Surgical de-escalation in high-risk resectable melanoma with major pathologic response (MPR) after neoadjuvant immune checkpoint inhibition (ICI).

9574 Background: Neoadjuvant ICI renders MPR in 50-60% of resectable Stage III/IV melanoma. Early data illustrated the ability to de-escalate surgery in cases of MPR in the index lymph node (ILN). However complete lymph node dissection (CLND), a procedure with considerably morbidity, remains the standard of care. Real-world data demonstrating the ability to de-escalate surgery while maintaining disease control, can inform optimal practice. Methods: In our retrospective study performed at two academic institutions (MGB/DFCI), patients with resectable, macroscopic Stage III/IV cutaneous melanoma treated with neoadjuvant ICI were identified. Pre-treatment fiducial placement was routinely performed in cases of macroscopic nodal disease to facilitate index node excision (INE). Data pertaining to treatment course, anti-tumor outcomes, and safety were collected. Signatera ctDNA was evaluated as a non-invasive biomarker of early response. Results: From 2020-2025, 126 patients received neoadjuvant ICI: 60 anti-PD-1 monotherapy, 62 ipilimumab/nivolumab (I/N) and 4 nivolumab/relatlimab (N/R). The majority had macroscopic stage III disease (95%) and completed the full neoadjuvant course (86%). Ten patients (8%) did not undergo surgery (clinical CR, n = 3; toxicity, n = 1; progression, n = 6). Of the 116 (92%) who underwent surgery; 43 (37%) had an upfront TLND; 52 (45%) had an INE and 21 (18%) excision of N1c or M1a disease. After INE (n = 52), reflex CLND was performed in 7 (13%) all due to non-MPR. The MPR of the total cohort was 54% (n = 63) with a pCR rate of 51% (n = 59). The MPR/pCR rate was similar between ICI regimens. In the MPR cohort, 35 underwent an INE only whereas 17 underwent CLND; the remainder had excision of N1c/M1a disease. Post-operatively, 15 required drain placement, of whom 2 had an INE. Adjuvant ICI was utilized in 23 patients, the majority receiving peri-operative pembrolizumab (n = 20). After a median follow-up of 15.5mths (3.2-68.7mths), in those who underwent surgery, 20% (23/116) have recurred; 3 with a MPR (INE, n = 1; excision, n = 2). Of these, 2 were distant metastases with no nodal recurrence. Notably, 33 patients had pre-operative ctDNA results (Signatera). At the time of surgery, ctDNA was undetectable in the majority of MPR patients (19/20), while the majority of non-MPR patients remained detectable (8/13). Pre-surgery ctDNA assessment prognosticated RFS for the 20 patients who were detectable at baseline (p = 0.035) with ctDNA clearance associated with both MPR and improved RFS. Updated clinical and ctDNA data will be presented at the meeting. Conclusions: Similar to published data, patients with a MPR had low rates of recurrence, with no difference between those who underwent INE compared to upfront CLND. Pre-operative ctDNA levels, particularly ctDNA clearance, correlate with clinical outcomes and may inform de-escalation strategies.