PURPOSE:Stage IIB/IIC melanoma has a high risk of recurrence after resection. Combined BRAF/MEK inhibitor therapy showed benefit in resected high-risk stage III and advanced melanoma. The objective of this study was to investigate its role in stage IIB/IIC. METHODS:Adult patients with resected stage IIB/IIC cutaneous melanoma which had a BRAF V600E/K mutation were randomized 1:1 to receive encorafenib (enco) 450 mg QD + binimetinib (bini) 45 mg BID orally for one year or placebo. The study planned to randomize 815 patients and was designed to demonstrate superiority regarding recurrence-free survival (RFS). Following a premature termination of accrual, the study was amended with safety as the primary endpoint and RFS as secondary endpoint. RESULTS:Between June 9, 2022, and October 9, 2023, 339 patients were screened for a BRAF mutation and 110 randomized. Data cutoff was 19 Nov. 2024, after the last patient discontinued study participation. Among randomized patients, 87 (79%) had a BRAF V600E mutation, and 39 (35%) AJCC8 stage IIC. Median follow-up was 12 and 7 months for enco/bini and placebo arms, respectively. Among 54 patients who initiated enco + bini, grade ≥ 3 treatment-related adverse events (AE) occurred in 13 (24%) patients, and 18 (33%) patients had an AE leading to permanent treatment discontinuation. RFS at 12 months was 86% (95% CI: 65-95%) in the enco + bini and 70% (95% CI: 46-85%) in the placebo arm, distant metastasis-free survival at 12 months was 92% (95% CI: 77-97%) for enco + bini and 82% (95% CI: 55-93%) for placebo. CONCLUSION:EORTC 2139 - Columbus-AD demonstrated a consistent and manageable safety profile and encouraging efficacy results for the combination of enco and bini in resected stage IIB/C BRAF V600E/K-mutated cutaneous melanomas.

Background Circulating tumor DNA (ctDNA) is a promising biomarker in melanoma, with higher sensitivity for tumor burden detection than conventional diagnostics. While well established in research, clinical routine implementation remains pending. Key global questions concern optimal clinical applications and barriers to adoption. Methods A web-based survey of 116 members of the Melanoma World Society Study Group assessed international expert opinions on ctDNA utility across predefined clinical scenarios. The questionnaire included 18 general questions on ctDNA use and 5 clinical vignettes with de-identified patient data and retrospectively obtained ctDNA results. Results ctDNA was rated most valuable for detecting minimal residual disease (mean score 3.63), surveillance of recurrent disease (3.85), and stage IV melanoma (3.82), with limited utility in early stages. Experts considered ctDNA superior to S100 and LDH for early relapse detection and identifying progressive disease. Most participants (80%) agreed that ctDNA correlates with radiographic response, and 82% favored its integration into routine follow-ups. In urgent high-tumor-burden settings, 82.8% would initiate BRAFi/MEKi therapy based on ctDNA if tissue analysis was pending, and 93.9% if unavailable. For central nervous system lesions, 62% did not support blood ctDNA, while 66% considered cerebrospinal fluid valuable. Pragmatic approaches with small to mid-size targeted panels and short turnaround times were preferred. Major barriers included the need for prospective trials (85%), standardized guidelines (83%), and reimbursement policies (82%). Conclusion Key opinion leaders regarded ctDNA as a valuable adjunct selected melanoma scenarios. Validation through prospective studies, guideline development, and reimbursement frameworks are essential for broader clinical implementation.

