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).

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 & 49% for adjuvant PEMBRO (P=0.004), while the phase 3 NADINA trial confirmed superiority of NAT IPI/NIVO over adjuvant NIVO (2-year RFS 83.7% vs 57.2%, HR 0.32). Pathological response, particularly major pathological response (MPR; ≤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 & improved quality of life compared to therapeutic lymph node dissection (TLND). However, PRADO was a single-arm proof-of-concept study. An international survey of 117 melanoma experts showed 71% believe a phase 3 randomized controlled trial is needed to change practice. The MSLT-3 trial will definitively establish whether ILN RES is non-inferior to standard TLND for MPR pts. Methods: This phase 3, international, multicenter, randomized, non-inferiority trial will enroll approximately 1,574 pts with resectable stage IIIB-D cutaneous melanoma to identify 496 with MPR following NAT. Eligible pts must have cytologically/histologically confirmed resectable stage IIIB-D melanoma with at least one macroscopic lymph node in groin, axilla or neck basins. All pts are randomized 1:1 to ILN RES or TLND, stratified by continent/region, AJCC stage, & NAT regimen. Prior to NAT, all pts undergo radiological placement of a marker in the largest metastatic lymph node. Pts receive NAT per institutional standard of care (minimum one PD-(L)-1 checkpoint inhibitor, maximum 6 weeks duration) followed by surgery at weeks 6-9 according to randomized arm. Pathological response is assessed per INMC criteria. Pts with MPR in the ILN arm undergo surveillance only; 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 .