Circulating tumor DNA (ctDNA) dynamics during anti-PD-1 based therapy to predict clinical outcomes in advanced stage melanoma: A multicenter retrospective study.

9523 Background: ctDNA has shown promise as a prognostic biomarker for disease relapse in resected tumors. The significance of ctDNA changes in the advanced or metastatic disease setting for predicting treatment response and survival characteristics is still under investigation. In our study, we evaluated the association between early ctDNA changes after anti-PD-1 based therapy initiation and clinical outcomes in patients with advanced stage melanoma. Methods: We performed a multicenter, retrospective analysis using a personalized, tumor-informed ctDNA assay (Natera) on prospectively collected plasma samples from patients with unresectable stage III/IV melanoma treated with anti-PD-1 based therapy. Baseline ctDNA levels were assessed prior to the start of treatment and at 6-8 weeks. Patients were divided into 3 cohorts based on ctDNA changes: ctDNA clearance (6-8 week level undetectable or 0 MTM/mL), ctDNA decrease (6-8 week level decreased from baseline but detectable), or ctDNA increase (6-8 week level increased from baseline). Logistic regression models were used to evaluate the odds of disease control based on the change in ctDNA levels between both time points. Cox proportional hazard models were used to study the effects of ctDNA changes on progression-free survival (PFS) and overall survival (OS). Results: We identified 95 patients with unresectable stage III (18%; n=17) or stage IV (82%; n=78) melanoma with cutaneous (72%; n=68), uveal (12%; n=11), mucosal (8%; n=8), or unknown (8%; n=8) primaries who were treated with dual anti-PD-1/anti-CTLA-4 (60%; n=57), dual anti-PD-1/anti-LAG-3 (17%; n=16), or anti-PD-1 monotherapy (23%; n=22). At baseline, median age was 75, median baseline ctDNA was 363 mTM/ml, and median follow up was 13.1 months; 29% (n=28) had liver metastases, 26% (n=25) had brain metastases. Using ctDNA clearance (n=40) as reference, patients with ctDNA decrease (n=23) had lower odds of disease control (OR=0.09, 95% CI 0.01-0.85, p=0.035), and shorter PFS (HR=5.15, 2.25-11.79, p<0.001), and OS (HR=5.72, 1.52-21.56, p=0.010); patients with ctDNA increase (n=32) had even lower odds of disease control (OR=0.01, 0.00-0.09, p<0.001) and even shorter PFS (HR=5.67, CI 2.62-12.24, p<0.001) and OS (HR=8.76, CI 2.55-30.11, p=0.001). 12-month PFS for ctDNA clearance, ctDNA decrease, and ctDNA increase were 94.3%, 63.0%, and 48.2%, respectively. 12-month OS for ctDNA clearance, ctDNA decrease, and ctDNA increase were 95.4%, 64.6%, and 50.5% respectively. Conclusions: ctDNA dynamics after 6-8 weeks of anti-PD-1 therapy in patients with advanced stage melanoma may be predictive of disease control, progression-free survival, and overall survival. ctDNA clearance is associated with favorable clinical outcomes. Larger studies are needed to validate the role of ctDNA as an early response biomarker in advanced disease.