TPS9601 Background: Immune checkpoint inhibitors (ICIs), including anti-PD-1 antibodies, reverse tumor induced immune suppression and promote effective anti-tumor T-cell responses. They have drastically improved outcome in advanced melanoma therapy, yielding durable improvements in progression-free survival (PFS) and overall survival (OS). Although adding anti-CTLA-4 or anti-LAG-3 enhances efficacy beyond anti-PD-1 alone, these approaches do not directly target dominant myeloid-mediated resistance mechanisms within the tumor microenvironment, and new agents targeting this axis are needed. EIK1001, a TLR7/8 dual-agonist, activates myeloid and plasmacytoid dendritic cells to stimulate innate inflammation and adaptive immunity. Across multiple studies, EIK1001 has been well tolerated and has demonstrated clinical activity both as monotherapy and in combination with ICIs. Methods: TeLuRide-006 (NCT#06697301) is a global, multicenter, randomized, double-blind, adaptive Phase 2/3 trial of EIK1001 or placebo, in combination with pembrolizumab (pembro), as first-line therapy for participants (pts) with advanced cutaneous melanoma. Approximately 740 pts will be randomized, including a dose-optimization (DO) stage in which pts are randomized 1:1:1 to two EIK1001 dose levels or placebo, each administered with pembro, followed by Phase 2/3 expansion evaluating the selected EIK1001 dose versus placebo, with pembro. Interim analyses will guide progression from DO to Phase 2 and subsequently to Phase 3. EIK1001 or placebo is administered IV QW until the end of Week 27 then Q3W; while pembro is administered IV Q3W. Pts are stratified by prior anti-PD-1 adjuvant therapy, LDH level, and BRAF mutational status. Key eligibility criteria include patients ≥12 years (with country-specific variations), life expectancy ≥3 months, unresectable Stage III or Stage IV melanoma, known BRAF V600 status, at least one RECIST v1.1–measurable lesion, and no prior or current pneumonitis/interstitial lung disease. Primary objectives are to assess the efficacy and safety of two EIK1001 doses with pembro in DO, and to compare PFS (RECIST v1.1 by blinded independent central review [BICR]) and OS between the selected EIK1001 dose and placebo in combination with pembro. Secondary objectives include safety and tolerability of either EIK1001 dose with pembro, objective response rate and duration of response per RECIST v1.1 by BICR. Exploratory objectives include time to response, EIK1001 exposure-response relationships, and health-related quality of life. This study enrolled (randomized) its first participant on 5/21/2025 and is activated at 91 sites in 22 countries at the time of abstract submission.

QuestionIs prior adjuvant pembrolizumab associated with the risk of developing subsequent cutaneous malignant neoplasms in patients with high-risk stage II melanoma?FindingsIn this secondary analysis of 976 participants in the randomized, double-blind, phase 3 KEYNOTE-716 study, the incidence of new primary melanoma was similar between participants treated with adjuvant pembrolizumab and placebo, whereas nonmelanoma skin cancers were more common with placebo. The study also found that the recurrence-free survival benefit associated with pembrolizumab remained after accounting for new primary melanomas, and immune-mediated severe skin reactions occurred infrequently and were manageable.MeaningThese findings suggest that patients with resected stage IIB or IIC melanoma are at risk of developing new skin cancers, supporting the use of adjuvant pembrolizumab for high-risk stage II melanoma. This secondary analysis of a randomized clinical trial assesses new skin cancers, recurrence-free survival with new melanomas considered events, and immune-mediated severe skin reactions among patients receiving pembrolizumab or placebo for stage II melanoma. ImportancePatients with melanoma are at risk of developing subsequent cutaneous malignant neoplasms, and the effect of prior immunotherapy is unknown.ObjectiveTo analyze new skin cancers in participants with high-risk stage II melanoma treated with adjuvant pembrolizumab or placebo.Design, Setting, and ParticipantsThe multicenter double-blind, phase 3 KEYNOTE-716 randomized clinical trial enrolled 976 participants 12 years or older with completely resected stage IIB or IIC cutaneous melanoma between September 23, 2018, and November 4, 2020. Follow-up was completed on February 16, 2024. This analysis was not prespecified in the trial protocol.InterventionsParticipants were randomly assigned to receive intravenous pembrolizumab, 200 mg (2 mg/kg for pediatric participants), or placebo, every 3 weeks for no more than 17 cycles.Main Outcomes and MeasuresSecondary analyses of incidence and time to diagnosis of new melanoma or other cutaneous malignant neoplasm, sensitivity analysis of recurrence-free survival (RFS) with new primary melanoma counted as an event, and incidence of immune-mediated severe skin reactions.ResultsA total of 976 participants were assigned to treatment (487 to pembrolizumab and 489 to placebo), of whom 589 (60.3%) were male (median age at diagnosis, 61 [IQR, 52-69] years). The median follow-up was 52.8 (range, 39.4-64.8) months. In the pembrolizumab group, 37 participants (7.6%) were diagnosed with new skin cancers (median time to diagnosis, 168.0 [range, 1.0-1182.0] days); 12 (2.5%) had new invasive primary melanoma, 6 (1.2%) had new primary melanoma in situ, 19 (3.9%) had basal cell carcinoma (BCC), and 9 (1.8%) had cutaneous squamous cell carcinoma (cSCC). In the placebo group, 56 participants (11.5%) were diagnosed with new skin cancers (median time to diagnosis, 177.0 [range, 1.0-1043.0] days); 9 (1.8%) had new invasive primary melanoma, 9 (1.8%) had new primary melanoma in situ, 26 (5.3%) had BCC, and 17 (3.5%) had cSCC. Median RFS with new primary melanoma counted as an event was not reached with pembrolizumab and was 59.2 months (95% CI, 53.9 months to not reached) with placebo (hazard ratio, 0.65; 95% CI, 0.52-0.80); 48-month RFS was 68.7% and 56.5%, respectively. Immune-mediated severe skin reactions occurred in 16 of 483 participants (3.3%) in the pembrolizumab group and 3 of 486 (0.6%) in the placebo group (grade 3 or 4: 14 [2.9%] vs 3 [0.6%]).Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, the incidence of new primary melanoma was not different between groups, whereas nonmelanoma skin cancers were more common with placebo. The RFS benefit of pembrolizumab remained after accounting for new primary melanomas. Immune-mediated severe skin reactions occurred infrequently and were manageable. These findings support the use of adjuvant pembrolizumab in high-risk stage II melanoma.Trial RegistrationClinicalTrials.gov Identifier: NCT03553836

