Background: Adjuvant (adj) immune checkpoint inhibition (ICI) improves relapse free survival (RFS) in stage III melanoma patients (pts). However, preclinical and translational data suggest that neo-adjuvant (neoadj) treatment might be favorable due to broader immune activation. The phase 1b OpACIN study comparing neoadj to adj IPI plus NIVO demonstrated a high pathological response rate (pRR) of 78% complicated by 90% gr 3-4 immune-related adverse events (irAEs). The phase 2 OpACIN-neo trial tested safety and efficacy of three different schemes of neoadj IPI+NIVO and identified two cycles of IPI 1mg/kg + NIVO 3mg/kg as well tolerated (20% gr 3-4 irAEs), with a high pRR of 77%. In both trials, none of the pts with a pathologic response have relapsed after a median follow-up of 30 and 8.3 months. In stage IV melanoma, long-term benefit is observed in patients achieving CR with ICI, even after cessation of therapy. This raises the question of whether a therapeutic lymph node dissection (TLND) can be omitted when a deep pathologic response with neoadj IPI+NIVO is achieved. Methods: The aim of this international multi-center investigator-initiated phase 2 PRADO extension study is to confirm the pRR and toxicity of 2 cycles of neoadjuvant IPI 1mg/kg + NIVO 3mg/kg (the preferred OPACIN-neo regimen) and to test response-driven subsequent therapy i.e. omitting surgery and adjuvant ICI based on the pathological response. 100-110 pts with stage IIIB/C melanoma and a measurable lymph node (≥15mm according to RECIST 1.1) will receive two cycles of IPI 1mg/kg + NIVO 3mg/kg after marker placement into the largest lymph node metastasis. After six weeks, pts will undergo resection of the index lymph node. For pCR/near pCR, pts will not undergo TLND; For pPR, pts will undergo TLND; and for pNR, pts will undergo TLND and start adjuvant NIVO or targeted therapy +/- radiotherapy for 52 weeks. Primary endpoints are pRR of marked lymph node and RFS at 24 months. Baseline biopsies, blood samples (week 0, 6, 12) and faeces (week 0, 6) will be collected for translational research analyses. The first patient in this trial was included in October 2018; 22 patients have been enrolled. Clinical trial information: NCT02977052