Background Therapeutic options for BRAFV600-mutant melanoma in patients who progress on BRAF/MEK-inhibitors (BRAF/MEKi) and immune-checkpoint-inhibitor (ICI) therapy, are limited. We conducted a retrospective registry study to investigate post-ICI rechallenge with BRAF/MEKi, stratified by type of initial BRAF/MEKi therapy. Methods This retrospective study analysed patients from the EUMelaReg registry, who received adjuvant or first-line (1L) BRAF/MEKi in the advanced setting, followed by ICI therapy and were later retreated with BRAF/MEKi. Overall response rate (ORR) for rechallenge served as primary endpoint, disease-control rate (DCR), progression-free survival (PFS), and overall survival (OS) were further endpoints. A covariate-matched control group of patients who received BRAF/MEKi only after 1L ICI failure was selected for comparison. Results Among patients previously treated with adjuvant (n=42) or non-adjuvant (n=142) BRAF/MEKi, rechallenge after one interim ICI line resulted in ORRs of 26.2% and 30.3% and DCRs of 42.9% and 61.8%, respectively. Median PFS was 8.4 and 5.1 months, median OS 13.8 and 8.6 months, respectively. Overall, the rechallenge group had a 1-year OS of 43.2%, lower than the matched control (58.9%). The adjuvant subgroup was similar to control (55.4%), while the advanced subgroup showed notably poorer survival (39.9%). Subgroup analyses showed that both the pre-ICI response to BRAF/MEKi treatment and progressive disease prior to ICI were associated with outcome of the BRAF/MEKi rechallenge. Conclusion Rechallenge with BRAF/MEKi therapy under real-world conditions for advanced melanoma provides a valid treatment option. For patients who received their initial BRAF/MEKi therapy as adjuvant therapy there seems to be only limited impairment of outcomes.

9576 Background: Patients with resected stage III BRAF V600 mutated melanoma can be treated with combined dabrafenib and trametinib (D/T) with significant improvement of recurrence-free survival (RFS). The results of the pivotal Combi-AD study showed overall survival (OS) improvement only for patients with BRAF V600E mutations, while for V600K there was even an OS impairment as compared to placebo, although not statistically significant. Methods: We analysed EUMelaReg data for patients with adjuvant D/T therapy for resected stage III melanoma. Only patients with V600E and V600K mutations were selected, where n=93 from a total of 1,033 patients (9.0 %) harboured V600K. Results: Demographics of patients with V600K mutations differed significantly for age (67 vs. 58 years, p <0.001) and a higher proportion of males (67.0% vs. 54.6%, p=0.03) at baseline. Other baseline variables, including substage, were not significantly different. One year of treatment was completed in 51.6% for V600K, and 62.8% for V600E, respectively, while with V600K mutations 22.6% of the patients stopped for toxicity (vs. 18.8% with V600E), and 10.8% for disease recurrence (vs. 6.9%), which was not statistically significant. After a median follow-up of 41.7 (V600K) and 41.2 (V600E) months, Kaplan-Meier analysis estimated 4-year overall survival of 75.7% for V600K compared to 77.8% for V600E. The 4-y-RFS estimates were 48.3% for V600K and 47.0% for V600E. These differences were not statistically significant. Cox regression analysis revealed no different results when adjusted for demographic co-variates, including age and sex, for RFS and OS, respectively. Conclusions: It appears that V600E and V600K mutations are not associated with a different outcome from adjuvant treatment with combined D/T. The findings offer no explanation for differences found in the Combi-AD trial, although part of these differences also resulted from a different natural course of V600K mutated melanomas the placebo group. A longer follow-up will help to further confirm these results and also analyse the possible role of further treatments in the metastatic setting. Baseline characteristics and outcome. V600E(N=940) V600K(N=93) P-value SEX 0.035 Female 426 (45.3%) 31 (33.3%) Male 514 (54.7%) 62 (66.7%) AGE <0.001 Mean (SD) 57.4 (13.8) 65.6 (11.9) Median [Min, Max] 58.0 [17.0, 90.0] 67.0 [28.0, 87.0] ECOG 0.1 0 846 (90.0%) 82 (88.2%) 1 51 (5.4%) 8 (8.6%) 2 5 (0.5%) 2 (2.2%) Baseline Stage 0.34 III 8 (0.9%) 1 (1.1%) IIIA 126 (13.4%) 7 (7.5%) IIIB 293 (31.2%) 29 (31.2%) IIIC 470 (50.0%) 54 (58.1%) IIID 43 (4.6%) 2 (2.2%) STAGE III DIAGNOSIS TYPE 0.96 Primary Diagnosis 679 (72.2%) 68 (73.1%) Relapse 260 (27.7%) 25 (26.9%) SUBTYPE 0.06 SSM 358 (38.1%) 26 (28.0%) NMM 315 (33.5%) 44 (47.3%) NOS 207 (22.0%) 18 (19.4%) MUP 49 (5.2%) 4 (4.3%) OUTCOME 4-Year RFS (95%-CI) 0.47 (0.43; 0.51) 0.48 (0.38; 0.61) 0.94 4-Year OS (95%-CI) 0.78 (0.75; 0.81) 0.76 (0.65; 0.88) 0.94