Intravenous administration of anti-CTLA4 with anti-PD1 provides durable tumour responses but causes severe treatment-related adverse events in patients with cancer1. Intratumoural administration at lower doses but high local concentrations could enhance antitumour efficacy while minimizing systemic exposure and toxicity. Here we report the randomized multicentre phase 1b NIVIPIT trial (ClinicalTrials.gov: NCT02857569 ), which enrolled 61 patients with untreated metastatic melanoma, randomly assigned 2:1 to receive intravenous nivolumab (anti-PD1; 1 mg kg-1) combined with either intratumoural ipilimumab (anti-CTLA4; 0.3 mg kg-1) or intravenous ipilimumab (3 mg kg-1). The primary end-point was met with significantly lower incidence of grade 3 or 4 treatment-related adverse events at 6 months in the intratumoural versus intravenous arm (22.6% versus 57.1%), equivalent to anti-PD1 monotherapy. RECIST (response evaluation criteria in solid tumours) best objective response rate reached 65.7% for anti-CTLA4 injected lesions and 50% for uninjected lesions, confirming the relationship between intratumoural exposure to anti-CTLA4 and efficacy. Baseline tumour immune profiling revealed that protumoural activated regulatory T (Treg) cells and M2 macrophages predict durable clinical benefit, regardless of the anti-CTLA4 administration route. A decrease in activated intratumoural Treg cells occurred only in patients who showed durable clinical benefit, who also presented high intratumoural Fcγ receptor (FcγR) expression. Our results provide a rationale for intratumoural anti-CTLA4 strategies in oligometastatic and early-stage cancers and indicate that high intratumoural activated Treg cell and FcγR+ M2 macrophage numbers are prerequisites for efficacy of combined anti-CTLA4 and anti-PD1.

This guideline was developed in close collaboration with multidisciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF) and the European Organization for Research and Treatment of Cancer (EORTC). Recommendations for the diagnosis and treatment of melanoma were developed on the basis of systematic literature research and consensus conferences. Cutaneous melanoma (CM) is the most dangerous form of skin tumor and accounts for 90% of skin cancer mortality. The diagnosis of melanoma can be made clinically and must always be confirmed by dermoscopy. If melanoma is suspected, a histopathological examination is always required. Sequential digital dermoscopy and whole-body photography can be used in high-risk patients to improve the detection of early-stage melanoma. If available, confocal reflectance microscopy can also improve the clinical diagnosis in special cases. Melanoma is classified according to the 8th version of the American Joint Committee on Cancer classification. For thin melanomas up to a tumor thickness of 0.8 mm, no further diagnostic imaging is required. From stage IB, lymph node sonography is recommended, but no further imaging examinations. From stage IIB/C, whole-body examinations with computed tomography or positron emission tomography CT in combination with magnetic resonance imaging of the brain are recommended. From stage IIB/C and higher, a mutation test is recommended, especially for the BRAF V600 mutation. It is important to perform a structured follow-up to detect relapses and secondary primary melanomas as early as possible. A stage-based follow-up regimen is proposed, which in the experience of the guideline group covers the optimal requirements, although further studies may be considered. This guideline is valid until the end of 2026.

