LBA9517 Background: PIVOTAL (NCT02938299) is an open-label, randomized, multicenter, phase 3 trial evaluating daromun as a neoadjuvant intralesional (IT) therapy for resectable, locally advanced stage III melanoma. The trial enrolled 256 efficacy-evaluable patients (pts) in the EU and met its primary endpoint, demonstrating a statistically significant improvement in recurrence-free survival (RFS; HR = 0.59; p = 0.005) for daromun versus upfront surgery, at a median follow-up (FU) of 21 months from randomization (Kähler et al, Ann Onc 2025, 36, 1166). Methods: Pts with skin and/or lymph node metastatic melanoma amenable to complete surgical resection were randomized (1:1) to receive 4 weekly IT injections of daromun (13 Mio IU of L19IL2 and 400 μg of L19TNF) followed by surgery or upfront surgery alone. Prior surgery, radiotherapy (RT) and/or systemic therapies (ST) were permitted, as well as any approved adjuvant treatment post-surgery.The primary endpoint was RFS, the secondary endpoints included DMFS, OS and safety. An event-free survival (EFS) sensitivity analysis was conducted, considering progression to unresectable melanoma before surgery, recurrence of the disease, or death due to melanoma or treatment as events. Results: An updated primary outcome analysis at a median FU of over 36 months from randomization (database cut-off Nov. 29, 2025) confirmed a clinically relevant improvement in RFS (HR = 0.60; p = 0.003) for daromun versus upfront surgery. The EFS sensitivity analysis carried out in the overall population was consistent with the RFS results (HR = 0.66; 95% CI = 0.47-0.92).The PIVOTAL trial included two clinically distinct subgroups: pts with newly diagnosed disease (n = 32; 12%) and pts with recurrence(s) after surgery and/or systemic (neo)adjuvant treatment (n = 224; 88%). Among the recurrent cohort, 86 pts (38.3%) had received and failed previous ST, while 138 pts (61.6%) had only received surgery/RT. Sensitivity EFS analyses were also performed in i) the recurrent cohort (HR = 0.59; 95% CI = 0.41-0.85), ii) the subgroup of pts in the recurrent cohort who had only received previous surgeries and/or RT (HR = 0.55; 95% CI = 0.34-0.89), and iii) the pts subgroup in the recurrent cohort who received prior ST (HR = 0.63; 95% CI = 0.36-1.08 ). The rate and type of treatment-related adverse events at a longer FU were consistent with previous reports, and no new safety risks were identified. Conclusions: With longer FU the highly significant reduction in the risk of recurrence or death with neoadjuvant daromun in pts with locally advanced stage III melanoma is confirmed. The sensitivity EFS analyses provide consistent, confirmatory evidence of daromun’s efficacy across the entire trial population and, more importantly, in the subgroup of pts with recurrent disease, regardless of any prior ST. No new safety signals were reported. Clinical trial information: NCT02938299 .

The prospective, German NICO study (ClinicalTrials.gov identifier: NCT02990611) evaluated real-world effectiveness and safety with nivolumab plus ipilimumab or nivolumab alone (any-line) in patients with advanced melanoma with/without melanoma brain metastasis (MBM). A total of 755 patients treated with nivolumab plus ipilimumab (n = 486; median follow-up, 46.8 months) or nivolumab alone (n = 269; median follow-up, 38.7 months) were enrolled. Baseline characteristics differed between the treatment groups, with the nivolumab plus ipilimumab group being younger and having poorer prognostic factors. At baseline, 221 patients (29.3%) had MBM, among whom 15 patients had symptomatic MBM based on dexamethasone use. In patients with/without MBM receiving first-line nivolumab plus ipilimumab, objective response rates (ORRs) were 46.2% and 54.0%, respectively; 3-year overall survival (OS) rates were 34.0% and 47.0%. In patients with/without MBM receiving first-line nivolumab alone, ORRs were 61.5% and 55.1%, respectively; 3-year OS rates were 42.7% and 47.8%. In a 3-month landmark analysis, patients with MBM with a complete/partial response demonstrated 3-year OS rates of 71.9% with nivolumab plus ipilimumab and 89.6% with nivolumab alone. Three-year OS rates were 42.2% and 20.0% with asymptomatic and symptomatic MBM, respectively. There were no substantial differences in the rates of serious grade 3/4 treatment-related adverse events between patients with/without MBM. HRQoL was stable. Results from this real-world study show that a substantial proportion of patients with MBM derive long-term benefit from nivolumab plus ipilimumab or nivolumab alone, particularly those with asymptomatic MBM.

