9502 Background: Patients (pts) with stage II melanoma account for ~50% of those who develop metastatic disease. Checkpoint inhibitor neoadjuvant therapy (NAT) is standard for resectable stage III melanoma (NADINA & SWOG 1801) and pathological response correlates with recurrence. Other NAT benefits include personalised prognosis, tailored subsequent management, and collection of translational specimens to explore response and resistance mechanisms. The NeoReNi II trial aimed to determine feasibility, response and safety of NAT nivo+rela in resectable stage II melanoma. Methods: Eligible pts had biopsy (partial) confirmed AJCC (v8) clinical stage IIA (T2b, T3a), IIB (T3b, T4a), or IIC (T4b) cutaneous melanoma with residual macroscopic primary disease at enrolment. IIA pts had ≥20% 5 yr recurrence risk according to Melanoma Institute Australia stage II risk calculator (melanomarisk.org.au). All pts underwent sentinel lymph node (SLN) mapping at baseline and peri-operatively, and resection (wide excision + SLN biopsy [RES]) at wk 6 following 2 doses of nivo (480 mg, IV) + rela (160 mg, IV). Pts without major pathological response (MPR) had 11 cycles (Q4W) of adjuvant nivo/rela. FDG PET/CT was performed at baseline; CT prior RES; dermoscopy and reflectance confocal microscopy (RCM) baseline, wk 3 and prior to RES. The primary endpoint was the path complete response (pCR) rate. Secondary endpoints included feasibility of NAT in stage II, RECIST response, RFS, OS, safety/tolerability, surgical outcomes, QOL. Exploratory; biomarker, dermoscopy and RCM analyses. Results: From 6 Oct 2023 to 21 Oct 2025, 20 pts were recruited and received NAT, demonstrating partial biopsy leaving residual macroscopic stage IIA-C primary melanoma was feasible. Median age 67 yrs (46-81yrs), 9 females, 8 IIA, 8 IIB and 4 IIC. 18 (90%) pts received both NAT doses. 12 (60%) pts had pCR in the primary melanoma, 1 near-pCR (MPR 65%), 1 pPR and 6 (30%) pNR. Drug treatment related adverse events (TRAE) gd ≤ 2 occurred in all 20 pts (100%); 11 (55%) with fatigue, 8 rash (40%) and 5 arthralgia (25%). 3 (15%) pts had gd 3 (secondary adrenal insufficiency, nephritis, pneumonitis). There were no gd 4 or 5 TRAEs. 1 (5%) pt had a gd 3 AE related to surgery (cellulitis). 19 (95%) pts had no change in SLN mapping from pre to RES. 2 pts with pNR in primary melanoma had postitive SLN and 1 pt with pCR had focal fibrosis within a negative SLN, suggestive of possible treatment effect. Dermoscopy showed regression in all 12 MPR (100%) pts; 11 also showed changes in RCM (collagen reorganization and imflammatory infiltrates) concordant with pathology. At datacut off (11 Dec 25) 2 pts recurred, 5 and 11 mo respectively (both pNR);1 died due to melanoma (15 mo after 1 st recurrence; 20 mo after enrolement. Positive SLNBx at pNR). Conclusions: NAT with nivo + rela in resectable stage II melanoma was feasible and induced a high rate of pCR and MPR in the primary melanoma. Clinical trial information: NCT05418972 .

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 .

