Early ctDNA dynamics assessed by a personalized whole-genome sequencing-based assay as a predictor of outcomes with immune checkpoint blockade in advanced melanoma.

3053 Background: Circulating tumor DNA (ctDNA) is an emerging biomarker for assessing treatment outcomes and monitoring disease recurrence in melanoma. However, evidence supporting its clinical utility at very early on-treatment timepoints remains limited. We evaluated whether ctDNA dynamics relative to a single cycle of immune checkpoint blockade (ICB) are associated with treatment outcomes in patients (pts) with advanced melanoma. Methods: In this prospective, single-center cohort, pts with unresectable stage III or IV melanoma were enrolled. Treatment included anti-PD1 monotherapy (n=22, 40%) or anti-PD1+anti-CTLA-4 therapy (n=33, 60.0%). ctDNA analysis was performed using a personalized, tumor-informed assay (Signatera Genome, Natera, Inc.) designed from WGS of matched tumor and normal pairs. ctDNA (reported in mean tumor molecules per mL, MTM/mL) was subsequently tracked in the pts’ longitudinal blood samples, which were collected at baseline (T0) and prior to cycle 2 (T1; 3-4 weeks after ICB initiation). ctDNA dynamics were categorized as favorable (ctDNA clearance at T1 or >10-fold decrease from T0 to T1) or unfavorable (rising ctDNA or <10-fold decrease from T0 to T1). Associations between these categories and progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier estimates and Cox proportional hazards models. Results: A total of 55 pts with unresectable stage III (n=12, 21.8%) or stage IV (n=43, 78.2%) melanoma were included. Median follow-up was 36.43 months (mo) (range, 31.47-41.39). ctDNA-positivity was 83.6% (46/55) at baseline and 80.0% (44/55) at T1. Table 1 summarizes survival outcomes per ctDNA profile. Pts with an unfavorable profile (UP) of ctDNA dynamics experienced worse PFS and OS in contrast to those with a favorable profile (FP). Median PFS was 2.1 mo in the UP group versus 28.8 mo in the FP group; median OS was 19.3 vs 37.8 mo, respectively. All pts (n=21, 100%) with progressive disease had an UP, including 52.3% (11/21) with rising ctDNA and 47.7% (10/21) with <10-fold decrease. Median ctDNA levels at T1 were also higher in pts without objective response compared with responders (56.69 vs 0.38 MTM/mL; p<0.001). Conclusions: ctDNA dynamics assessed by a personalized WGS-based assay after a single cycle of ICB were strongly associated with response and survival outcomes in advanced melanoma. These findings support the evaluation of treatment-adaptation strategies based on early ctDNA dynamics in pts receiving immunotherapy. ctDNA profile median PFS (mo) 6-mo PFS 12-mo PFS PFS HR (95%CI)p-value median OS (mo) 6-mo OS 12-mo OS OS HR (95%CI)p-value FavorableN=24 28.8 100% (24/24) 91.7% (22/24) Reference 37.8 100% (24/24) 100% (24/24) Reference UnfavorableN=31 2.1 22.6% (7/31) 22.6% (7/31) 5.29(2.39–11.75)p<0.001 19.3 80.6% (25/31) 67.7% (21/31) 9.96(2.66–37.37)p<0.001