Background Although most studies of anticancer T-cell immunity focus on αβ T cells, γδ T cells are attracting increasing attention due to their involvement in antitumor immune responses in various cancer entities, including melanoma. While immune checkpoint blockade (ICB) using the antagonistic programmed cell death protein 1 (PD-1) antibodies nivolumab and pembrolizumab significantly improved the survival of patients with melanoma with distant metastasis, prognosis remains poor. PD-1 is not only expressed by αβ T cells but also by γδ T cells, making this numerically minor population of unconventional T cells, whose role in melanoma is still elusive, a target of ICB.Methods Here, we present a detailed γδ T-cell profiling study in late-stage melanoma at single-cell level using mass and polychromatic flow cytometry, T-cell receptor repertoire analyses and immunohistochemistry.Results Our analyses link high frequencies of peripheral Vδ1 T cells before the start of anti-PD-1 therapy to a significantly reduced overall survival. In these patients, the Vδ1 compartment is dominated by a late-differentiated senescent-like phenotype that is presumably unresponsive to therapy. This phenotype is less prevalent at the tumor site and analysis of RNA sequencing data revealed that the abundance of Vδ1 T cells within the tumor was positively associated with survival.Conclusions Our study suggests that Vδ1 T cells are associated with clinical outcomes, with a responsive subset expanding under ICB in patients where such a response remains possible. The observed clinical effects may be supported by the infiltration of these cells into the tumor, where they contribute to cancer immunosurveillance.

Daromun (L19IL2/L19TNF) was investigated as a neoadjuvant, intralesional therapy for patients with fully resectable stage III melanoma in the phase III PIVOTAL trial (ClinicalTrials.gov identifier: NCT02938299). The trial enrolled 256 patients in the European Union and met its primary end point, demonstrating a statistically significant improvement in recurrence-free survival (RFS; hazard ratio, 0.59; P = .005) for daromun followed by surgery versus up-front surgery, at a median follow-up (FU) of 21 months from random assignment. PIVOTAL included two clinically distinct subgroups, namely, patients with de novo diagnosed metastatic disease (n = 34; 13%) and patients with recurrence(s) after surgery with or without radiotherapy and/or adjuvant systemic therapies (n = 222; 87%). Here, we present an updated analysis of the primary and secondary end points, including safety data, at a median FU of 36.8 months from random assignment (database cutoff: November 28, 2025), alongside new sensitivity analyses of event-free survival (EFS). The updated analysis confirms the clinically and statistically meaningful improvements in RFS and distant metastasis-free survival recorded in the neoadjuvant daromun versus control arm. The EFS post hoc analysis, conducted in both the overall population and the recurrent patient subgroups (with or without prior systemic therapies), provides consistency and robustness to the benefit of neoadjuvant daromun observed for the primary efficacy end point. No new safety signals of concern were recorded.