INTRODUCTION:It is widely accepted that definitive surgical treatment for primary cutaneous melanoma should occur promptly, but the effects of a delay between initial diagnosis and definitive surgery remain unclear. In addition, high quality evidence is lacking for an optimal time-to-surgery from initial melanoma diagnosis. The aim of this study was to determine whether the timing of surgical treatment for Stage I & II melanoma was associated with survival outcome and whether there was an optimal time interval between melanoma diagnosis and definitive surgical treatment with respect to survival. METHODS:This was a retrospective cohort study of patients with primary cutaneous melanoma treated at a single institution between 1990 and 2015. The associations between time-to-surgery and clinical outcomes including overall survival (OS) and recurrence-free survival (RFS) were described using the Kaplan-Meier method. Multivariable Cox proportional hazard models were used to quantify the relationship between each time-to-surgery cohort and clinical outcome. RESULTS:In total 18, 242 patients were included in the analysis. Their average age was 57.5 years and 57% were male. The majority of primary melanomas were located on the trunk (32.5%) and upper limb (24.7%). Mean Breslow thickness was 1.8 mm (range 0.1-50 mm) and 64% were of superficial spreading subtype. Time to surgery was divided into ≤ 1 week, 1-4 weeks, 4-8 weeks, 8-12 weeks and > 12 weeks (n = 2453, 8882, 5906, 870 and 126, respectively). Increased delay of definitive surgical treatment was associated with poorer OS and RFS, with an OS HR of 1.23 for the 8-12 week group compared to the 1-4 week group. For RFS HR was 1.36 for the same cohorts. CONCLUSION:Definitive surgical treatment of patients with primary cutaneous melanoma between 1-4 weeks post-diagnosis with excision-biopsy was associated with improved OS & RFS compared to those treated within 1 week and greater than 4 weeks in this patient cohort treated prior to the use of adjuvant drug therapy.

TPS9610 Background: Neoadjuvant immunotherapy (NAT) with immune checkpoint inhibitors (ICI) has emerged as superior treatment for stage III melanoma, demonstrating improved outcomes compared to adjuvant therapy. The SWOG-1801 trial showed 23% EFS benefit at 2 years for NAT versus adjuvant PEMBRO (72% vs 49%, P=0.004), while the 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 pooled analysis (N=610 ICI patients) demonstrating 3-year RFS of 93% for MPR patients versus 41% for those with no pathological response. However, standard NAT with IPI (1mg/kg) and NIVO (3mg/kg) achieves MPR in only ~60% of patients. Multi-omic biomarkers can predict poor response to anti-PD-1 therapy, identifying patients who may benefit from intensified ICI therapy. The NeoIRENIE trial evaluates whether intensified ICI regimens improve pathological response in poor prognosis patients identified by biomarker prediction, treatment failure, or mucosal histology. Methods: Phase 2, non-comparative, multicenter, randomized trial with 3 cohorts (N=493, Table 1). All pts undergo therapeutic lymph node dissection/completion surgery at week 6 with path response evaluation per INMC criteria. Cohorts 1a, 2 and 3 pts without MPR receive adjuvant NIVO 480mg Q4W for 11 doses. CT, MRI brain and FDG PET/CT performed at baseline, pre-surgery and during 10-year follow-up. Tumor, blood and stool samples collected at baseline, wk 3, surgery and recurrence. Primary endpoint: path response rate in each INMC response category. Secondary endpoints: event-free survival, RECIST response rate, metabolic response rate, overall survival, safety/tolerability, surgical outcomes and quality of life. Exploratory endpoints: biomarker analyses and validation of multi-omic predictive model. Clinical trial information: NCT06999980 . Cohort N Resectable Melanoma Patient Population *Arms(Randomization) 1a 168 Stage IIIB/C/D cutaneous; biomarker-predicted poor responders; treatment-naïve A-D(1:1:1:1) 1b 154 Stage IIIB/C/D cutaneous; biomarker-predicted high responders; treatment-naïve E-F(1:1) 2 111 Stage IIIB/C/D cutaneous; recurrence within 6 months of adjuvant or NAT ICI therapy A-C(1:1:1) 3 60 Any stage mucosal melanoma; treatment-naïve A-B(1:1) * Arms: A=IPI 3mg/kg + NIVO 1mg/kg Q3W x2. B=NIVO 480mg + RELA 160mg + IPI 1mg/kg Q4W x2. C=NIVO 480mg + RELA 160mg Q4W x2. D=IPI 1mg/kg + NIVO 3mg/kg Q3W x2. E=IPI 1mg/kg + NIVO 3mg/kg Q3W x2. F=PEMBRO 200mg Q3W x2.

