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

Abstract

Background 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. Methods 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. Results 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 6 weeks 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 14.67 months, whereas ctDNA‐positive patients experienced disease progression. Conclusion 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.

Potential of circulating tumor DNA to refine immunotherapy

“…An alternative use of ctDNA in the adjuvant setting is to identify those patients who are not responding to adjuvant therapy or to detect molecular relapse following its completion. In the post‐immunotherapy cohort ( n = 10, stage II/IV) Eroglu et al 1 . found that all of the ctDNA negative patients remained disease‐free whereas the three patients with ctDNA detected had disease progression.…”

“…Similarly in colorectal cancer, noninferiority of a ctDNA‐guided approach compared to adjuvant chemotherapy has been demonstrated in stage II disease 8,9 . Eroglu et al 1 . add to this literature by providing further insight into ctDNA dynamics during immune‐checkpoint inhibitors (ICI) in both adjuvant and advanced melanoma.…”

“…Studies such as Eroglu et al 1 . provide initial insights as to how ctDNA could be used in clinical practice to augment use of immunotherapy.…”

“…An intriguing use of ctDNA may be through dynamic monitoring for early escalation of therapy in advanced disease. Eroglu et al 1 . showed that patients with any increase in ctDNA level at weeks 3–11 on immunotherapy had a significantly shorter PFS, compared to patients with a decrease in ctDNA levels.…”

“…In this issue of Cancer, Ergolu and colleagues 1 describe the emerging utility of circulating tumor DNA (ctDNA) as a predictor of immunotherapy treatment outcomes in melanoma. 1 Although this study is only an initial glimpse into the potential of ctDNA to impact on clinical practice, it seems likely that noninvasive disease assessment will have a major role in oncology moving into the future. Many studies across tumor types have now demonstrated ctDNA as a marker of tumor burden and cancer proliferation.…”