PURPOSE:Surrogate endpoints are widely used to support interim analyses and regulatory approval of adjuvant therapies in resected solid tumours, yet many lack formal trial-level validation. We evaluated disease-free survival (DFS) and distant metastasis-free survival (DMFS) as surrogate endpoints for disease-specific survival (DSS) and overall survival (OS) in resected melanoma and assessed the suitability of OS as primary endpoint. PATIENTS AND METHODS:A total of 10,379 patients with AJCC stage I-III melanoma treated between 2000 and 2023 at five international centres were analysed; all underwent sentinel node biopsy. Trial-level surrogacy was assessed using centre-specific log hazard ratios and restricted mean survival time at prespecified surrogate horizons (12 to 48 months), with primary endpoints truncated at 60 months. Individual-level surrogacy was evaluated using Kendall's τ. Prespecified subgroup analyses compared pT-defined IB-IIA and IIB-IIC disease. RESULTS:There were 2,418 DFS events, 1,833 DMFS events, and 1,235 melanoma-specific deaths. Trial-level surrogacy for DFS with DSS was strongest at 24 to 36 months (R2 up to 0.95). DMFS showed consistently high surrogacy for DSS from 24 to 48 months (R2 0.87 to 0.91). Correlations with OS were weak at all horizons (R2 < 0.40). Surrogacy was stage-dependent, with robust performance in pT-defined IIB-IIC disease and limited surrogacy in IB-IIA disease. CONCLUSION:DFS and DMFS are valid surrogate endpoints for DSS in resected melanoma at later time horizons, particularly in higher-risk disease. OS shows attenuated correlation with recurrence-based endpoints, limiting its utility for early endpoint evaluation in adjuvant 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.

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.

Melanoma of the ear accounts for approximately 1

Predicting which patients with American Joint Committee on Cancer (AJCC) T1–T2 melanomas will have a positive sentinel lymph node (SLN) is challenging. Melanoma Institute Australia (MIA) developed an internationally validated SLN metastatic risk calculator. This study evaluated the nomogram’s impact on T1–T2 melanoma patient management at MIA. SLN biopsy (SLNB) rates were compared for the pre- and post-nomogram periods of 1 July 2018–30 June 2019 and 1 August 2020–31 July 2021, respectively. Overall, 850 patients were identified (pre-nomogram, 383; post-nomogram, 467). SLNB was performed in 29.0

Heterogeneous resistance to immunotherapy remains a major challenge in cancer treatment, often leading to disease progression and death. Using CITE-seq and matched 40-plex PhenoCycler tissue imaging, we performed longitudinal multimodal single-cell analysis of tumors from metastatic melanoma patients with innate resistance, acquired resistance, or response to immunotherapy. We established the multimodal integration toolkit to align transcriptomic features, cellular epitopes, and spatial information to provide deeper insights into the tumors. With longitudinal analysis, we identified an "immune-striving" tumor microenvironment marked by peri-tumor lymphoid aggregates and low infiltration of T cells in the tumor and the emergence of MITF+SPARCL1+ and CENPF+ melanoma subclones after therapy. The enrichment of B cell-associated signatures in the molecular composition of lymphoid aggregates was associated with better survival. These findings provide further insights into the establishment of microenvironmental cell interactions and molecular composition of spatial structures that could inform therapeutic intervention.