BACKGROUND:Discussion about sentinel lymph node biopsy (SLNB) is recommended for clinical management of patients whose melanomas meet certain criteria, however previous studies have shown relatively low uptake. It is unclear if SLNB uptake has changed over time. METHODS:A population-based study using record linkage was conducted in Australia for persons (n = 26,760) with a primary invasive melanoma diagnosis (Breslow thickness ≥0.75 mm) reported to the New South Wales (NSW) Cancer Registry between 2003 and 2018, which were linked to hospital records. We examined whether a SLNB was performed within six months of the melanoma diagnosis and factors that influenced uptake. RESULTS:Between 2003 and 2018, the annual numbers of melanoma diagnoses and SLNB procedures both increased, while the proportion of patients undergoing SLNB remained stable (between 34% and 39%) over time. The average proportion of patients who received a SLNB during the study period was 36% for those with an invasive melanoma ≥0.75 mm in Breslow thickness, 24% for Breslow thickness 0.75-1.2 mm and 43% for Breslow thickness >1.2 mm. Factors independently associated with uptake included age, Breslow thickness, body site, melanoma subtype, socio-economic status and geographic remoteness. CONCLUSIONS:There was minimal change to the proportion of patients receiving SLNB between 2003 and 2018, with the proportion remaining relatively low despite evolving clinical practice guidelines. Lower uptake among patients living outside major cities and for those with greater socio-economic disadvantage indicates possible inequities in care.

Neoadjuvant ipilimumab plus nivolumab has become standard therapy for stage III melanoma based on the NADINA trial, although long-term data are lacking. In the phase 2 PRADO cohort of OpACIN-neo, 99 patients with stage III macroscopic melanoma received this regimen. Here we report first-time 5-year survival data: 71 NCT02977052 . Five-year survival data and biomarker analysis of the PRADO extension cohort of the phase 2 OpACIN-neo trial, in which patients with high-risk stage III melanoma received neoadjuvant ipilimumab and nivolumab and underwent pathologic response-directed surgery and adjuvant therapy, show 71

BACKGROUND:Ductal carcinoma in-situ (DCIS) is a non-obligate precursor breast lesion with variable tendency to become invasive malignancy. Multiple studies have attempted to identify patient groups that could avoid radiation therapy (RT). We investigated the recent surgical management of DCIS in Australia and New Zealand (ANZ) and evaluated the likely rates of RT delivery dependent on differing low risk predictive criteria compared to actual practice. METHOD:The BreastSurgANZ Quality Audit identified patients with DCIS from 2018 to 2022. Data were analysed on multiple DCIS characteristics as well as postoperative RT recommendations. Existing potential RT avoidance characteristics, low risk classification criteria (LRCC) and RTOG 9804, were tested against the cohort. RESULTS:7790 cases were analysed with 5323 (68.33 %) undergoing breast conservation surgery (BCS). There was higher median age, lower tumour grade and smaller size in the BCS group compared to mastectomy (p < 0.001). According to the BQA, 25.38 % of patients had RT omitted. Using LRCC, 1659 patients (31.17 %) could omit RT but only 760 (45.81 %) of those patients did. When using RTOG 9804 criterion, 1287 patients (24.18 %) could omit RT but only 447 (34.73 %) did. Of 3477 patients with neither low risk classifying characteristics, 553 (15.9 %) had no RT. CONCLUSION:BCS is the preferred surgical management of DCIS in ANZ. Currently RT is omitted following BCS in 25 % of cases. Using LRCC and RTOG 9804 low risk classifiers there was inconsistent avoidance of RT, whereas RT was avoided in 15.9 % of higher risk patients. More consistent and transparent selection methods are desirable and currently genomic testing and clinico-molecular tools appears promising.

