A LARGE-SCALE study has shown that circulating tumour DNA (ctDNA) may be a powerful tool for predicting the risk of disease recurrence in patients with resected stage IIIB–D/IV melanoma receiving adjuvant immunotherapy. This prospective analysis, part of the CheckMate 915 trial, is the largest to date investigating ctDNA and its integration with other biomarkers in this high-risk group.
Using a tumour-informed, personalised approach, ctDNA was detected in 16.2% of patients at baseline after surgery. These patients had a higher risk of early recurrence, particularly within 13 weeks of starting immunotherapy. Importantly, longitudinal monitoring, conducted at weeks 13 and 29, provided greater predictive accuracy than baseline assessment alone. Patients whose ctDNA became undetectable had the lowest recurrence risk, while persistent positivity was associated with the highest.
Beyond ctDNA, the study assessed additional biomarkers such as tumour mutational burden (TMB), PD-L1 expression, and IFNγ-RNA signature scores. When ctDNA was evaluated in combination with these markers, predictive power for recurrence-free survival (RFS) increased significantly. The best outcomes were seen in patients who were ctDNA-negative and had high TMB and IFNγ-RNA scores.
Gene expression analysis also revealed that increased Myc-related gene expression correlated with poorer outcomes, while enhanced expression of immune-related genes was linked to improved RFS. High serum IL-8 and B2M levels were similarly associated with increased recurrence risk, aligning with previous research on immunotherapy resistance.
Despite limitations, including the lack of post-treatment tumour analysis and pre-resection ctDNA data, this study offers strong evidence for ctDNA as a dynamic, peripheral biomarker. Used alongside tumour characteristics, ctDNA could help guide decisions on whether to continue, de-escalate, or intensify adjuvant immunotherapy.
This work brings clinicians closer to offering truly personalised treatment plans by identifying patients at highest risk of early relapse, ultimately helping to optimise outcomes in melanoma care.
Reference
Long GV et al. Pretreatment and on-treatment ctDNA and tissue biomarkers predict recurrence in patients with stage IIIB-D/IV melanoma treated with adjuvant immunotherapy: CheckMate 915. J Immunother Cancer. 2025;13(7):e012034.