BackgroundPrimary cutaneous B cell lymphomas (CBCL) are chronic diseases with frequent relapses. Time to next treatment (TTNT) is an endpoint reflecting clinical benefit of treatments including patient perspectives. The objectives were to evaluate clinical characteristics, survival, prognosis and TTNT in CBCL.Patients and methodsIn this monocentric study, clinical data were extracted between 1998 and 2022. TTNT were calculated. Univariate and multivariate analyses were conducted.ResultsAltogether, 46 patients with follicle center lymphoma (pcFCL), 41 with marginal zone lymphoproliferative disorder (pcMZLPD) and 11 with diffuse large B-cell lymphoma, leg type (DLBCL-LT) were identified. 26% of pcFCL patients relapsed frequently. The 5-year relapse-free survival was 71%, 87% and 23% in pcFCL, pcMZLPD and DLBCL-LT, respectively. In pcFCL and pcMZLPD, skin-directed treatments, such as excision or intralesional triamcinolone, performed best based on TTNT, while chemotherapy achieved a mean TTNT of 38 months in DLBCL-LT. In multivariate analysis of all patients, leg involvement was significantly associated with a decreased TTNT of the first treatment, while comorbidities were associated with an increased TTNT.ConclusionsDLBCL-LT had the worst survival. Skin-directed treatments tend to achieve higher TTNT in pcFCL and pcMZLPD, while systemic treatments had higher TTNT in DLBCL-LT.

Background Understanding the risk of recurrence is crucial for planning of follow-up in cutaneous melanoma patients. Objectives This study aims to analyze time-dependent hazard rates (HR) for recurrences concerning follow-up recommendations for thin melanomas. Methods 12,132 patients in stages IA/IB were recorded by the German-Central-Malignant-Melanoma-Registry in 2000–2010. Survival rates, based on Kaplan-Meier estimates, and HR were calculated comparing three groups of tumor thickness (TTH). Results Recurrences were recorded in 916/12,132 patients (7.6 %), in 3.7 % with TTH < 0.8 mm, 9.8 % with TTH 0.8–1.0 mm and 15.8 % with TTH > 1.0–2.0 mm. Median follow-up-time was 48.0 months (IQR: 23.0;78.0) in tumors < 0.8 mm; 54.0 months (25.0;84.0) in tumors of 0.8–1.0 mm, 61.0 months (30.0;91.0) in tumors of 1.01–2.0 mm. Ten-year recurrence-free survival (RFS) was 91.5 % (95 %-CI: 90.1 %;92.9 %) in tumors with TTH < 0.8 mm; 81.9 % (79.0 %;84.8 %) with TTH 0.8–1.0 mm and 74.0 % (71.5 %;76.6 %) with TTH 1.01–2.0 mm. In years 1–5, HR for recurrences showed levels of ≤ 1:1111 per year for TTH < 0.8 mm, undulating but higher HR up to 1:313 in TTH of 0.8–1.0 mm and up to 1:222 in TTH of ≥ 1.01 mm. Limitations Few information can be given beyond a follow-up of 10 years. Conclusion Low HR were found for stage IA patients and TTH < 0.8 mm, therefore reduced surveillance intervals seem appropriate. Melanoma with a TTH of 0.8–1.0 mm showed higher HR rates, similar to stage IB patients. These data indicate that these patients may need more intensive follow-up in the first years.

Primär kutane B‐Zell‐Lymphome (CBCL) sind chronische Erkrankungen mit häufigen Rezidiven. Die Zeit bis zur nächsten Therapie ( Time to next treatment , TTNT) ist ein Endpunkt, der den klinischen Nutzen von Therapieoptionen einschließlich der Patientenperspektive widerspiegelt. Ziele waren es, klinische Merkmale, Überleben, Prognose und TTNT bei CBCL zu analysieren. In dieser monozentrischen Studie wurden klinische Daten von Patienten zwischen 1998 und 2022 erhoben. Die TTNT wurde berechnet. Es wurden univariate und multivariate Analysen durchgeführt. Insgesamt wurden 46 Patienten mit Follikelzentrumslymphom (pcFCL), 41 mit marginalzonen‐lymphoproliferativer Störung (pcMZLPD) und elf mit diffus großzelligem B‐Zell‐Lymphom, Bein‐Typ (DLBCL‐LT) identifiziert. Bei 26% der Patienten mit pcFCL traten mehrere Rezidive auf. Das rezidivfreie 5‐Jahres‐Überleben betrug 71%, 87% beziehungsweise 23% bei pcFCL, pcMZLPD und DLBCL‐LT. Bei pcFCL und pcMZLPD schnitten hautgerichtete Behandlungen wie Exzision oder intraläsionales Triamcinolon am besten ab, während Chemotherapien bei DLBCL‐LT eine mittlere TTNT von 38 Monaten erreichten. In der multivariaten Analyse war eine Beinbeteiligung signifikant mit geringerer TTNT der ersten Behandlung bei allen Patienten assoziiert, während Komorbidität mit höherer TTNT einherging. DLBCL‐LT hatte die schlechteste Überlebensrate. Hautgerichtete Therapieoptionen erreichten tendenziell eine höhere TTNT bei pcFCL und pcMZLPD, während systemische Behandlungen eine höhere TTNT bei DLBCL‐LT aufwiesen.