After its practice-changing success, immune checkpoint inhibitors (ICI) have possibly reached a treatment plateau and novel drug candidates are currently being investigated to overcome resistance to ICI including patients who never responded to ICI. With some of the recent failures of novel checkpoint inhibitors, there has been a shift of focus to other modalities such as antibody drug conjugates and radiopharmaceuticals. And skepticism towards novel agents in immunotherapy, including cell therapies, has yet to be replaced by renewed optimism. The combination of ICI with anti-angiogenic agents appeared as a promising new approach to avoid or revert resistance to ICI. Following these encouraging observations, bispecific agents have followed suit and are emerging as possible advancements. Targeting other immune cells, such as macrophages and epigenetic modulation hold additional promise to overcome resistance. Finally, the recent progress in vaccine development may provide a novel approach to selectively activate the global immune system and re-direct its components to reject tumors. Overall, it appears that the full potential of immunomodulators has not yet been fully achieved. Thus, improving the understanding of cancer biology, the interaction with the immune system and identifying patient subsets who might benefit from resetting their immune system continue to be opportunities for oncology drug development.

Background Metabolic conditions, such as obesity and type 2 diabetes mellitus (T2DM), cause changes in immune function that may influence immunotherapy effectiveness and immune-related adverse events (irAEs). Objectives To investigate the prognostic and predictive effects of BMI and T2DM and investigate the effect of BMI on toxicity using data from the EORTC 1325/KEYNOTE-054 randomised controlled trial. Methods Pembrolizumab (n=514) was administered every three weeks for 1 year and prolonged recurrence-free survival (RFS) compared to placebo (n=505) among patients with resected high-risk stage III melanoma. Here, we used multivariate Cox regression to investigate associations of BMI and T2DM with RFS, and Fine and Gray regression to investigate the association of BMI with the cumulative incidence of irAEs. Results BMI had an approximately U-shaped association with RFS (p=0.004) in both treatment arms combined. The RFS hazard ratios (HR)s for BMIs of 20, 30 and 35kg/m2 (compared to 25kg/m2) were 1.28 (95% CI 1.05-1.56), 0.96 (95% CI 0.88-1.06) and 1.14 (95% CI 0.98-1.34), respectively. There was no evidence that BMI was associated with pembrolizumab effectiveness (p=0.20) or the cumulative incidence of irAEs (p=0.74). T2DM was not associated with RFS (HR 1.01, 95% CI 0.73-1.40) in both arms combined and there was no evidence of an association between T2DM and pembrolizumab effectiveness (p=0.83). In summary, in patients with resected high-risk stage III melanoma, BMI was associated with RFS in patients overall and within each treatment group. Conclusions BMI appeared to confer a prognostic effect but was not predictive of pembrolizumab effectiveness regarding RFS. BMI was not related to irAEs among patients receiving pembrolizumab, while T2DM was not associated with RFS irrespective of treatment.