TPS9613 Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cancer of the skin with viral and sun related aetiologies, and an overall mortality rate twice that observed in cutaneous melanoma (33% vs 15%). The 5-year disease specific survival is 60% to 87% for those presenting with local disease, 39% to 62% for nodal disease and 11% to 20% for metastatic disease (1). Neoadjuvant therapy (NAT) is a powerful treatment platform to rapidly assess drug activity in resectable cancers. In melanoma, using International Neoadjuvant Melanoma Consortium (INMC) path response criteria (2), a major path response to immunotherapy (≤10% viable tumor) correlates with low risk of recurrence in resectable stage III disease (Menzies et al., 2021), and improved survival and EFS when immunotherapy is given neoadjuvantly as compared to adjuvant (adj) treatment (Patel et al., 2022). In a study of NAT anti-PD1 monotherapy with nivolumab, in patients (pts) with resectable IIA-IV MCC (N=36), 47.2% of pts achieved a complete path response (pCR) (Topalian et al., 2020). Other benefits of NAT include early insight into response, feedback to pts regarding their individual response and prognosis, ability to tailor subsequent management, and collection of translational specimens to explore mechanisms of response and resistance. The Neo-MCC trial will examine whether combination PD-1 blockade plus lymphocyte-activation 3 (LAG3) checkpoint inhibition will achieve a high rate of path response with manageable toxicity in pts with resectable stage I-III MCC. Methods: Pts with histologically confirmed resectable clinical stage I (≥ 10 mm), II or III Merkel cell carcinoma, are eligible (N=20). All pts undergo complete resection (RES) at wk 6 following NAT with 2 doses of nivo (480 mg, IV) plus rela (160 mg, IV) at wk 0 and 4. Standard of care sentinel lymph node biopsy will be completed as indicated. Pts with non-path response (>50% viable tumor) or partial path response (>10% - ≤50% viable tumor) at RES will receive adj radiotherapy (RT) to all disease sites, including the draining lymph node basin. Pts with pCR (0% viable tumor) or near-pCR response (≤10% viable tumor) will receive no further adj treatment. Pts with involved RES path margins will be considered for adj RT, following multidisciplinary team consultation to determine the role of further surgery. CT, and FDG PET/CT will be performed at baseline (BL), prior to RES to measure NAT response, and 6-monthly over a 10-year follow-up period. Tumor and fecal samples are collected at BL, RES, and recurrence. Blood samples are collected at BL, wk 4, RES, and recurrence. The primary endpoint is the rate of pCR at RES after NAT using INMC response criteria. Secondary endpoints include RFS, OS, safety/tolerability, surgical outcomes, QOL, and biomarker analyses. 1. Mistry, et al., 2022. 2. Tetzlaff et al., 2018. Clinical trial information: NCT06151236 .

PURPOSEImprovements in recurrence-free survival (RFS) were demonstrated in two recent randomized trials for patients with sentinel node (SN)-negative stage IIB or IIC melanoma receiving adjuvant systemic therapy (pembrolizumab/nivolumab). However, adverse events also occurred. Accurate individualized prognostic estimates of RFS and overall survival (OS) would allow patients to more accurately weigh the risks and benefits of adjuvant therapy. Since the current American Joint Committee on Cancer eighth edition (AJCC-8) melanoma staging system focuses on melanoma-specific survival, we developed a multivariable risk prediction calculator that provides estimates of 5- and 10-year RFS and OS for these patients.METHODSData were extracted from the Melanoma Institute Australia (MIA) database for patients diagnosed with stage II (clinical or pathological) melanoma (n = 3,220). Survival prediction models were developed using multivariable Cox regression analyses (MIA models) and externally validated twice using data sets from the United States and the Netherlands. Each model's performance was assessed using C-statistics and calibration plots and compared with Cox models on the basis of AJCC-8 staging (stage models).RESULTSThe 5-year and 10-year RFS C-statistics were 0.70 and 0.73 (MIA-model) versus 0.61 and 0.60 (stage-model), respectively. For OS, the 5-year and 10-year C-statistics were 0.71 and 0.75 (MIA-model) compared with 0.62 and 0.61 (stage-model), respectively. The MIA models were well calibrated and externally validated.CONCLUSIONThe MIA models offer accurate and personalized estimates of both RFS and OS in patients with stage II melanoma even in the absence of pathological staging with SN biopsy. These models were robust on external validations and may be used in everyday practice both with (ideally) and without performing SN biopsy to identify high-risk patients for further management strategies. An online tool will be available at the MIA website (Risk Prediction Tools).

