitor treatment response and relapse remains an important clinical challenge. Thus, a reliable biomarker is needed that can risk-stratify patients for disease recurrence and predict response to treatment. A retrospective analysis using a personalized, tumor-informed circulating tumor DNA (ctDNA) assay on prospectively collected plasma samples (n=555) from 69 patients with advanced melanoma was performed. Patients were divided into three cohorts: cohort A (N=30), stage III patients receiving adjuvant ICI/observation; cohort B (N=29), unresectable stage III/IV patients receiving ICI therapy; and cohort C (N=10), stage III/IV patients on surveillance after planned completion of ICI therapy for metastatic disease. In cohort A, compared to molecular residual disease (MRD)-negative patients, MRD-positivity was associated with significantly shorter distant metastasis-free survival (DMFS; hazard ratio [HR], 10.77; p=.01). Increasing ctDNA levels from the post-surgical or pre-treatment time point to after 6weeks of ICI were predictive of shorter DMFS in cohort A (HR, 34.54; p<.0001) and shorter progression-free survival (PFS) in cohort B (HR,22; p=.006). In cohort C, all ctDNA-negative patients remained progression-free for a median follow-up of 14.67months, whereas ctDNA-positive patients experienced disease progression. Personalized and tumor-informed longitudinal ctDNA monitoring is a valuable prognostic and predictive tool that may be used throughout the clinical course of patients with advanced melanoma.