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 Randomised trials recently showed that sequencing of first-line (1L) immune checkpoint inhibitor (ICI) and second-line (2L) BRAF-MEK-inhibitor (BRAF/MEKi) combination therapy provides better clinical outcomes in BRAFV600-mutated, irresectable/metastatic melanoma than the inverse sequence. However, efficacy benchmark data for 2L BRAF/MEKi are limited as the combination was developed for 1L use, lacking estimates for the impact of prior ICI. Methods This retrospectively study analysed 2,343 patients from the EUMelaReg registry with BRAFV600-mutated melanoma who received BRAF/MEKi either as 2L after failing 1L ICI (n=654) or as 1L treatment (n=1,689). Patients with prior adjuvant ICI or BRAF/MEKi were excluded. Prognostic imbalances between the two groups were adjusted using 1:1 inverse propensity score matching. Key efficacy outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and time on treatment (TOT). Results Patients in the 2L cohort achieved outcomes from start of treatment at least equivalent to the matched 1L BRAF/MEKi cohort. Kaplan-Meier estimates demonstrated longer median PFS (8.4 vs 7.7 months; p=0.01) and longer median TOT (7.8 vs 6.2 months; p=0.002) for patients treated with 2L BRAF/MEKi compared to 1L. Median OS from start of 2L (17.2 months) or 1L (16.0 months) BRAF/MEKi was similar (p=0.73) despite inherent bias from differing index dates. ORR among both groups (56.4% vs 53.5%; p=0.32) was equal. Conclusion This study further supports the recommended sequencing of ICI as 1L and BRAF/MEKi as 2L therapy for patients with BRAFV600-mutated melanoma. It shows that prior failure of ICI does not compromise the efficacy of BRAF/MEKi treatment.

