What question did this study set out to answer?

The trial aims to establish whether selective index lymph node resection is non-inferior to therapeutic lymph node dissection for patients with major pathological response following neoadjuvant immunotherapy.

May 30, 2026

A phase 3, international, multicenter, randomized, controlled trial of selective index lymph node resection versus therapeutic lymph node dissection after neoadjuvant immunotherapy for stage IIIB-D melanoma (MSLT-3/S2601/EORTC2519).

Key Points

The trial aims to establish whether selective index lymph node resection is non-inferior to therapeutic lymph node dissection for patients with major pathological response following neoadjuvant immunotherapy.
Phase 3, international, multicenter, randomized non-inferiority trial enrolling approximately 1,574 patients
Patients are randomized 1:1 to either selective index lymph node resection or therapeutic lymph node dissection
Primary endpoint is 2-year recurrence-free survival in patients with major pathological response.
The primary outcome will measure 2-year recurrence-free survival in patients after treatment, with a non-inferiority margin of -5%.
Secondary outcomes include event-free survival, overall survival, and quality of life assessments.
A total of 496 patients with major pathological response will be evaluated.

Abstract

TPS9609 Background: Neoadjuvant immunotherapy (NAT) with immune checkpoint inhibitors (ICI) is a standard therapy for resectable stage III melanoma, with randomized trials demonstrating superior outcomes compared to adjuvant therapy alone. The phase 2 SWOG-1801 trial showed 72% EFS at 2 yrs for NAT ≤10% viable tumor), strongly correlates with improved outcomes, with the International Neoadjuvant Melanoma Consortium (INMC) pooled analysis (N=610 ICI patients) demonstrating 3-yr RFS of 93% for MPR patients (pts) vs 41% for those with no pathological response. The PRADO trial demonstrated that selective index lymph node (ILN) resection (RES) can safely de-escalate surgery in MPR pts, with only 4/60 (6.7%) MPR pts recurring after median follow-up of 28.1 months, all locoregionally. ILN RES significantly reduced surgical morbidity non-MPR pts in the ILN arm proceed to TLND within 3 weeks. Primary endpoint is 2-year recurrence-free survival in MPR pts (non-inferiority margin -5%). Secondary endpoints include escalation to TLND for isolated nodal recurrence, salvage therapy rates, distant metastasis-free survival, event-free survival, overall survival, surgery-related AEs, quality of life (QLQ-C30, EQ-5D-5L, FACT-M), concordance of imaging/ctDNA with pathology & health economics. Clinical trial information: NCT07049276 .

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