INTRODUCTION:While BRAF-/MEK-inhibitor therapy is well established in V600E/K-mutated melanoma, the efficacy in advanced melanoma with rare BRAF mutations remains uncertain. This is an updated analysis of an international data collection including 49 new patients, accompanied by development of a publicly accessible global database. PATIENTS AND METHODS:A retrospective analysis was conducted at 20 international cancer centers, evaluating 143 patients with rare BRAF V600 (V600-nonE/K; 48 %) and non-V600 (52 %) mutations. Treatments included BRAF/MEK inhibitor combination therapy (BRAFi/MEKi) and the respective monotherapies. Clinical outcomes concerning overall response rate (ORR), progression-free (PFS), and overall survival (OS) were collected. RESULTS:Included patients had a median age of 65 years (range 20-93), 101 (71 %) were male. Most patients (n = 92, 64 %) received BRAFi/MEKi, 42 (29 %) BRAFi monotherapy, and 9 (6 %) MEKi monotherapy. The ORR was 35 % and higher in V600-nonE/K (45 %) than non-V600 melanomas (26 %, p = 0.025). Median duration of response was similar, with 8.2 months (range 2.9-53.1 +) for V600-nonE/K and 7.4 months (range 0.8-73.8 +) for non-V600. Combination therapy achieved best results in both groups, however, differences between V600-nonE/K and non-V600mutation were only found in ORR (51 % vs. 33 %, p = 0,11) and median PFS (6.5 vs. 3.2 months, p = 0.01). Patients with the longest PFS (> 50 months) had V600D/R, V600_K601D/E/N or K601E/N-, L597V/S/R/Q/P/K- mutations. OS was similar in both groups (16.1 vs. 11.7 months, p = 0.96). Of note, in non-V600 melanomas MEKi monotherapy revealed similar response rates as combination treatment (ORR 33 %, PFS 3 months); however, median OS was shorter (6.6 months, p = 0.02). CONCLUSIONS:This updated analysis reinforces the benefit of BRAFi/MEKi therapy in rare BRAF mutations. A database for ongoing data collection was developed and is available at https://www.klinikum.uni-heidelberg.de/en/hautklinik-zentrum/hauttumorzentrum/forschung/datenbank-seltene-braf-mutationen.