BACKGROUND:Melanoma of unknown primary (MUP) accounts for up to 10% of all cases of metastatic melanoma. The origin of MUP is unclear, and previous studies on the clinical course in comparison with cutaneous melanoma have reported varying results. OBJECTIVES:The study was conducted to assess the oncogenic pattern of MUP and to compare the clinical course with that of melanoma of known cutaneous primary (MKP). METHODS:Patients with MUP diagnosed between 1999 and 2022 were included in this cohort study from the prospective multicentre real-world DeCOG (German Dermatologic Cooperative Oncology Group) registry ADOREG and from the tumour database of the University Hospital Essen. For comparison, a cohort of consecutive patients with MKP with stage III or IV disease from the skin cancer centre Essen between 1999 and 2022 was used. The median follow-up was 3.5 years. Available tumour samples were genetically analysed using next-generation sequencing. Survival outcome adjusted for age, sex and tumour stage was compared between patients with MUP and those with MKP, using the Kaplan-Meier method. RESULTS:In total, 727 patients with MUP and 587 with MKP were identified. Median age at first diagnosis was 62 years [interquartile range (IQR) 53-73] for MUP and 63 years (IQR 52-75) for MKP. Most patients were male, 448 (61.6%) with MUP and 330 (56.2%) with MKP. Of the 727 patients with MUP, 337 (46.4%) had stage III disease at first diagnosis. Overall survival (OS) at 48 months was 65% [95% confidence interval (CI) 61-69] for all patients with MUP and 68% (95% CI 64-72) for all patients with MKP. Survival analyses adjusted for age, sex and tumour stage showed comparable OS rates for patients with MUP and MKP. Genetic analyses of tumours from 110 patients with MUP detected C>T and CC→TT mutations as the most common nucleotide variations. Median tumour mutational burden was 5 mutations per Mb (95% CI 4-5). Activating BRAF V600E (c.620T>A) mutations were detected in 43 patients (39.1%), activating NRAS mutations in 37 (33.6%), RAC1 P29S mutations in 7 (6.3%) and TERT promoter mutations in 73 (66.4%) of the analysed tumour samples. No activating KIT mutations were detected. CONCLUSIONS:The oncogenic pattern of MUP showed an ultraviolet mutation signature, suggesting an origin in sun-exposed areas. OS of MUP is comparable with that of MKP.

9535 Background: MUM carries a poor prognosis with few effective treatments, especially for HLA-A*02:01-negative pts. While a subset of MUM pts responds to immune checkpoint inhibitors, the comparative efficacy of IPI+PD1 versus PD1 monotherapy is unclear. This study compares objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety between these regimens in MUM. Methods: MUM pts treated with PD1 or IPI+PD1 at 15 major melanoma centres (from Australia, Europe, United States and Israel) were included. Demographics, patient and disease characteristics, and clinical outcomes were examined. Univariate and multivariate (MVA) analyses were performed to identify clinical predictors of response and survival. Results: Of 412 MUM pts treated, 150 (36%) had PD1 and 262 (64%) received PD1+IPI. Compared to the PD1 group, PD1+IPI-treated pts were younger (64 vs. 70 years; p<0.001), had higher rate of elevated LDH (44% vs. 31%; p=0.037), and more frequently had prior treatment with tebentafusp (6.5% vs. 1.3%; p=0.031). Median follow-up from commencement of PD1+/-IPI was 4.9 years (95% CI 4.7 – 6.1). ORR was higher in IPI+PD1 group (18%) vs. PD1 (9%) (p=0.008), particularly in males (p=0.009), patients with liver metastases (p=0.018) and with lung metastases (p=0.011), with elevated LDH (p=0.047) and with no prior treatment with tebentafusp (p=0.007). PFS and OS at 1 and 2 years were numerically higher with IPI+PD1 (1- and 2-year PFS: 23% and 15%; 1- and 2-year OS: 63% and 39%) vs. PD1 (1- and 2-year PFS: 17% and 11%; 1- and 2-year OS: 54% and 36%), but these differences were not statistically significant (p>0.05). On MVA, adjusting for predefined variables (age, gender, ECOG PS, LDH, presence/absence of liver/lung metastases, prior treatment with tebentafusp), IPI+PD1 was associated with higher ORR (OR 2.71, 1.30 – 6.05; p=0.01) but not with PFS or OS compared to PD1. Presence of liver metastases (ORR [OR 0.28; 95% CI 0.13 - 0.64], PFS [HR 1.61; 95% CI 1.11 - 2.34], OS [HR 2.02; 95% CI 1.32 - 3.10]), ECOG PS≥2 (PFS [HR 1.82; 95% CI 1.07 - 3.10], OS [HR 2.24; 95% CI 1.25-4.01]), elevated LDH (PFS [HR 1.66; 95% CI 1.30 - 2.11], OS [HR 2.39; 95% CI 1.84-3.10]) and prior tebentafusp treatment (OS [HR 2.36; 95% CI 1.21-4.59]) were also independent predictors of response and/or survival. A higher percentage of pts experienced grade ≥3 immune-related adverse events (irAEs) in the IPI+PD1 group compared to the PD1 group (34% vs 13%, p<0.0001). Most pts ceased treatment due to progression (234, 57%), and more pts stopped due to toxicity in the IPI+PD1 vs. PD1 group (25% vs. 9%, p<0.0001). Conclusions: In pts with MUM, IPI+PD1 demonstrated a higher ORR but did not improve survival compared with PD1 alone. IPI+PD1 was more toxic, leading to early treatment discontinuation in one-quarter of pts. These findings may help guide treatment selection in MUM.