Background: The Melanoma Institute Australia (MIA) sentinel node (SN) metastasis risk-prediction online calculator[Lo2020] is now widely used around the world. The tool comprises eight models that variously use between three and six input parameters. However, the full (six-parameter) model has only been validated in the US population, the model with missing mitoses was validated for the Dutch and Swedish populations. Furthermore, some confidence intervals (CIs) of the tool are large due to uncommon input parameter values. This study further validated the tool in other populations and improved the precision of the risk estimates. Methods: Validation data were pooled from the Danish national Melanoma Database and eight cancer centres: UK(3), US(2), New Zealand(1), Sweden(1), Brazil(1). CI refinement data were pooled from this and previous validation and development cohorts. All patients had the SN result and the minimum data required for the tool (age, Breslow thickness and melanoma subtype), while the presence of ulceration, lymphovascular invasion or mitoses were included where available. The performance of the tool was assessed using C-statistics for discrimination and via a calibration plot. Re-calculation of CIs for the estimated risks was performed using the combined data from all original risk calculator development and validation cohorts. Results: The validation cohort consisted of 15,371 patients, 4,989 of whom had all six input parameters for the full model. The C-statistics were 73.0% (95% CI 70.6–75.3%) in the subset with all six parameters available, Receiver operating characteristic (ROC) curves showing the accuracy (AUC) and confidence intervals (CI) of the Melanoma Institute Australia (MIA) risk calculator to predict sentinel node positivity in the development cohort (black), n=3,477, and the international validation cohort with all six input parameters available (red), n=4,989. and 70.8%, 71.5% and 70.1% when 1, 2 or 3 optional parameters were missing. Calibration was excellent, with an intercept and calibration slope of 0.01 (95% CI -0.02–0.03) and 1.03 (95% CI 0.90–1.16), respectively. The revised CIs were substantially smaller than in the original tool, with a median reduction of over 75%. Conclusions: The results demonstrated that the MIA sentinel node risk-prediction tool performance was robust across a wide geographical range of populations. Furthermore, the precision of the models has been substantially improved with updated CIs based on a larger population sample. This study will therefore give users greater confidence in the tool's reliability in predicting the risk of SN positivity. References [Lo2020] Lo, S. N., Ma, J., Scolyer, R. A., Haydu, L. E., Stretch, J. R., Saw, R. P. M., Nieweg, O. E., Shannon, K. F., Spillane, A. J., Ch'ng, S., Mann, G. J., Gershenwald, J. E., Thompson, J. F., Varey, A. H. R., (2020), Improved Risk Prediction Calculator for Sentinel Node Positivity in Patients With Melanoma: The Melanoma Institute Australia Nomogram, Journal of Clinical Oncology, 2719–2727, 38/24, doi: 10.1200/JCO.19.02362

9523 Background: This study sought to describe the changes seen with FDG-PET following neoadjuvant immunotherapy in melanoma patients (pts), and explore associations with pathological response and recurrence-free survival (RFS). Methods: Two prospective clinical trial cohorts of stage III pts with RECIST measurable nodal melanoma were included; 1) NeoTrio, 13 pts received 2 doses of preoperative pembrolizumab alone, and 2) NeoPele, 20 pts received 2 doses of pembrolizumab and 5 weeks of lenvatinib preoperatively. All pts underwent baseline and week 6 (preoperative) FDG-PET assessments and all had surgery. PET responses were evaluated based on the modified EORTC criteria. In addition to the standard categories Complete Metabolic Response (CMR), Partial Metabolic Response (PMR), Stable Metabolic Disease (SMD), and Progressive Metabolic Disease (PMD), a novel category was established, near-CMR, where the maximum standardized uptake value (SUVmax) decreased by more than 90%. PET responses were determined while blinded to the outcome data. Pathological response was determined as per INMC criteria. Results: 33 pts were included, 67% male, median age 65 years, 48% BRAF mutant. Pathological response, PET response and correlations are shown in the Table. All 8 (24%) pts achieving CMR or near-CMR obtained major pathologic response (MPR), while the 14 pts (42%) with PMR had variable pathological outcomes (57% MPR, 21% pPR, 21% pNR). For the 6 pts with PMD, 5 (83%) had pNR and the one pts who achieved pCR recurred with brain metastases. After a median 29.9 mo follow-up (95% CI 27.0-33.1), PET response associated with RFS; those with CMR/near CMR had 100% 24mo RFS (nil recurrences to date) while those with PMR or SMD had inferior survival (79% and 80% 24mo RFS), and those with PMD the worst outcomes (17% 24mo RFS, all pts except one have recurred) (p=0.0029). The predictive value of PET and pathology for RFS was assessed using the Cox Proportional Hazards model. 12- and 24-month RFS AUCs of PET and pathology response were similar at 81.5% (95% CI: 67.7-95.3) vs. 80.9% (95% CI: 67.8-93.9), and 83.3% (95% CI: 69.1-97.5%) vs. 80.8% (95% CI: 66.6-94.9), respectively. Conclusions: FDG-PET demonstrates utility in predicting pathological response and survival with neoadjuvant immunotherapy in melanoma. PET may identify pts who are not going to be pathological responders and who have the worst survival outcomes, enabling a potential switch of neoadjuvant systemic therapy. [Table: see text]

BACKGROUND:Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS:NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS:Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS:Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

