KEY POINTS
- This multicentre retrospective study included 50 patients with unresectable stage III/IV melanoma treated with immune checkpoint inhibition plus palliative RT across five institutions between 2021 and 2025.
- All patients had tumor-informed, exome-based ctDNA testing before and within 90 days after RT. Eleven achieved ctDNA clearance, 12 had detectable but decreasing ctDNA, 18 had increasing ctDNA and nine remained persistently undetectable.
- Disease was predominantly advanced: 92% had stage IV melanoma and 48% had M1d disease. Immunotherapy consisted mainly of ipilimumab/nivolumab (70%), while the most common irradiated site was the CNS (50%).
- One-year overall survival strongly separated by molecular response: 87.5% with persistently undetectable ctDNA, 83.3% after clearance, 46.3% with detectable/decreasing ctDNA and 21.4% with increasing ctDNA.
- After adjustment for age, stage, melanoma subtype and CNS versus other RT site, increasing ctDNA versus clearance remained associated with worse survival (HR 2.52, 95% CI 1.20–5.29; p=0.015).
- A 90-day landmark analysis produced an even stronger but imprecise association for increasing ctDNA (HR 8.09, 95% CI 1.01–64.80; p=0.048). In a time-dependent model, currently detectable ctDNA was also associated with worse survival (HR 2.62, 95% CI 1.28–5.37; p=0.009).
- Major limitations are substantial: median observed follow-up was only 7.1 months, treatment and ctDNA-testing intervals were heterogeneous, and the study did not collect RT dose, fraction number or number of irradiated lesions, performance status, LDH or BRAF status.
CLINICAL TAKEAWAY
ctDNA dynamics after palliative RT may identify advanced melanoma patients whose disease remains biologically active despite checkpoint inhibition and local treatment. The signal is strong enough to justify prospective study, but it is prognostic—not yet evidence that RT should be escalated, repeated or systemic therapy changed according to ctDNA.