Circulating tumor DNA (ctDNA) clearance after immune checkpoint inhibition (ICI) with radiotherapy (RT) as a prognostic indicator for patients with advanced melanoma.

Abstract

9533 Background: ctDNA is becoming a useful biomarker for ICI treatment response assessment in advanced melanoma. RT is capable of producing an abscopal effect, potentially enhancing ICI efficacy. The utility of ctDNA monitoring with concurrent ICI and RT remains incompletely explored. Here, we describe the clinical characteristics and survival outcomes of patients with advanced stage melanoma treated with ICI and palliative RT based on ctDNA dynamics. Methods: In this multicenter, retrospective study, patients with unresectable stage III/IV melanoma treated with ICI and palliative RT were identified. Patients had prospectively collected, tumor-informed, exome-based, ctDNA monitoring (Natera). Within 3 months prior to RT, patients had a baseline ctDNA level. Patients were separated into 3 cohorts based on nadir ctDNA dynamics within 3 months after RT. Those with undetectable ctDNA were categorized as “ctDNA cleared.” Patients with a positive fold ctDNA change were “increasing ctDNA” and negative fold change were “decreasing ctDNA.” Hazard ratios for overall survival (OS) probability were determined via log-rank tests and multivariate analysis (MVA) used cox proportional hazard models. Results: 50 patients treated with ICI and palliative RT were analyzed. Median follow up was 8.0 months from RT start. Median age was 65 (24-86) and median baseline ctDNA level was 8.9 MTM/mL (0-11390 MTM/mL). Melanoma primaries included: 82% (41) cutaneous, 10% (5) mucosal, 8% (4) unknown primary. ICI regimens included 70% (35) ipilimumab/nivolumab, 16% (8) nivolumab/relatlimab, 2% (1) anti-PD-1/investigational ICI, 12% (n=6) anti-PD-1 monotherapy. 20 patients had ctDNA clearance, 12 patients had decreasing ctDNA, and 18 patients had increasing ctDNA following RT with ICI. The most common RT sites were the CNS (50%, n=25) and skin/soft tissue (24%, n=12), followed by lymph nodes and bone (each 14%, n=7), and lung and liver (each 6%, n=3). Patients with ctDNA clearance had longer OS (p=0.001) 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, 22.0% for increasing ctDNA. In a MVA adjusting for age, M substage, radiation site, and melanoma subtype, 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). 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 ctDNA within 3 months following RT. Ongoing prospective studies are needed to understand the long-term clinical impact of RT on ICI-treated patients with melanoma, and better define the role of ctDNA monitoring for this population.