LBA9501 Background: Resected stage IIB/IIC melanoma has a high risk of recurrence. While, for decades, surgery was the only option for high-risk stage II disease in most countries, adjuvant therapies now exist. Anti-PD-1 significantly improve recurrence-free survival (RFS) vs. placebo in patients with fully resected stage IIB/IIC melanoma. Combined BRAF&MEK inhibitor therapy showed benefit in high-risk stage III & advanced disease, but its role in patients with fully resected BRAF -mutated stage IIB/IIC melanoma is unknown. Encorafenib and binimetinib could be considered a valuable alternative with a lower risk of chronic toxicities. Methods: Adult patients with fully resected stage IIB or IIC cutaneous melanoma who harbored a BRAF mutation V600E or K were randomized 1:1 to receive encorafenib (enco) 450 mg QD + binimetinib (bini) 45 mg BID orally for one year or placebo. The study planned to randomize 815 patients. It was designed to demonstrate superiority regarding the primary endpoint RFS defined as time from randomization to the earliest of recurrence, new melanoma that was either ulcerated, thick or requiring a treatment other than surgery, or death with a power of 97% to detect a hazard ratio (HR) of 0.55 and 91% to detect a HR of 0.6 with a level of statistical significance of 0.025 for a one-sided log-rank test. Following a premature termination of accrual, the study was amended to become a randomized trial with safety as the primary and RFS a secondary endpoint. Results: Between June 9, 2022, and October 9, 2023, 339 patients were screened for a BRAF mutation and 110 were equally randomized between enco+bini and placebo arms. Median age was 59 yrs and 54% were male. Data cutoff was on 19 Nov. 2024, after the last patient was discontinued from the study. Among randomized patients, 87 (79%) had BRAF V600E and 23 (21%) V600K mutation, 71 (65%) AJCC8 stage IIB and 39 (35%) IIC. Median follow-up was 12 and 7 months for enco+bini and placebo arms. Among 54 patients who initiated enco+bini, grade ≥3 treatment-related adverse events (AE) occurred in 13 (24%) patients, and 18 (33%) patients had an AE leading to permanent treatment discontinuation. A serious treatment-related adverse event occurred in 1 patient. No patients died. In the enco+bini and placebo arm, respectively, 4 and 9 patients had an RFS event and 3 and 5 developed distant metastases. Descriptive RFS at 12 months was 86% (95% CI: 65-95%) in the enco+bini and 70% (95% CI: 46-85%) in the placebo arm, Distant Metastasis-Free Survival (DMFS) at 12 months was 92% (95% CI: 77-97%) for enco+bini and 82% (95% CI: 55-93%) for placebo arms. Conclusion: EORTC 2139 - Columbus-AD demonstrated a consistent safety profile for enco+bini. Descriptive analyses of efficacy show encouraging results of the combination of enco+bini for adjuvant treatment of stage IIB/C BRAF V600E/K cutaneous melanoma. Clinical trial information: NCT05270044 .

The cancer problem is expanding, particularly in low‐ and middle‐income countries (LMICs). Preventive measures can reduce the incidence by 40–50%, and cure rates have increased during the past decades in a number of cancers. However, optimizing prevention programmes and increasing cure rates of cancer remain significant research challenges. The main focus of the conference was on P4 Cancer Medicine (Predictive, Preventive, Personalized and Participatory), a comprehensive strategy encompassing Health‐Related Quality of Life (HRQoL) research, aiming to enhance the well‐being of patients and individuals at risk. Addressing the cancer problem requires two key elements: translational cancer research and the development of relevant infrastructures. A Comprehensive Cancer Centre (CCC) acts as an innovation hub by integrating high‐quality, multidisciplinary therapy and care, with healthcare‐dependent prevention, research, and education. The United States has been at the forefront, providing quality‐assured CCCs and the Cancer Moonshot for strategic cancer research. The EU has followed with the European Research Council for basic research, the European Innovation Council to boost disruptive innovation, and two EU initiatives on cancer, Europe's Beating Cancer Plan (EBCP) and the Mission on Cancer. The increasing complexity of cancer biology and technologies presents both a research challenge and a healthcare demand. For most patients, a CCC is not available. A critical discussion focused on quality assurance of healthcare outside the catchment area of a CCC and involving patients in clinical research. The strategic deployment of resources to support collective healthcare efforts and research aimed at reducing the cancer problem was discussed with representatives from the United States, EU, Africa, China, India and Taiwan. Analyses of translational cancer research have revealed important gaps in implementing innovations, assessment of clinical effectiveness, HRQoL, outcome and health economics research. The increased release of new anticancer agents over the last 25 years, accompanied by insufficient information on clinical benefits, presents both an economic and ethical problem. Direct healthcare costs have increased due to expenses for anticancer agents for the treatment of patients with incurable diseases. Evidence‐based treatment based on HRQoL research is an unmet need. Basic/preclinical research aimed at increasing the cure rate should identify new, broader targets for therapy and develop extended diagnostic technologies for stratifying patients, to inform innovative clinical trials. Present research strategies convert cancer to a chronic disease, a growing burden for the healthcare systems. The increasing complexity of cancer biology and technology, the growing need for translational cancer research, and the demand for supporting infrastructures underscore the importance of international collaborations between CCCs. However, funding for cancer research is not currently aligned to reduce the cancer problem. While public funding for cancer research doubled between 2005 and 2024, the pharmaceutical industry's spending on cancer research increased tenfold. Increasing funding by public and non‐profit funding organizations is mandatory. Education is another significant need, but it is currently fragmented and underfunded. The last session of the conference summarized the strategies in a Statement with a strong emphasis on global collaboration addressing the growing cancer burden and pronounced inequalities. Expanding partnerships and fostering innovative, multidisciplinary approaches to cancer prevention, therapeutics/care, as well as research, are not just urgent but essential steps towards reducing incidence, increasing cure rates and enhancing the well‐being of cancer patients. Data‐driven cancer medicine is currently under development, and modern communication technologies for diagnostics may facilitate interactions across geographical distances. A global cancer research agenda can become a model of solidarity, sustainability, and ethical responsibility.