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.

BACKGROUND:Immune checkpoint inhibitors (ICI) have transformed the treatment landscape of advanced cutaneous squamous cell carcinoma (cSCC). The influence of comorbidities and concomitant medications on treatment efficacy remains incompletely defined. OBJECTIVES:To evaluate the impact of comorbid conditions and commonly prescribed medications on progression-free survival (PFS) and overall survival (OS) in patients with advanced cSCC receiving ICI. METHODS:In this multicentre cohort study, 273 patients with unresectable or metastatic cSCC treated with ICI were identified from the prospective ADOReg skin cancer registry. Data on comorbidities, such as haematologic malignancies, immunosuppressive conditions, cardiovascular disease and concomitant medications, such as immunosuppressive agents and anticoagulants, were analysed. Treatment outcomes were measured as PFS and OS. RESULTS:Among first-line patients (n = 253), immunosuppressive conditions were associated with shorter PFS (5.5 vs. 24.4 months, p = 0.012) and OS (16.6 vs. 34.1 months, p < 0.001). Haematologic malignancies were likewise linked to poorer PFS (18.6 vs. 27.0 months, p = 0.032) and OS (17.0 vs. 33.6 months, p = 0.0067). Concomitant anticoagulant therapy correlated with longer PFS (49.3 vs. 17.4 months, p = 0.032), but not OS (p = 0.22). In multivariate analysis, immunosuppressive disease remained independently associated with shorter OS (HR = 9.88, 95% CI: 1.11-87.5, p = 0.040) and anticoagulant use with longer PFS (HR = 0.34, 95% CI: 0.15-0.80, p = 0.014). These associations were confirmed in Cox models weighted by inverse probability of treatment (IPTW), supporting robustness to confounding. No effect was attributable to any specific anticoagulant subclass. CONCLUSIONS:Our analyses suggest that immunosuppressive disease is an independent predictor of shortened OS, underscoring the critical role of host immune competence. We further report a novel, independently significant association between anticoagulant use and prolonged PFS. Other associations should be regarded as exploratory. These findings highlight host-related factors as potential modulators of ICI efficacy and merit prospective validation.

PURPOSE:Data on treatment approaches in geriatric melanoma patients are scant. Efficacy of oncologic treatments across age groups, with special focus on immunotherapy, and the impact of comorbidities were analyzed. METHODS:A retrospective multicenter cohort study of the ADOREG registry included patients with cutaneous melanoma, who received oncological drugs at German skin cancer centers between 2013 and 2023. Outcomes were objective response rate (ORR), progression-free survival (PFS), melanoma-specific survival (MSS), toxicities and reasons for treatment discontinuation. Age groups were prespecified as < 75 vs ≥ 75 years (geriatric), comorbidities were summarized by Charlson-Comorbidity-Index (CCI). Comparisons across groups were conducted with X2-test, survival outcomes were compared via log-rank tests. RESULTS:Of 14,356 melanoma patients, 8213 met the inclusion criteria, 6063 and 2150 were < 75 and ≥ 75 years old, respectively. Among the 3646 patients with metastatic disease, older patients received fewer treatment lines and were less likely to undergo surgery, radiotherapy and systemic therapy. However, efficacy of any first-line treatment did not differ between both age groups (p = 0.306). Immunotherapy selection at any line was similar in both groups (p = 0.109), but geriatrics were treated mainly with first-line anti-PD1 monotherapy, whereas combination ICIs was preferred in younger patients. Efficacy was not impaired (PFS and MSS: p > 0.05), while toxicity rates were lower. This pattern persisted across CCI categories. CONCLUSION:Age influenced treatment selection in melanoma patients. However, in geriatric patients, efficacy was not impaired, and a balanced toxicity profile was noticed, particularly for immunotherapy. Future studies considering biological age and impairment by comorbidities seems important to assess individualized treatment approaches.