Background CV8102, a toll-like receptor 7/8 and RIG I agonist, has demonstrated antitumor immune responses in preclinical studies. We investigated intratumoral (IT) administration of CV8102 in patients with anti-programmed cell death protein-1 (PD-1) therapy-naïve or anti-PD-1 therapy-refractory cutaneous melanoma (cMEL) and in patients with advanced cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma and adenoid cystic carcinoma.Methods This open-label, cohort-based, phase I dose escalation study aimed to establish the maximum tolerated dose (MTD), recommended dose (RD), safety and preliminary efficacy of CV8102 as monotherapy or in combination with a PD-1 inhibitor. The preliminary efficacy of the RD was assessed in patients with cMEL in the expansion cohorts.Results Between September 2017 and October 2022, 98 patients were enrolled in monotherapy and combination therapy dose escalation and dose expansion cohorts. Two patients in the CV8102 monotherapy dose escalation cohort experienced relevant toxicities at the 900 µg dose level. One patient had Grade 3 aspartate transaminase/alanine aminotransferase elevation which met dose-limiting toxicity (DLT) criteria. Another patient experienced Grade 3 immune-mediated pneumonitis. No DLTs occurred in the combination therapy dose escalation cohort. The MTD was not formally reached and the RD for expansion was 600 µg. Common treatment-emergent adverse events were fever (57%), chills (37%) and fatigue (25%). In the dose escalation part, objective responses occurred in 3/33 patients treated with CV8102 as monotherapy and in 2/25 patients treated with CV8102 plus a PD-1 inhibitor. In the expansion cohorts in patients with anti-PD-1 therapy-refractory melanoma, 0/10 patients treated with CV8102 as monotherapy and 5/30 patients (17%) treated in combination with a PD-1 inhibitor experienced objective responses.Conclusions IT CV8102 was generally well tolerated with preliminary signs of efficacy as monotherapy and in combination with a PD-1 inhibitor.Trial registration number NCT03291002.

2523 Background: The most common type of cutaneous T-cell lymphoma is Mycosis Fungoides (MF) accounting for 50-60% of cases. Extracutaneous involvement occurs mainly in lymph nodes or blood; 25% of patients are diagnosed at advanced stage with a 5-year survival of 15-25%. Lacutamab is a first-in-class monoclonal antibody designed to specifically deplete KIR3DL2-expressing cells via antibody-dependent cell-cytotoxicity and phagocytosis. KIR3DL2 is a killer immunoglobulin-like receptor expressed in MF patients. Methods: TELLOMAK is an international, multi-cohort phase 2 trial (NCT03902184). MF patients who had received at least 2 prior systemic therapies were treated with lacutamab 750 mg until disease progression or unacceptable toxicity. Primary endpoint was Objective Response Rate (ORR) by global response score based on the evaluation of 4 compartments: skin, blood, lymph nodes and viscera according to the International Consensus criteria Olsen 2011. Key secondary endpoints included duration of response (DoR), progression free survival (PFS), safety, and quality of life. Here we report long term follow-up data of MF patients. Results: As of October 17, 2024, recruitment was completed, with 107 MF patients enrolled. The median age was 62 years. The median number of previous systemic lines was 4 (range: 1-14). Median follow-up was 22.1 months (m) (95% CI 19.4, 23.6). Global confirmed ORR was 19.6% (CI 13.2, 28.1; Olsen 2011), and response in skin was 29.0% (CI 21.2, 38.2). Median time to response was 2.8 m (min, max 1-37) and median DoR was 13.8 m (7.4, NE), median PFS was 10.2 m (CI 8.0, 15.4). Among the KIR3DL2 ≥1% pts (N = 48), ORR was 20.8% (CI 11.7, 34.3; Olsen 2011), and response in skin was 33.3% (CI 21.7, 47.5), median DoR was 13.8 m (CI 4.6, NE) and median PFS 11.8 m (CI 5.6, 16.8). Among the KIR3DL2 < 1% pts (N = 59), ORR was 18.6% (CI 10.7;30.4; Olsen 2011), and response in skin was 25.4 (CI 16.1, 37.8), median DoR was 15.7 m (CI 5.1, NE) and median PFS 9.5 m (CI 6.5;16.6). Grade ≥ 3 related Treatment-Emergent Adverse events (TEAEs) were observed in 5/107 (4.7%) patients, serious related TEAEs in 4/107 (3.7%) patients and related TEAEs leading to study drug discontinuation in 3/107 (2.8%) patients. The most common ( > 10%) related TEAEs were fatigue (12.1%), nausea (13.1%), asthenia (11.2%) and arthralgia (11.2%). Data from additional key endpoints and translational data will also be presented. Conclusions: The long-term follow-up data from the heavily pre-treated MF population enrolled to the TELLOMAK study confirms promising clinical activity of lacutamab regardless of KIR3DL2 expression, with ORR 20.8%, a median duration of response of 13.8 m, a median PFS of 10.2 m and a favorable safety and tolerability profile. These data support the further development of lacutamab in an effort to bring improved treatments to patients with MF. Clinical trial information: NCT03902184 // EU CT number: 2023-507777-18-00 .