Previous results from the KEYNOTE-716 trial demonstrated significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) with adjuvant pembrolizumab versus placebo in patients with resected stage IIB or IIC melanoma. We present a post hoc analysis of efficacy according to primary tumor location. KEYNOTE-716 (NCT03553836) is a randomized, multicenter, double-blind, phase III study. Patients aged ≥ 12 years with newly diagnosed, resected stage IIB or IIC melanoma (sentinel node-negative) were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. This post hoc analysis evaluated RFS and DMFS by primary tumor location of the head/neck, trunk, or extremities. Overall, 976 patients were assigned to pembrolizumab (n = 487) or placebo (n = 489). Median follow-up was 39.4 months (range 26.0–51.4). The hazard ratios HRs (95

Background: The gut microbiome plays a pivotal role in regulating immunity. Gastric acid suppressants (GAS) are known to alter the gut microbiome and might therefore modify response to immunotherapy in cancer patients. We estimated associations of GAS with recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in the EORTC 1325/KEYNOTE-054 trial. Methods: Patients with resected stage III melanoma were randomized to receive 200 mg of pembrolizumab or placebo. Pembrolizumab prolonged RFS and DMFS (reported elsewhere). We used Cox models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for the association between GAS at baseline, and RFS and DMFS, overall and by treatment arm. Results: Out of 1019 randomized patients, 109 (10.7 %) used GAS at baseline. We did not find a prognostic importance for RFS (HR 1.06, 95 % CI 0.79-1.42) or DMFS (HR 1.05, 95 % CI 0.77-1.43), neither a predictive importance (HR for RFS in the pembrolizumab arm: 1.02 (95 % CI 0.66-1.56) and 1.09 (95 % CI 0.74-1.62) in the placebo arm (p = 0.81); corresponding HRs for DMFS: 1.17 (95 % CI 0.75-1.82) and 0.95 (95 % CI 0.62-1.48) (p = 0.52)). Conclusion: GAS showed no impact on RFS or DMFS in patients with stage III melanoma receiving adjuvant pembrolizumab or placebo.

Background: Cancer immunotherapy has revolutionized melanoma treatment, but the high number of non- responders still emphasizes the need for improvement of therapy. One potential avenue for enhancing antitumor treatment is through the modulation of coagulation and platelet activity. Both have been found to play an important role in the tumor microenvironment, tumor growth and metastasis. Preclinical studies indicate a beneficial effect, clinical data has been inconsistent. Methods: We examined a cohort of advanced, non-resectable melanoma patients (n = 2419) derived from the German prospective multicenter skin cancer registry ADOReg, who were treated with immune checkpoint inhibitors (ICI). The patients were classified based on whether it was documented that they received platelet aggregation inhibition (PAI) (n = 137) (acetylsalicylic acid (ASA) or clopidogrel), anticoagulation (AC) (n = 185) (direct oral anticoagulation (DOAC), phenprocoumon, heparins) at the start of ICI or no antithrombotic medication (n = 2097) at any point during ICI treatment. The study endpoints were best overall response (BOR), progression-free survival (PFS) and overall survival (OS). Results: A significantly improved PFS was observed in patients documented to receive ASA (15.1 vs 6.4 months, HR 0.67, 95 % CI: 0.5 to 0.88, p = 0.0047) as well as in patients to receive AC (15.1 vs. 6.4 months, HR 0.7, 95 % CI: 0.53 to 0.91, p = 0.01) compared to patients for whom no antithrombotic medication was documented. Multivariate analysis of OS showed significant risk reduction in patients who received DOAC (HR 0.68, 95 % CI: 0.49 to 0.92, p = 0.0170) or phenprocoumon (HR: 0.44, 95 % CI: 0.19 to 0.85, p = 0.0301). Conclusion: Our study indicates a positive prognostic effect of anticoagulant and antiplatelet concomitant medication in melanoma patients receiving ICI. Further studies are needed to confrim the cancer-related benefit of adding anticoagulation or platelet inhibition to ICI treatment.

