ctDNA clearance durability and progression-free survival in unresectable or metastatic cutaneous malignancies.

9591 Background: Circulating tumor DNA (ctDNA) has emerged as a sensitive biomarker for disease monitoring and prognostication across malignancies. Yet, the clinical relevance of sustained ctDNA negativity (“clearance”) as a guide for immunotherapy duration in advanced cutaneous cancers remains poorly defined. This study evaluated the prognostic impact of durable ctDNA clearance in patients with unresectable or metastatic skin cancers treated with immune checkpoint inhibitors (ICIs). Methods: A single-institution retrospective study was performed using a personalized ctDNA assay (Signatera, Natera Inc.) on prospectively collected plasma from patients with stage III–IV unresectable cutaneous malignancies receiving ICIs every 3-6 weeks. ctDNA clearance was defined as a change from ctDNA-positive to ctDNA-negative on at least two consecutive samples obtained ≥4 weeks apart during ICI therapy and categorized as transient (<12 months) or sustained (≥12 months). Demographics and clinical characteristics were summarized with descriptive statistics; progression-free survival (PFS) was estimated using the Kaplan-Meier method, and hazard ratios (HRs) were calculated with Cox proportional hazards models. Results: Among 75 patients (stage III: 23%, stage IV: 77%), most were male (72%) and had melanoma (87%), with a median age of 72 years and median follow-up of 20.4 months. Median ICI treatment duration was 6.9 months; all patients received ICIs, most commonly relatlimab/nivolumab (49%) or pembrolizumab (40%). Median ctDNA clearance duration was 8.2 months. Patients with sustained ctDNA clearance (n=25) experienced markedly improved 12-month PFS compared with those with transient clearance (n=50) (92.0% 95% CI, 71.6–97.9 vs 58.1% 95% CI, 42.6–70.8). In a multivariable model adjusting for age, malignancy type, and treatment regimen, transient ctDNA clearance was associated with significantly worse PFS than sustained clearance (HR 12.1; 95% CI, 2.7-53.4). Conclusions: Sustained ctDNA clearance (≥12 months) is strongly associated with superior PFS in advanced cutaneous malignancies treated with ICIs, underscoring its potential as a dynamic biomarker to inform the treatment duration. Validation in larger, multi-institutional cohorts is warranted to confirm these findings and refine cDNA-guided immunotherapy strategies.