To assess the safety and efficacy of performing degradable starch microspheres transarterial chemoembolization (DSM-TACE) in metastatic melanoma (MM) patients with progressive liver metastases following immune checkpoint inhibitors (ICI) treatment. This case series evaluates 10 adult patients with MM who exhibited hepatic progression after an initial response to ICI therapy and underwent DSM-TACE without discontinuation of systemic checkpoint inhibitor therapy from January 2023 to September 2024. Tumor response was assessed using RECIST 1.1 criteria. The primary outcome measure of the study was the best overall response rate. Secondary outcome measures included local tumor control, progression-free survival, and overall survival. Adverse events were monitored and recorded. Ten melanoma patients (median age: 69.5 years; six females) who underwent DSM-TACE due to hepatic progression following an initial response to ICI therapy were included for safety analysis. Imaging data were unavailable for two patients, who were therefore excluded from further analyses. Best overall response rate was 87.5

BackgroundFor patients with locally advanced (la) or metastatic (m) cutaneous squamous cell carcinoma (cSCC) who are not candidates for curative surgery/radiation or systemic anti-PD1 therapy, anti-EGFR in combination with chemotherapy is a rational treatment option.Patients and MethodsWe analyzed data from 20 patients with cSCC in this monocentric, retrospective study. 4/20 patients had laSCC and 16/20 patients had mSCC. Patients received combined cetuximab and 5-FU between 2015 and 2023. Nine patients received cetuximab + 5-FU as second-line therapy (8 patients after anti-PD-1, 1 patient after radiochemotherapy).ResultsOne patient had partial response (PR) and 9/20 (45.0%) had stable disease (SD). Disease control rate (PR + SD) was 50%. No complete remissions were observed. One of the non-responders suffered from laSCC, nine patients had mSCC with distant metastases (including parotid) and locoregional lymph node metastases. Treatment was well tolerated, with a median PFS of 3 months (95% confidence interval [CI] 2 months to not assessable [NA]) and median overall survival (OS) of 29 months (95% CI 11-NA). The most common adverse event was acne-like rash in 40.0% of patients.ConclusionsFor patients with advanced cSCC who are contraindicated to or have progressed on first-line cemiplimab, combination of cetuximab and 5-FU is a well-tolerated but limited treatment option.

BACKGROUND:Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with neuroendocrine differentiation characterized by frequent recurrences. Large epidemiological databases (e.g., SEER, IARC) lack granularity in analyzing associations between tumor, patient characteristics, locoregional interventions and recurrence patterns. PATIENTS AND METHODS:Within the pre-immunotherapy era (1998-2017) the DeCOG MCC registry included 1049 patients with histopathologically confirmed MCC. Patient/tumor characteristics, treatment details, and outcomes were analyzed. Primary endpoints were progression-free probability (PFP) and disease-specific survival (DSS). RESULTS:Median age at diagnosis was 74 years; 50.4 % were males. Primary tumors most frequently occurred on the head/neck (32.2 %) and upper extremities (29.1 %). One-third of patients presented with stage ≥IIIA disease. At a median follow-up of 10 years, 36- and 60-months PFP rates were 69.0 % and 63.9 %, respectively; DSS rates were 86.9 % and 82.6 %. Surgical margins of 1-2 cm provided the best PFP and DSS improvement; margins > 2 cm did not further improve clinical outcome. Similarly, for stage IIIA patients a complete lymph node dissection (CLND) did neither improve PFP nor DSS. Early radiotherapy (<8 weeks post-diagnosis) significantly improved PFP (HR 1.36) and DSS (HR 1.79). Expansion of radiotherapy to lymph node bed showed no additional benefit. Patients with multiple metastases at first recurrence had poorer DSS (HR 2.0) compared to those with single metastases, irrespective of locoregional or distant spread. CONCLUSIONS:MCC outcomes are optimized with surgical margins of 1-2 cm and timely adjuvant radiotherapy. Larger margins, CLND in stage IIIA, or extended treatment radiation fields did not improve survival outcomes.

