Dissecting the PRADO (Personalized Response-driven ADjuvant cOmbination therapy) trial in melanoma for surgical oncologists; safety and feasibility of surgical de-escalation after neo-adjuvant immunotherapy for macroscopic stage III melanoma

<h2>Abstract</h2> The Personalized Response-directed surgery and Adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma (PRADO trial) is an international, multicenter, single arm, non-randomized prospective phase 2 trial that investigated neoadjuvant immunotherapy (ipi-nivo) in patients with macroscopic stage III melanoma. Depending on tumor response after index lymph node resection (ILN), patients were offered follow up only (major pathologic response, MPR ≤10% viable melanoma); therapeutic lymph node dissection (TLND) without adjuvant therapy (partial pathologic response, pPR; 11-50% viable tumor cells), and finally, TLND +/- adjuvant radiotherapy to the nodal field, followed by adjuvant systemic therapy (pathologic non response (pNR; >50% viable tumor cells), and switch to BRAF/MEK inhibition in case of a BRAF V600 mutation. Primary endpoints were confirmation of pathologic response rate (pRR) of the ipi-nivo; to investigate whether TLND can be safely omitted in patients achieving MPR, with the hypothesis that MPR is durable and transcends the need for TLND. <h3>Results</h3> showed that MPR could be achieved 61% of patients and TLND could safely be omitted in these patients with significantly lower surgical morbidity and better QoL, with durable DFS and DMFS at 2 years. Summarizing, the PRADO trial showed that in macroscopic stage III melanoma 2 doses of neoadjuvant ipi-nivo leads to a high MPR rate and suggests TLND can be safely omitted in favor of ILN. Validation of this concept will follow in MSLT-3.