BACKGROUND The decision to perform a sentinel lymph node biopsy (SLNB) procedure can be guided by risk prediction tools. We aimed to investigate the impact of an online risk prediction tool for sentinel node metastasis on clinical decision-making. METHODS We conducted a mixed methods study using an online questionnaire and semi-structured interviews between April 2022 and March 2023. Australian clinicians and patients/carers who were using the Melanoma Institute Australia risk prediction tool were invited to participate. RESULTS Sixty-one participants completed the questionnaire (52 clinicians including 36 general practitioners of whom 32 worked at skin cancer clinics; 14 surgeons; and 9 patients/carers). More than half of the clinicians reported that the tool had influenced the number of patients they were referring for SLNB procedures: 40% reported increased referrals, 9% reported fewer referrals, and 33% reported no change. Over half (57%) of the patient/carer participants reported using the risk tool alongside a clinician for shared decision-making. Interview findings suggested that the tool made clinicians feel more confident in their clinical decision to perform or refer patients for consideration of SLNB. Clinicians found the tool useful in guiding discussions about SLNB. However, there was uncertainty in interpreting risk scores if they had wide confidence intervals and some ambiguity in clinical decision-making if the risk score did not align with the clinician’s expectations. CONCLUSION This online risk prediction tool was acceptable to clinicians and patients/carers, useful for clinical decision-making and led to increased discussion between clinicians and patients regarding the SLNB procedure.

Neoadjuvant systemic therapy (NAST) for patients with stage III melanoma achieves high major pathologic response rates and high recurrence-free survival rates. This study aimed to determine how NAST with targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) influences surgical outcomes after lymph node dissection in terms of complications, morbidity, and textbook outcomes. Patients who underwent a lymph node dissection after either NAST in a clinical trial or upfront surgery for stage III melanoma between 2014 and 2022 were identified from an institutional research database. The study included 89 NAST-treated patients and 79 upfront surgery-treated patients. The rate of postoperative complications did not differ between the NAST- and upfront surgery-treated patients (55

Background Although most melanomas drain to the more common major lymph node basins (axilla, groin, neck), rarely they drain to deep SLN locations such as intra-abdominal and intra-thoracic (including intercostal and internal mammary) sites, which pose a higher surgical risk and complexity for procurement. Our study is aimed at determining the rate of positivity and likelihood of recurrence in these nodal sites to guide management decisions for patients with truncal melanomas which drain to these ‘deep’ SLN locations. Methods Retrospective data collected between May 2008 and May 2022 including all patients with truncal melanomas who underwent lymphoscintigraphy resulting in the identification of deep SLNs in intra-abdominal and intra-thoracic sites were included. The associations between retrieval of SLNs and recurrence-free survival (RFS) and overall survival (OS) were investigated. Results 74 patients with a total of 91 SLNs located at deep sites were included. 11 (15%) patients with a total of 12 lymph nodes had SLNB of these deep nodes, all of which were intercostal nodes. Only 1 patient had a positive SLNB. In total, 24 (32%) patients developed recurrence. However, the remaining patients did not recur at the deep SLN sites. There were no statistically significant associations between retrieval of deep SLNs and RFS or OS. 3-year RFS in the patients who had deep SLNB performed was 62% compared to 54% and 50% in those who had no SLNB or incomplete SLNB, respectively (p=0.63). Conclusion In this study omitting procurement of these deep SLNs did not result in reduced RFS or OS.

BACKGROUND In phase 1-2 trials in patients with resectable, macroscopic stage III melanoma, neoadjuvant immunotherapy was more efficacious than adjuvant immunotherapy. METHODS In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or nonresponse received adjuvant treatment. The primary end point was event-free survival. RESULTS A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% in patients in the neoadjuvant group who had a major pathological response, 76.1% among those with a partial response, and 57.0% among those with a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab.