Despite advances in systemic therapies, cutaneous melanoma remains a highly deadly disease. Patients with high-risk stage III melanoma have a significant likelihood of recurrence following surgery. Although adjuvant immunotherapy has been the standard of care, recent evidence demonstrates that neoadjuvant immunotherapy is more effective for higher-risk stage III patients, showing superior survival outcomes compared with adjuvant immunotherapy. This has led to an immediate paradigm shift in clinical practice toward neoadjuvant therapy for this cohort. The NeoTrio clinical trial assessed the efficacy of sequential or combination BRAF-targeted therapy with anti-programmed cell death-1 in the neoadjuvant setting. However, research on longitudinal histopathologic changes during this treatment period remains limited. Analysis of hematoxylin and eosin slides from 60 patients across 4 matched neoadjuvant timepoints revealed dynamic changes in a number of treatment response features. Females achieved significantly higher rates of major pathologic response (P = .002) and displayed higher levels of inflammatory fibrosis (P = .04) and hyalinized fibrosis (P = .01). The presence of tertiary lymphoid structures (P = .013) and plasma cells (P = .02) at resection was significantly associated with response. Combination scoring of histopathologic features (composite score and the immune-related pathologic response [irPR] score) was significantly associated with response early during the neoadjuvant period (composite score at week 2 on-treatment, P = .03; high irPR score at week 2 on-treatment, P = .01). A high irPR score at week 2 on-treatment was also found to be significantly associated with a lower chance of recurrence at this early neoadjuvant timepoint (P = .02). Other features associated with a lower likelihood of recurrence included increased hyalinized fibrosis (P = .015) and the presence of extensive lymphocyte density score (P = .01), tertiary lymphoid structures (P = .03), and plasma cells (P = .01). This study deepens our understanding of treatment response markers and their dynamic changes during neoadjuvant therapy. It underscores the significance of these features, particularly given their early emergence and strong associations with response and recurrence.

Accurate information about locoregional breast cancer treatments following neoadjuvant systemic therapy (NST) is essential for meaningful interpretation of oncological outcomes but reporting is currently poor. We developed a core outcome set (COS) to improve the quality and consistency of locoregional outcome reporting in breast cancer NST trials. The COS was developed in three phases according to COS-STAD guidance, with the generation of a list of relevant outcome domains, prioritisation of outcomes through two rounds of an international online multi-stakeholder Delphi survey and a consensus meeting. 159 unique locoregional outcomes were classified into 101 outcome domains for inclusion in the Delphi survey, which was completed by 470 international professionals. The final 15-item COS, which included the pre-NST surgical plan, details of surgery performed following completion of treatment and details of radiation therapy, was agreed at an in-person consensus meeting. Widespread COS implementation will improve the quality and value of future NST trials.

