P56 Trial redesign for the phase II/III DETECTION trial: circulating tumour DNA-guided therapy for stage IIB/C melanoma after surgical resection
Despite patients with stage II melanoma being relatively high risk, contributing to 30% of melanoma-associated deaths, there remains a relatively low individual chance of melanoma recurrence. Therefore, strategies are required to better select those patients at highest risk of recurrence. We have developed assays using circulating tumour DNA (ctDNA) to detect minimal residual disease (MRD) or molecular recurrence of melanoma. Originally, the DETECTION trial was designed to perform ctDNA sampling in addition to clinical follow-up in patients with stage IIB/C melanoma. Those with ctDNA detected were randomized 1 : 1 in a double-blind fashion to continue routine follow-up with the investigators’ choice of treatment if they developed disease recurrence or were unblinded and treated with nivolumab. Since its opening, adjuvant therapy has been licensed, with trials showing approximately 6% absolute reduction in distant metastasis in stage IIB/C melanoma with 1 year of antiprogrammed cell death protein 1 therapy; however, grade 3 or 4 toxicity was observed in 16% of patients, with 25% experiencing lifelong endocrine disorders. Better enrichment of patients at high risk of recurrence, and avoiding treatment toxicity in those who do not require it, therefore remains highly relevant. As DETECTION had only started recruitment, there was opportunity to redesign it, which we present here. We have designed tumour-informed assays targeting BRAF (V600E/K/R), NRAS (G12D, Q61K/L/R) and the H-TERT promoter region (−124 and −146) mutations for ctDNA detection using droplet digital polymerase chain reaction. DETECTION has been redesigned as a phase III trial with the primary objectives of elucidating (i) whether MRD/molecular relapse following curative intent surgery can be identified earlier than clinical relapse and (ii) whether early treatment of molecular recurrence based on ctDNA detection is noninferior to adjuvant therapy in preventing distant metastasis. Patients (n = 1000) with stage IIB/C/III/IV resected BRAF/NRAS/TERT promoter mutant cutaneous melanoma, ECOG 0/1 and adequate organ function, with complete resection performed within 12 weeks and radiological/clinical disease-free status confirmed and no prior immune/targeted therapy will be included. Patients will be randomized 1 : 1 to either 1 year of adjuvant therapy (arm A) or longitudinal ctDNA monitoring (arm B) and treatment only if a local recurrence (surgery followed by 1 year of adjuvant therapy with ongoing ctDNA monitoring) or ctDNA detection (2 years of the investigators’ choice of therapy). The primary endpoint is distant metastasis-free survival. CtDNA is a useful tool to monitor for MRD/molecular relapse. The DETECTION trial will assess whether it can be used to safely monitor patients and systemically treat only those at highest risk of melanoma progression.