Biomarker analysis of circulating tumor DNA in clinical stage III melanoma patients treated with neoadjuvant immunotherapy combined with targeted therapy

Background: Circulating tumor DNA (ctDNA) is predictive of recurrence in resected stage III melanoma, yet its role in the neoadjuvant setting for clinical stage III (cSIII) is unclear. Objective: Assess the association between ctDNA and outcomes following neoadjuvant immunotherapy (IO) + targeted therapy (TT) in cSIII melanoma. Design: Patients in the NeoACTIVATE study were treated with neoadjuvant IO + TT, underwent lymphadenectomy, and received adjuvant immunotherapy. Methods: Patients with ctDNA testing performed at baseline, pre- and post-operation were analyzed. Baseline positron emission tomography–computed tomography volumetrics and surgical, major pathological responses (MPR) were assessed. Results: Thirteen patients had serial ctDNA, 10 (77%) were detectable at baseline, and 9/10 (90%) had ctDNA clearance. Seven (54%) achieved MPR, all with undetectable preoperative ctDNA, yet 3/7 (43%) had disease recurrence. Conclusion: ctDNA and MPR are poor predictors of recurrence following neoadjuvant IO + TT for cSIII melanoma patients. Further studies are warranted to define the role of ctDNA in this setting.