Importance:The Melanoma Institute Australia (MIA) sentinel node (SN) metastasis risk calculator provides estimates of positivity for individual patients based on 6 standard clinicopathological parameters and the full 6-parameter model has been externally validated previously using US data. However, given its geographically widespread use, further validation is required to ensure its applicability to other populations. Objective:To further externally validate the MIA SN metastasis risk calculator and increase its precision by refinement of the 95% CIs. Design, Setting, and Participants:A retrospective multicenter cohort study was carried out using data from 4 continents, including the national Danish Melanoma Database and cancer centers in the UK (n = 3), US (n = 2), New Zealand (n = 1), Sweden (n = 1), and Brazil (n = 1). All patients aged 18 years or older who had an SN biopsy performed for an invasive primary cutaneous melanoma and data available on the following parameters: SN status, patient age at diagnosis, Breslow thickness, and melanoma subtype were included (n = 15 731). Available data were also collected on ulceration status, lymphovascular invasion, and the tumor mitotic rate. Data were collected between July 2021 and December 2023, and the analysis was conducted between January 2024 and June 2024. Main Outcomes and Measures:The primary outcome was the area under the curve (AUC) of the receiver operating characteristics for the full (6-parameter) risk prediction model. Secondary outcomes were the AUCs for each country and for the limited models (3-5 parameters), the model calibration, and the recalculated 95% CIs for the models. Decision curve analysis was performed to assess the tool's clinical utility. Results:The whole pooled cohort consisted of 15 731 patients; 4989 had all 6 parameters available. The AUC was 73.0% (95% CI, 70.6%-75.3%) in the subset with all 6 parameters available, and 70.8%, 71.5%, and 70.1% when 1, 2, or 3 optional parameters were missing, respectively. Calibration was excellent, with an intercept and calibration slope of 0.01 (95% CI, -0.02 to 0.03) and 1.03 (95% CI, 0.90-1.16), respectively. The updated 95% CI ranges were substantially tighter, with a median reduction of more than 75%. Conclusions and Relevance:This study found that the MIA SN-positivity calculator performed best with all 6 parameters and has been significantly improved (version 2), with the same risk point estimates but much tighter 95% CIs. These results demonstrated that the calculator was robust, precise, and applicable to geographically widespread melanoma populations.

BACKGROUND:Prognosis for AJCC stage III melanoma varies significantly. Adjuvant therapies, including pembrolizumab, nivolumab, and dabrafenib/trametinib, have markedly reduced recurrence risk, as shown in pivotal trials (Keynote-054, CheckMate-238, and Combi-AD). Despite these advancements, clinicians lack tools to dynamically assess recurrence risk across the patient journey. PATIENTS AND METHODS:Using pooled individual patient data (IPD) from Kaplan-Meier curves of these trials, we developed a tool to dynamically estimate relapse-free survival (RFS) and distant metastasis-free survival (DMFS) over time. Conditional survival analyses incorporated AJCC-8 substages, treatment regimens, and recurrence data. RESULTS:The analysis included 2206 patients (IIIA: 174, IIIB: 768, IIIC: 1169, IIID: 95). Of these, 861 received adjuvant anti-PD-1 therapy (pembrolizumab or nivolumab), 434 were treated with dabrafenib/trametinib, and 911 were in the observation group. Median follow-up ranged from 61 to 74 months. The dynamic calculator, hosted at the MIA website (Risk Prediction Tools: www.melanomarisk.org.au), allows input of time since treatment initiation, AJCC-8 stage, and therapy type, providing dynamic RFS and DMFS estimates up to 60 months. Case examples illustrate both baseline and conditional risks, facilitating tailored clinical discussions. CONCLUSIONS:This tool enhances accessibility to individualized, dynamic, time-specific risk estimates for patients with stage III melanoma. It serves as a practical resource for clinicians to support personalized follow-up plans, empowering informed decision-making. Updates will incorporate emerging data to maintain clinical relevance.

