Background/Objectives: ctDNA is evolving as an important biomarker for prognostic assessment in advanced melanoma. However, the utility of ctDNA monitoring during concurrent ICI with RT remains incompletely explored. Methods: In this multicenter retrospective study, patients with unresectable stage III/IV melanoma treated with ICI and palliative RT were identified. Patients had retrospectively collected, tumor-informed, exome-based, ctDNA monitoring within 3 months following RT. Results: A total of 50 patients treated with ICI and palliative RT were analyzed. Compared with ctDNA clearance, ctDNA detectable and increasing was associated with worse OS (adjusted HR 2.52, 95% CI 1.20–5.29; p = 0.015), whereas ctDNA detectable and decreasing was not significantly different from ctDNA clearance (adjusted HR 1.58, 95% CI 0.69–3.65; p = 0.282). One-year OS was 87.5% with persistently undetectable ctDNA, 83.3% for ctDNA clearance, 46.3% for detectable and decreasing ctDNA, and 21.4% for detectable and increasing ctDNA. In a multivariable analysis, detectable and increasing ctDNA was associated with worse OS compared with ctDNA clearance (HR 2.52, 95% CI, 1.20–5.29, p = 0.015). Conclusions: Among patients with advanced melanoma treated with ICI and palliative RT, ctDNA clearance is associated with significantly improved OS compared to patients with detectable and increasing ctDNA within 3 months following RT. Ongoing prospective studies are needed to understand the role of ctDNA in this population.

CtDNA is evolving as an important biomarker for ICI treatment response assessment in advanced melanoma. However, the utility of ctDNA monitoring during concurrent ICI with RT remains incompletely explored. In this multicenter, retrospective study, patients with unresectable stage III/IV melanoma treated with ICI and palliative RT were identified. Patients had retrospectively collected, tumor-informed, exome-based, ctDNA monitoring within 3 months following RT. 50 patients treated with ICI and palliative RT were analyzed. Patients with ctDNA clearance had significantly longer OS (HR 2.10, 95% CI 1.16-3.80, p=0.014) compared to those with increasing or decreasing and detectable ctDNA following RT. One-year OS was 85.9% with ctDNA clearance, 30.6% with decreasing ctDNA, and 22.0% for increasing ctDNA. In a multivariable analysis, both decreasing and increasing ctDNA were associated with worse OS compared with ctDNA clearance (HR 5.08 [95% CI, 1.26–20.48, p=0.022] and HR 9.83 [95% CI, 2.69–35.94, p< 0.001], respectively). Among patients with advanced melanoma treated with ICI and palliative RT, ctDNA clearance is associated with significantly improved OS compared to patients with detectable ctDNA within 3 months following RT. Ongoing studies are needed to understand the role of ctDNA in this population.