Background/Objectives: Malignant melanoma is a highly aggressive cancer associated with significant mortality, underscoring the need for continued research efforts. COMBI-EU (NCT03944356) is a prospective, non-interventional study that aims to assess adjuvant dabrafenib and trametinib usage in clinical practice, the impact of AE management, and the usage of app-based documentation on treatment adherence. Methods: Adults with complete surgical resection of stage III BRAF V600-mutant cutaneous melanoma were included. The primary endpoint was median time on treatment (TOT). Adverse event (AE) management was classified as either a high or low level of management. The rating of AE management based on a self-developed algorithm and rules from COMBI-APlus was used to analyze the impact of AE management on TOT. App-based documentation of medication intake and patient-reported outcomes (CANKADO PRO-React; version 6.0, 06.03.2019) was offered. Results: For 225 patients, the median TOT was 11.8 months (95% confidence interval [CI]: 11.7, 12.0). Treatment was completed by 138 patients (61.3%); 37 (16.4%) discontinued due to treatment-related AEs (TRAEs). TRAEs (≥1) were experienced by 181 patients (80.4%); the most common was pyrexia (38.2%). High-level AE management showed a trend toward improved treatment adherence (high versus low level: hazard ratio [HR]: 0.74; 95% CI: 0.49, 1.14); this improvement was significant with pyrexia management (HR: 0.52; 95% CI: 0.29, 0.93). Seventy-nine (35%) and 33 patients (15%) intended to use and eventually used the app, respectively. A similar proportion of patients remained on treatment for 12 months irrespective of app usage (use, 39.4% vs. non-use, 36.5%). Conclusions: High-level TRAE management showed a trend toward improved treatment adherence, which was statistically significant for pyrexia. Optional use of an app did not influence treatment adherence.

BACKGROUND:The anti-PD1 antibody (PD1i) cemiplimab is approved as second-line treatment for locally advanced or metastatic basal cell carcinoma (BCC), resulting in an ORR of 20-30 %. This study aimed to investigate the efficacy of cemiplimab as first-line or second-line treatment of BCC in a German real-world patient cohort. METHODS:Patients with histologically confirmed locally advanced or metastatic BCC who were treated with cemiplimab were retrospectively identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Therapy outcome was compared between patients receiving first-line cemiplimab and patients treated with cemiplimab in second-line. RESULTS:37 patients from 17 skin cancer centers were identified who received cemiplimab. The median follow-up after start of any first-line treatment was 37.1 months, and 17.9 months after initiation of any cemiplimab treatment. Patients who received first-line cemiplimab (n = 8) had an ORR of 62.5 %, compared to an ORR of 31.0 % for patients who received second-line cemiplimab (n = 29); Median PFS was 19.8 months for first-line cemiplimab and 5.3 months for second-line cemiplimab. Reinduction with HHIs after progression on second-line cemiplimab resulted in an ORR of 20.0 % and a median PFS of 3.8 months. CONCLUSION:We demonstrate a comparable outcome for cemiplimab as second-line treatment of BCC in our real-world patient cohort as reported in previous registration studies. Additionally, we found a trend for a more favorable outcome in first-line therapy, suggesting a rationale to further investigate cemiplimab as first-line treatment of advanced BCC.