Neoadjuvant therapy followed by surgery is the current standard for stage III melanoma, but 60% of patients achieve a major pathological response (MPR) with good long-term outcomes. This raises the potential for modifying treatment strategies to identify patients who may safely omit surgery. Biomarkers such as circulating tumor DNA (ctDNA) and imaging modalities have shown promise in assessing therapeutic response, yet each has limitations when used independently. This study evaluates the relationship between ctDNA clearance and changes in fluorodeoxyglucose(FDG)-positron emission tomography(PET) SUVmax from pre-treatment to pre-surgery, to predict pathological response and the feasibility of non-surgical management in appropriately selected patients. In the discovery cohort, plasma ctDNA levels and computed tomography (CT) RECIST data were retrospectively analyzed in stage III melanoma patients from the OpACIN-neo trial (N=9), where two doses of neoadjuvant combination immunotherapy was administered. For validation, FDG-PET SUVmax changes and ctDNA dynamics will be assessed in two trial cohorts: NeoTrio (N=45, pembrolizumab ± dabrafenib and trametinib) and NeoPele (N=20, pembrolizumab and Lenvatinib). PET responses will be categorized into complete metabolic response (CMR), near-CMR (SUVmax reduction >90%), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). In the OpACIN-neo cohort, 7/9 (78%) patients achieved ctDNA clearance pre-surgery and RECIST partial response, with five achieving MPR and two non-MPR. Two patients with persistent ctDNA pre-surgery, which cleared post-surgery, had RECIST stable disease (one achieved MPR and one non-MPR). None of these nine patients experienced clinical recurrence. Preliminary data from the validation cohort shows that all eight patients (8/33; 24%) with CMR or near CMR achieved MPR, while 5/6 (83%) patients with PMD were pathological non-responders. CT RECIST was useful in evaluating disease burden in the discovery cohort; however, PET imaging is expected to provide greater specificity and stronger correlation with pathological outcomes. Furthermore, ctDNA clearance has demonstrated potential in identifying patients who may avoid surgery and remain recurrence-free, highlighting the complementary value of both modalities. Combining ctDNA dynamics with FDG-PET SUVmax changes can improve the prediction of pathological response to neoadjuvant therapy in stage III melanoma. This integrated approach could help identify patients who will achieve durable responses and can safely avoid surgery, supporting the development of more personalized treatment strategies. Wei Yen Chan, Li Zhou, Edward Hsiao, Jenny H. Lee, Ashleigh Stewart, Russell J. Diefenbach, George Au-Yeung, Maria Gonzalez, Andrew J. Spillane, Robyn P. Saw, Sydney Ch'Ng, Matteo Carlino, Richard A. Scolyer, Alexander M. Menzies, Georgina V. Long, Helen Rizos. Integrating ctDNA and FDG-PET dynamics to predict pathological response following neoadjuvant systemic therapy in stage III melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 731.

Objective To determine how often the sentinel node (SN) with the highest gamma count after lymphoscintigraphy was metastasis-free in SN-positive melanoma patients. Background SN biopsy (SNB) is a standard staging procedure for patients with primary cutaneous melanoma. After pre-operative radiotracer injection, intra-operative gamma counts are used, with blue dye localization, to guide SN retrieval. Sometimes only the “hottest” nodes are removed, but the reliability of predicting SN-positivity on the basis of a node's gamma count is uncertain. Methods Patients who had a SNB and in whom ≥2 SNs were removed, at least one of which contained metastatic melanoma, were identified from an institutional database. After preoperative lymphoscintigraphy using Tc-99m antimony sulfide colloid injected at the primary melanoma site, residual radioactivity in SNs was used to assist their intra-operative localization. Gamma counts were recorded for all SNs that were removed, and correlated with SN-positivity on subsequent histopathology. Results In 550 of 715 patients with complete data for analysis the “hottest” SN contained metastatic melanoma, but the remaining 165 patients (23 %) had metastatic disease exclusively in a SN with a lower gamma count. Conclusions For accurate intraoperative identification of SNs containing metastatic melanoma, gamma counts may be unreliable. The key to accuracy is high-quality lymphoscintigraphy, ideally with SPECT-CT imaging, for precise preoperative identification and localization of SNs. Use of a gamma-detection probe intraoperatively will assist in the search for these pre-operatively identified SNs, but removal of only the “hottest” node will not reliably indicate whether regional node metastasis has occurred.