TPS9604 Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor response. Significant advances for the treatment of advanced melanoma have been made using ICIs, with overall survival (OS) benefit conferred by ICI monotherapy. While encouraging results have been observed with combinations of ICIs, no α-controlled, statistically significant OS benefit of combinations over monotherapy has been demonstrated in Phase 3 studies. Despite these advances, 5-year survival for advanced disease is only 15 to 20%, motivating development of new therapies. EIK1001 is a TLR7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity, distinct from effects on checkpoint proteins, enhances antitumor T-cell activity alone or in combination with ICIs. Methods: TeLuRide-006 (NCT#06697301) is a global, multicenter, randomized, double-blind, adaptive Phase 2/3 study of EIK1001 or placebo in combination with pembrolizumab (pembro) as first-line therapy in participants (pts) with advanced melanoma. This study includes dose-optimization (DO), in which pts are randomized 1:1:1 to receive 1 of 2 doses of EIK1001 or placebo in combination with pembro, followed by adaptive Phase 2/3 expansion at the Selected Dose of EIK1001 + pembro or placebo + pembro. Interim analyses will determine whether the study advances from DO to Phase 2 to Phase 3. EIK1001 or placebo is administered intravenously QW until the end of Week 27 then Q3W. Pts are stratified by prior anti-PD-1 adjuvant therapy, LDH level, and BRAF mutational status. Key eligibility criteria: pts ≥ 18 years of age with a life expectancy of ≥ 3 months, Stage 3 (unresectable) or Stage 4 metastatic melanoma, known BRAF V600 mutational status (or consent to BRAF mutation testing), ≥ 1 measurable lesion by RECIST v1.1, and no history of or current pneumonitis/interstitial lung disease. Primary objectives are to evaluate the efficacy and safety of 2 doses of EIK1001 in combination with pembro (DO only) and to compare progression-free survival per RECIST 1.1 by blinded independent central review (BICR) and OS of pts receiving EIK1001 + pembro relative to pts receiving placebo + pembro (at Selected Dose). Secondary objectives include evaluation of the safety and tolerability of the Selected Dose of EIK1001 + pembro relative to placebo + pembro, as well as evaluation of objective response rate and duration of response per RECIST 1.1 by BICR. Exploratory objectives include evaluation of time to objective response, evaluation of potential EIK1001 exposure-response relationships, and evaluation of health-related quality of life, health utilities, and melanoma concerns in pts receiving EIK1001 + pembro relative to placebo + pembro. This study opened on 24 December 2024. Clinical trial information: 06697301 .