9502 Background: Lentigo maligna (LM) is a form of melanoma in situ that occurs mainly on sun exposed skin. For patients with LM who are not suitable for surgery due to location, size, patient preference or co-morbidities, topical imiquimod or radiotherapy are alternative non-surgical treatments. There are no prospective randomized controlled trial data to form the basis of any recommendations for the management of LM. This multi-institutional, international randomized phase 3 trial evaluated the efficacy and safety of imiquimod verus radiotherapy for patients with LM. The primary hypothesis was that treatment of LM with topical imiquimod would result in fewer treatment failures than radiotherapy. Methods: Patients aged > 18 years old with LM not suitable for surgery were randomly assigned (1:1) to imiquimod or radiotherapy. The primary endpoint was treatment failure within 24 months. Secondary endpoints included development of invasive disease within the area, side effects and patient-reported quality of life (QOL) assessed with validated questionnaires (skin-specific Skindex-16 and generic EQ-5D-5L). Results: Between August 2015 and November 2021, 126 patients were randomised from 8 centres (imiquimod 60, radiotherapy 58 in final analysis). The median age was 72 years and 94.9% of lesions were on the head and neck area. Median follow-up was 27 months (range 3-62 months). Six (10.5%) patients in the imiquimod group and 12 (24.0%) patients in the radiotherapy group developed recurrence within 24 months (OR 2.68, 95% CI, 0·92-7.8, p = 0.063). Median time to recurrence was not reached in either group. Treatment failure was significantly different within the subgroup of patients who had reflectance confocal microscopy (RCM) follow up of the LM (imiquimod 4/46, 8.7% radiotherapy 13/52 25.0%; OR 3.50 95% CI 1.05-11.65, p = 0.033). Only one RCM feature was associated with failure at 24 months and significantly different between treatment groups : the presence of atypical round cells at the dermal-epidermal junction (6.9 % of imiquimod failure and 27% of radiotherapy failure: p = 0.035). There were no differences between trial groups in patient-reported skin symptoms (itching, burning/stinging, pain, irritation), skin-specific emotional and functional QOL impacts, or generic QOL at any time points. Conclusions: Both imiquimod and radiotherapy are valid, well-tolerated and efficient non-surgical options for LM. There is no significant difference in the acute or long term QoL for the two treatments. Clinical trial information: NCT02394132 .

Desmoplastic melanoma (DM) is an uncommon subtype of melanoma with distinct clinicopathological features. It is classified into pure desmoplastic melanoma (PDM) when the proportion of desmoplastic melanoma is >90% of the dermally-invasive component, and mixed desmoplastic melanoma (MDM) when the proportion of desmoplastic melanoma is <90%. Studies have reported a lower sentinel lymph node biopsy (SLNB)-positivity rate in PDM compared to MDM and non-DM. As a result, some have recommended not performing SLNB in PDM patients. When PDM is identified in a partial biopsy of a melanoma, there is a risk that sampling bias may under-recognise MDM, but to the best of our knowledge this has not been previously assessed or quantified.The aim of this study was to assess the concordance of the proportion of desmoplastic melanoma in an initial partial biopsy of PDM with the proportion in the entire tumour following complete excision, in patients with cuta-neous melanoma. A secondary aim was to determine how frequently this potentially resulted in a patient not receiving a SLNB.Seventy-eight cases of cutaneous melanoma were identi-fied from the Melanoma Institute Australia (MIA) database and 23 cases from the Memorial Sloan Kettering Cancer Centre (MSKCC), where an initial biopsy contained PDM and a subsequent wide excision had residual invasive melanoma. Clinicopathological features were analysed in all patients, including whether a SLNB was performed, the results of SLNB, and any subsequent recurrence. Ninety percent (91/101) of cases were still classified as PDM in the complete wide excision specimen while 10% (10/101) of cases were reclassified as MDM, which was a significant change in classification of final desmoplastic melanoma subtype (p<0.001). The proportion of desmo-plastic melanoma was also significantly different between the initial and excisional biopsies (p=0.004). For ty-eight (48/101) patients had a SLNB, of which two (4.5%) were positive for metastatic melanoma; both cases were PDM in the excision specimen. Of the 10 cases demonstrating MDM in the excision specimen, the initial biopsy was a punch biopsy in six cases, shave biopsy in two cases and subcutaneous tissue was sampled in two patients (one punch biopsy, one incisional biopsy). Four of these 10 patients underwent SLNB which was negative in all cases. Twenty-two patients developed recurrence in the follow-up period (median 30 months, range 1-192 months), three with MDM in their excision specimen. One patient did not have a SLNB and developed regional lymph node recurrence.In this study there was a 10% risk that the percentage of desmoplastic melanoma in an initial biopsy of PDM was not representative of the entire lesion, resulting in reclas-sification as MDM in the excision specimen. If a SLNB is not performed in such cases, a positive SLNB may be missed (one patient in our study) which could impact treatment options for the patient. We recommend caution in not offering a SLNB in the setting of an initial biopsy of PDM if the biopsy is small compared with the overall lesion. If a SLNB is not procured at the time of wide excision in such cases, the SLNs should still be mapped by lymphoscintigraphy to facilitate careful follow up and to enable earlier detection and treatment of nodal disease.