e12570 Background: Accurate information about locoregional (LR) treatments following neoadjuvant systemic therapy (NST) for breast cancer is essential for interpretation of oncological outcomes, but reporting is currently poor. We aimed to develop a core outcome set (COS) to improve quality and consistency of LR outcome reporting in trials. Methods: The COS was developed in three phases according to COS-STAD guidance: 1. Generation of a long list of relevant outcome domains from a systematic literature review and stakeholder interviews. 2. Prioritisation of outcome domains using two rounds of an online Delphi survey. 3. An in-person consensus meeting to agree the final COS. Results: In total, 159 unique LR outcomes were identified from phase 1 and categorised into 101 (69 surgical/32 RT) outcomes for survey inclusion. 470 international participants (206 surgeons/144 medical oncologists/98 radiation oncologists) took part in survey Round 1, of whom 336 (71.5%) (153 surgeons/90 medical oncologists/ 77 radiation oncologists) participated in Round 2. After Round 2, 31 outcomes, combined into 15 summary outcomes, were scored as ‘consensus in’, 60 as ‘consensus out’ and 10 as ‘no consensus’. 23 professionals and 5 patient advocates attended the consensus meeting, where ‘consensus in’/’consensus out’ items were ratified, and ‘no consensus’ items discussed. A final 15 item COS for LR outcome reporting was agreed and ratified (Table). Conclusions: A COS for LR treatment reporting in NST trials has been robustly developed using an internationally collaborative approach. Widespread implemention will improve the quality and value of future breast cancer NST trials. Final COS 1 Type of breast and axillary surgery planned before starting NST 2 Proportion of patients not having surgery after NST due to disease progression, treatment toxicities or other comorbidities 3 Number/proportion of patients with a complete response to NST not having surgery to the breast and/or axilla, and how response was assessed 4 How response to NST in the breast and axilla was assessed 5 Type of initial breast and axillary surgery performed after NST 6 Proportion of patients with involved margins after initial and final surgery, and number of procedures required 7 Total number of excised and involved axillary lymph nodes, with extent of involvement 8 Further axillary treatment in patients with ypN+ disease after sentinel node biopsy/targeted axillary dissection (SLNB/TAD) 9 Proportion of patients in whom breast and/or axillary surgery was downstaged 10 Proportion of patients having radiation therapy 11 Indications for radiation therapy at trial level 12 Details of breast/chest wall and nodal targets 13 Details of dose and fractionation to breast/chest wall and nodal areas 14 Receipt of boost; indications for boost (at trial level) 15 Morbidity of locoregional treatments (short/long term as defined in protocol)

We compared health outcomes and costs of inguinal lymphadenectomy (IL) versus ilio-inguinal lymphadenectomy (I-IL) for removal of metastatic melanoma to lymph nodes of the groin in adults with stage III melanoma. A within-trial cost-utility analysis was performed alongside an international randomized trial (EAGLE-FM) with 36 months follow-up from a health system perspective. Healthcare costs were measured by using trial records, and effectiveness measured in quality-adjusted life years (QALYs). Deterministic sensitivity analyses assessed the impact of changes in costs or quality of life on overall results. Statistical bootstrapping was employed to estimate confidence intervals around the cost-utility ratio. Among 98 trial participants (IL n = 50, I-IL n = 48), with no pelvic or distant disease clinically or on PET/CT imaging, the mean life years saved for those randomized to IL showed a small but nonsignificant increase of 0.05 years compared with those in the I-IL group (2.56 vs. 2.51 years, 95