9567 Background: Sentinel lymph node biopsy (SLNB) is still the gold standard for nodal assessment used in the clinical staging of cutaneous melanoma (CM) pts by AJCC v8. Recently, we showed in a small cohort that CP-GEP also has the potential to risk stratify pts who did not undergo SLNB in low and high-risk for recurrence (Amaral et al, EJC 2023). SLNB may be challenging in pts with head and neck (H&N) melanoma, due to the regional course of cranial nerves and lymphatic drainage. Here we focus on the ability of CP-GEP to stratify pts with H&N melanoma in particular those with lentigo maligna, who did not undergo SLNB, for their risk of recurrence. Methods: We analyzed formalin-fixed paraffin-embedded primary tumor samples of 930 pts of which 206 were localized in the H&N region, with stage I/II CM diagnosed between 2000-2017 who did not receive SLNB. The CP-GEP model used combines the expression of 8 genes (SERPINE2, GDF15, ITGB3, CXCL8, LOXL4, TGFBR1, PLAT and MLANA) by quantitative reverse transcription polymerase chain reaction with age and Breslow thickness to obtain a binary output: CP-GEP Low- or High-Risk. Relapse-free survival (RFS), distant metastasis free survival (DMFS) and Melanoma Specific Survival (MSS) were evaluated using Kaplan-Meier curves. Results: We included 930 pts (stage IA-IIC) of which 206 pts (22.3%) were diagnosed with H&N melanoma. Patient characteristics: 41% were females, median age was 73-year-old, median Breslow thickness was 0.5 mm and 75.6% were lentigo maligna melanomas. Median follow up was 51 months (RFS). All H&N pts showed the following survival: 5-year RFS 82.5%, DMFS 94.0 and MSS 95.5%. CP-GEP risk stratification identified 17 patients as CP-GEP High-Risk and 188 as CP-GEP Low-Risk. The 5-year RFS rate was 86.7% for CP-GEP Low-Risk and 39.7%% for CP-GEP High-Risk pts (HR 7.85; p<0.001), 5-year DMFS was 96.3% for CP-GEP Low-Risk and 68.9% High-Risk pts (HR 10.26; p<0.001) and the 5-year MSS was 98.5% for CP-GEP Low-Risk pts and 64.7% for CP-GEP High-Risk pts (HR 24.45; p<0.01). Conclusions: Pts with H&N CP-GEP Low-Risk tumors have a good long-term survival compared to High-Risk pts even though SLN status was not assessed. This prognostic information may allow the clinicians to skip SLNB in this difficult anatomic localization and in frail and/or older pts.

9574 Background: Sentinel lymph node biopsy (SLNB) is the gold standard for nodal assessment in staging cutaneous melanoma (CM) according to AJCC v8 guideline. 80-85% of pts are negative for nodal metastasis, but most pts who relapse or die from melanoma are initially diagnosed as ‘low risk’ early-stage. Previously we showed that the clinicopathological-gene expression profiling (CP-GEP) model is able to stratify SLNB negative pts for their risk of recurrence (1). Later we showed in a small cohort (n=80) that CP-GEP also has the potential to stratify pts who did not undergo SLNB in low and high-risk of recurrence (2). Here we investigate CP-GEP ability to stratify pts who did not undergo SLNB for their risk of recurrence in an expanded cohort. Methods: We analysedformalin-fixed paraffin-embedded primary tumor samples of 451 pts with stage I/II CM diagnosed between 2000-2017, included in the Central Malignant Melanoma Registry, who did not receive SLNB. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome. The CP-GEP model used combines the expression of 8 genes ( SERPINE2, GDF15, ITGB3, CXCL8, LOXL4, TGFBR1, PLAT and MLANA) by quantitative reverse transcription polymerase chain reaction with age and Breslow thickness to obtain a binary output: CP-GEP Low- or High-Risk. Relapse-free survival (RFS), distant metastasis free survival (DMFS) and Melanoma Specific Survival (MSS) were evaluated using Kaplan-Meier curves. Results: We included 451 pts (stage IA-IIC). 40% were females, median age was 63-year-old, median Breslow thickness was 0.5 mm, and the majority were not ulcerated (96%). An interim analysis was performed on samples from 159 pts and showed the following survival: 5-year RFS 85.8%; DMFS 94.1; MSS 95.7%. The median follow-up time of 57 months (RFS). CP-GEP identified 149 pts as Low-Risk and 10 pts as High-Risk. The 5-year RFS rate was 90.5% and 0% (HR 23.85; p < 0.001), 5-year DMFS was 97.2% and 27% (HR 43.14; p < 0.001), respectively for CP-GEP Low-Risk and High-Risk pts. The 5-year MSS was 99.1% for Low-Risk pts and 25.7% for High-Risk patients (HR 112.96; p < 0.001), capturing 4 out of 5 melanoma specific deaths in the CP-GEP High-Risk group. The final survival analysis of the whole cohort will be presented at the congress. Conclusions: This study shows that CP-GEP has the potential to stratify pts with early-stage melanoma who did not undergo SLNB based on their risk of recurrence. Pts with CP-GEP Low-Risk have a good long-term survival. Contrary, pts with CP-GEP High-Risk have a high risk of recurrence. CP-GEP may have the potential to stratify pts beyond SLNB. 1. Amaral et al, ASCO 2022. 2. Amaral et al, EJC 2023.