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TPS9603
Background: Circulating tumor DNA (ctDNA; the tumor derived fraction of circulating free DNA in the blood) is a well recognized, minimally-invasive biomarker of tumor burden/progression in many cancers. We have previously shown in retrospective and prospective cohorts of patients with melanoma that ctDNA analysis of serial blood samples following curative intent surgery can identify minimal residual disease (MRD) or molecular relapse. The majority of patients with resected stage II melanoma do not recur, therefore better strategies to identify high risk patients are required. Furthermore, a consistent finding in studies of immune therapy in stage IV melanoma is that patients with small volume disease have the best outcome. We aim to test whether early relapse can be identified by ctDNA analysis and acted upon in a clinically relevant timeframe, and if early treatment of molecular recurrence with immune therapy improves outcomes for patients with resected stage IIB/C melanoma. Methods: We designed a phase II/III multicenter study across 21 UK and 4 Australian sites with a tumor informed approach employed for ctDNA detection. Droplet digital assays for BRAF/NRAS/TERT promoter mutations were validated for sensitive ctDNA detection across two accredited clinical testing laboratories. Patients with stage IIB/C melanoma, BRAF/NRAS/TERT promoter mutant cutaneous melanoma, ECOG 0/1, adequate organ function, with complete resection (including sentinel lymph node biopsy) performed within 12 weeks and radiological/clinical disease-free status confirmed within 4 weeks prior to registration, no prior immune/targeted therapy will be followed up with blinded ctDNA sampling in addition to clinical follow-up. Patients with ctDNA detected will be randomised 1:1 in a double blind fashion to continue routine follow-up with investigators choice treatment if they develop disease recurrence, or unblinded and treated with nivolumab 480mg IV Q4-weekly. Primary objectives include i) whether MRD/molecular relapse following curative intent surgery can be identified earlier than clinical relapse, ii) whether early treatment of molecular recurrence with nivolumab improves overall survival. 1050 patients are planned to be enrolled. The study opened in the UK in November 2021 and will open in Australia in Spring 2022. Clinical trial information: NCT04901988.