In-transit metastasis (ITM) of melanoma occurs between the primary tumor and draining lymph nodes. ITM can be managed by by adjuvant immunotherapy after resection, or immunotherapy alone when unresectable. Nevertheless, nearly half of ITM patients are resistant, which constitutes a clinical challenge. Multiomic spatial profiling offers insights into features influencing immunotherapy response, but the tumor microenvironment (TME) and biological determinants of ITM remain poorly defined. This study aims to characterize molecular and spatial TME attributes in ITM patients to improve understanding of immunotherapy response and resistance. Fifty-four samples from ITM patients treated with immunotherapy were collected at pre-treatment (PRE) and progression (PROG). Patients with a complete or partial response in the advanced setting, or recurrence-free survival over 12 months in the adjuvant setting, were classified as "responsive," and others as "resistant". Single-cell sequencing and 40-marker imaging were conducted on 18 matched tumor dissociates and FFPE samples at PRE (n=3 resistant, n=5 responsive) and PROG (n=10). Whole genome sequencing on 12 fresh frozen samples (n=4 resistant, n=8 responsive at PRE) were used to identify somatic variants. While regional immune cell proportions were broadly similar across response groups, PRE responders showed increased intra- and peri-tumoral T cells, and surprisingly, reduced CD141+ dendritic cells (cDC1s) compared to resistant patients (P=0.024). K-means clustering identified 7 spatially resolved cellular neighborhoods (CNs) across all ITMs with heterogeneous cellular constitution; nevertheless, lymphocyte-enriched CNs were more dispersed in PRE responders and interacted with other immune and tumor CNs, while remaining peripheral in PRE resistant tumors. Despite having a lower DC density, pairwise interaction analysis highlighted significant interactions between cDC1s and CD14+ macrophages in PRE responders, and between macrophages and IDO1+ CD4+ T cells or Granzyme B+ CD8+ T cells (P<0.05, log2 fold change>0.2), suggesting enhanced macrophage-driven local T cell stimulation in the absence of DCs. Single-cell transcriptomics analysis comfirmed the reduced proportion of cDC1s in PRE responders compared to resistant ITM (P=0.006). Genomic profiling revealed EREG mutations exclusively in resistant ITMs, which has been linked to immunoregulationand tumor invasion through the EGFR pathway. Ongoing analysis explores interactions among DCs, macrophages, T cells, B cells, melanocytes, and endothelial cells to elucidate TME dynamics associated with immunotherapy outcomes. These findings deepen our understanding of tumor-immune interactions in ITM patients and inform personalized immunotherapy approaches tailored to their unique TME. Xinyu Bai, Camelia Quek, Ghamdan Al-Eryani, Sonny Ramkomuth, Louise Baldwin, Jiabao Tian, Nurudeen A. Adegoke, Ismael A. Vergara, Felicity Newell, Kate Harvey, John Reeves, Andrew J. Spillane, Nicola Waddell, Serigne N. Lo, Alexander M. Menzies, Ines P. da Silva, Umaimainthan Palendira, Georgina V. Long, Richard A. Scolyer, Alexander Swarbrick, James S. Wilmott. Spatial and multiomics analysis reveals immune interactions as key drivers of immunotherapy outcomes in melanoma patients with in-transit metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 179.

Background: Pathologic response following neoadjuvant immune checkpoint blockade (ICB) in stage III melanoma serves as a surrogate marker for long-term outcomes. This may support more personalized, responsedirected treatment strategies. Methods: The OpACIN-neo and PRADO trials were phase 2 studies evaluating neoadjuvant treatment with ipilimumab and nivolumab in stage III melanoma. In OpACIN-neo, all patients underwent therapeutic lymph node dissection (TLND) without subsequent adjuvant therapy. In contrast, PRADO explored a response- directed strategy, where patients achieving a major pathologic response (MPR) omitted TLND and adjuvant therapy, while those without a pathologic response (pNR) received TLND and adjuvant therapy. Here, we provide a descriptive post-hoc comparison of 3-year survival outcomes between the non-personalized approach in OpACINneo and the response-directed approach in PRADO. Results: For patients who achieved an MPR, the 3-year recurrence-free survival (RFS) was 93 % for those without TLND versus 96 % for those with TLND (log-rank p = 0.47), and distant metastasis-free survival (DMFS) was 98 % compared to 96 % (log-rank p = 0.49), respectively. For patients with pNR, 3-year RFS rates were 64 % for those receiving adjuvant systemic therapy and 35 % for patients without (log-rank p = 0.10). DMFS rates were Conclusions: These data suggest that TLND and adjuvant therapy may be safely omitted in most patients achieving an MPR, while adjuvant systemic therapy following TLND appears to improve RFS and DMFS in patients with pNR. Although these results are hypothesis-generating and require further validation, they offer a potential foundation for developing personalized neoadjuvant immunotherapy approaches.