BACKGROUND:Melanoma is the main cause of skin cancer-related death. Treatment with immune checkpoint inhibitors (CPI) has improved the prognosis in recent years. However, subtypes of melanoma differ in their response. Acral lentiginous melanoma (ALM) has a worse prognosis compared to cutaneous melanoma other than ALM (CM) and is therefore of particular relevance. AIMS:To evaluate the efficacy of CPI in first-line treatment of patients with advanced ALM compared CM. METHODS:Retrospective analysis of patients with metastatic ALM (n = 45) or CM (n = 328) who received first-line CPI therapy from the multicenter prospective skin cancer registry ADOREG. Study endpoints were best overall response (BOR), progression-free survival (PFS) and overall survival (OS). RESULTS:ALM patients had significantly higher rates of ulcerated tumors, loco regional metastases and fewer BRAF-mutated tumors compared to CM patients. Combined CPI was administered in 48.9 % ALM patients and 39.3 % of CM patients, while the remaining patients received PD-1 monotherapy. OS trended to be shorter in patients with ALM (18.1 vs. 43.8 months, p = 0.10) with no significant differences in PFS (7.0 vs. 11.5 months, p = 0.21). In patients with CM, median OS with combined CPI was not reached, whereas the median OS after PD-1 monotherapy was 37.8 months (p = 0.22). Conversely, in patients with ALM, OS with combined CPI was 17.8 months, compared to 26 months with PD-1 monotherapy (p = 0.15). There were no significant differences in BOR between patients with ALM or CM. CONCLUSION:Analysis of this real-world cohort of patients with metastatic melanoma showed a trend towards poorer survival outcomes upon first-line treatment with CPI in ALM compared to cutaneous melanoma of other subtypes.

BackgroundModern therapeutic strategies have significantly improved the prognosis of advanced melanoma patients. Predictive factors of therapy response include serum LDH; however, predictive markers for long-term survival are currently largely lacking.Patients and methodsPatients diagnosed with stage IV melanoma (AJCCv8) of cutaneous origin or unknown primary were identified from the prospective multicenter German Dermatologic Cooperative Oncology Group (DeCOG) skin cancer registry ADOREG. Baseline characteristics were compared between patient groups with short-term versus long-term survival. Statistical analysis included ROC analysis and multinomial regression analysis.ResultsOf 3066 stage IV melanoma patients entered into the ADOREG between 05/2014 and 06/2021, 395 were identified for this study, of whom 301 (76.2%) survived ≤1 year, and 94 (23.8%) survived ≥5 years after stage IV diagnosis. The median follow-up time was 6 months (range 0-129 months). Regarding the baseline characteristics, only elevated serum LDH (P <0.001) was found to be independently predicting survival ≤1 year. Type of first-line therapy, immune checkpoint inhibition (ICI) versus BRAF/MEK targeted therapy (TT), was not predictive of long-term survival ≥5 years. For survival ≤1 year, the presence of brain metastases at treatment start was an independent predictor in BRAF-mutated patients regardless if they received TT (N=113; P=0<0.001) or ICI (N=69; P=0.015), but not in BRAF-wildtype patients who received ICI (N=161; P=0.47).ConclusionsLow serum LDH independently predicts long-term survival of stage IV melanoma patients in every subgroup of treatment type and BRAF status. Brain metastasis has a negative impact on long-term survival in BRAF-mutated, but not in BRAF-wildtype patients. Investigation of molecular features of brain metastases in BRAF-mutated vs. BRAF-wildtype melanomas may lead to new insights in tumor biology and may yield new therapeutic approaches.

BackgroundAlthough systemic therapies have improved considerably over the last decade, up to 50% of patients with metastatic melanoma still die due to disease progression. Oncological treatment at the end-of-life phase is challenging. The aim of this study was to investigate the frequency and type of systemic therapy received by melanoma patients in their end-of-life phase.MethodsPatients with metastatic melanoma who had died between January 1, 2018 and October 31, 2022 were identified from the prospective multicenter skin cancer registry ADOReg. Study endpoints were percentage of patients who had been treated with systemic therapy within the last three months of life, timepoint of initiation of the last-line therapy, overall survival, treatment benefit and the incidence of treatment-related adverse events.ResultsIn total, 1067 patients from 46 skin cancer centers were included. Most of the patients (63%) had received immune checkpoint inhibitors (ICI) as last-line therapy, 22% targeted therapies (TT) and 12% chemotherapy (CTX). Comparing last-line ICI and TT, patients with TT were significantly more likely to benefit from treatment and had significantly fewer and milder treatment-related AE than patients with ICI. Even though two thirds of patients had received ICI as a last-line therapy, the majority of these patients (61%) had stopped therapy within the last 30 days of life, whereas the majority of patients with TT (66%) still continued their treatment to the end of life. We found markedly fewer patients with initiation of ICI within 30 days before their death (19%) compared to a historic cohort including patients who died in 2016 or 2017 (39%).ConclusionTreatment approaches near the end of life have markedly changed in skin cancer centers in Germany over recent years, with ICI prescribed less frequently in the end-of-life phase. In contrast, TT are frequently administered, even within the last 30 days of life. It should also be considered that discontinuation of TT can result in rapid tumor progression. Due to the oral administration and a low rate of severe toxicity, TT appear to be a suitable treatment option, even in the end-of-life situation of melanoma patients.

