The Prognostic Impact of Circulating Tumour DNA in Melanoma Patients Treated with Systemic Therapies—Beyond BRAF Mutant Detection

SIMPLE SUMMARY: Circulating tumour DNA (ctDNA) has been shown to be an informative biomarker in melanoma. Here we analysed plasma ctDNA in a real-world metastatic melanoma cohort. We found the kinetics of ctDNA decline are delayed in patients treated with immunotherapy compared to those receiving MAPK inhibitors. Nonetheless, decreasing ctDNA levels within 12 weeks of immunotherapy or BRAF/MEK inhibitors was strongly concordant with treatment response and significantly associated with longer progression-free survival (PFS). Furthermore, exploratory analysis of nine patients commencing anti-PD-1 therapy showed a trend of high tumour mutational burden and neoepitope load in responders compared to non-responders. The results support the use of ctDNA as a dynamic biomarker for assessment of response in melanoma patients. ABSTRACT: In this study, we evaluated the predictive value of circulating tumour DNA (ctDNA) to inform therapeutic outcomes in metastatic melanoma patients receiving systemic therapies. We analysed 142 plasma samples from metastatic melanoma patients prior to commencement of systemic therapy: 70 were treated with BRAF/MEK inhibitors and 72 with immunotherapies. Patient-specific droplet digital polymerase chain reaction assays were designed for ctDNA detection. Plasma ctDNA was detected in 56% of patients prior to first-line anti-PD1 and/or anti-CTLA-4 treatment. The detection rate in the immunotherapy cohort was comparably lower than those with BRAF inhibitors (76%, p = 0.0149). Decreasing ctDNA levels within 12 weeks of treatment was strongly concordant with treatment response (Cohen’s k = 0.798, p < 0.001) and predictive of longer progression free survival. Notably, a slower kinetic of ctDNA decline was observed in patients treated with immunotherapy compared to those on BRAF/MEK inhibitors. Whole exome sequencing of ctDNA was also conducted in 9 patients commencing anti-PD-1 therapy to derive tumour mutational burden (TMB) and neoepitope load measurements. The results showed a trend of high TMB and neoepitope load in responders compared to non-responders. Overall, our data suggest that changes in ctDNA can serve as an early indicator of outcomes in metastatic melanoma patients treated with systemic therapies and therefore may serve as a tool to guide treatment decisions.