Background MEK inhibitors (MEKi) were shown to be clinically insufficiently effective in patients suffering from BRAF wild-type (BRAF WT) melanoma, even if the MAPK pathway was constitutively activated due to mutations in NRAS or NF-1. Thus, novel combinations are needed to increase the efficacy and duration of response to MEKi in BRAF WT melanoma. Disulfiram and its metabolite diethyldithiocarbamate are known to have antitumor effects related to cellular stress, and induction of endoplasmic reticulum (ER) stress was found to synergize with MEK inhibitors in NRAS-mutated melanoma cells. Therefore, we investigated the combination of both therapeutics to test their effects on BRAF-WT melanoma cells and compared them with monotherapy using the MEKi trametinib. Methods The effects of combined therapy with disulfiram or its metabolite diethyldithiocarbamate and the MEKi trametinib were evaluated in a series of BRAF-WT melanoma cell lines by measuring cell viability and apoptosis induction. Cytotoxicity was additionally assessed in 3D spheroids, ex vivo melanoma slice cultures, and in vivo xenograft mouse models. The response of melanoma cells to treatment was studied at the RNA and protein levels to decipher the mode of action. Intracellular and intratumoral copper measurements were performed to investigate the role of copper ions in the antitumor cytotoxicity of disulfiram and its combination with the MEKi. Results Diethyldithiocarbamate enhanced trametinib-induced cytotoxicity and apoptosis induction in 2D and 3D melanoma culture models. Mechanistically, copper-dependent induction of oxidative stress and ER stress led to Janus kinase (JNK)-mediated apoptosis in melanoma cells. This mechanism was also detectable in patient-derived xenograft melanoma models and resulted in a significantly improved therapeutic effect compared to monotherapy with the MEKi trametinib. Conclusions Disulfiram and its metabolite represent an attractive pharmaceutical approach to induce ER stress in melanoma cells that potentiates the antitumor effect of MEK inhibition and may be an interesting candidate for combination therapy of BRAF WT melanoma.

Background: Histopathologic regression of cutaneous melanoma is considered a favorable prognostic factor, but its significance in clinical practice remains controversial. Objective: To investigate the prognostic importance of regression in patients with primary cutaneous melanoma undergoing sentinel lymph node (SLN) biopsy and to assess its significance in patients progressing to an unresectable stage requiring systemic therapy. Methods: We retrospectively reviewed patients with newly diagnosed melanoma undergoing SLN biopsy between 2010 and 2015 and available information on histopathologic regression ( n = 1179). Survival data and associations of clinical variables with SLN status were assessed. Results: Patients with regressive melanoma showed favorable relapse -free (hazard ratio [HR], 0.52; P = .00013), distant metastasis e free (HR, 0.56; P = .0020), and melanoma -specific survival (HR, 0.35; P = .00053). Regression was associated with negative SLN (odds ratio, 0.48; P = .0077). In patients who progressed to an unresectable stage, regression was associated with favorable progression -free survival under immune checkpoint inhibition (HR, 0.43; P = .031) but not under targeted therapy (HR, 1.14; P = .73) or chemotherapy (HR, 3.65; P = .0095). Limitations: Retrospective, single -institutional design. Conclusions: Regression of cutaneous melanoma is associated with improved prognosis in patients eligible for SLN biopsy as well as in patients with unresectable disease receiving systemic therapy with immune checkpoint inhibitors. ( J Am Acad Dermatol 2024;90:739-48.)