Background Targeted therapies (TT) improve outcomes in BRAF-mutant melanoma. Pre-clinical data suggest that anticoagulation (AC) and platelet aggregation inhibition (PAI) may have antitumoral effects. We evaluated the impact of concomitant AC or PAI on outcomes in patients receiving TT. Methods We analyzed 1,296 patients with unresectable stage III-IV BRAF-mutant melanoma treated with BRAF plus MEK inhibitors (2016-2024) in the prospective multicenter ADOReg registry. Patients were categorized as receiving no antithrombotic therapy (ATT; n = 1,125), PAI (n = 73; acetylsalicylic acid or clopidogrel), or AC (n = 98; direct oral anticoagulants, low-molecular-weight heparin, or vitamin K antagonists). Results Median follow-up was 1.3 years. Compared with patients without ATT, those receiving AC had significantly improved 12-month progression-free survival (PFS; HR 0.55, 95 percent CI 0.39-0.78, p = 0.001) and overall survival (OS; HR 0.35, 95 percent CI 0.19-0.64, p = 0.001). Direct oral anticoagulants showed the most pronounced PFS benefit (HR 0.40, 95 percent CI 0.25-0.64, p < 0.001). PAI was not associated with a significant difference in PFS, but multivariable Cox regression indicated a reduced hazard of death (HR 0.48, 95 percent CI 0.27-0.87, p = 0.015). Conclusion Concomitant AC, particularly factor Xa-inhibiting direct oral anticoagulants, was associated with improved survival in melanoma patients undergoing TT. These findings support prospective trials evaluating AC as concomitant therapy in advanced melanoma.

BACKGROUND:Targeted therapies (TT) improve outcomes in BRAF-mutant melanoma. Pre-clinical data suggest that anticoagulation (AC) and platelet aggregation inhibition (PAI) may have antitumoral effects. We evaluated the impact of concomitant AC or PAI on outcomes in patients receiving TT. METHODS:We analyzed 1296 patients with unresectable stage III-IV BRAF-mutant melanoma treated with BRAF plus MEK inhibitors (2016-2024) in the prospective multicenter ADOReg registry. Patients were categorized as receiving no antithrombotic therapy (ATT; n = 1125), PAI (n = 73; acetylsalicylic acid or clopidogrel), or AC (n = 98; direct oral anticoagulants, low-molecular-weight heparin, or vitamin K antagonists). RESULTS:Median follow-up was 1.3 years. Compared with patients without ATT, those receiving AC had significantly improved 12-month progression-free survival (PFS; HR 0.55, 95 % CI 0.39-0.78, p = 0.001) and overall survival (OS; HR 0.35, 95 % CI 0.19-0.64, p = 0.001). Direct oral anticoagulants showed the most pronounced PFS benefit (HR 0.40, 95 % CI 0.25-0.64, p < 0.001). PAI was not associated with a significant difference in PFS, but multivariable Cox regression indicated a reduced hazard of death (HR 0.48, 95 % CI 0.27-0.87, p = 0.015). CONCLUSION:Concomitant AC, particularly factor Xa-inhibiting direct oral anticoagulants, was associated with improved survival in melanoma patients undergoing TT. These findings support prospective trials evaluating AC as concomitant therapy in advanced melanoma.

BACKGROUND:Adjuvant immune checkpoint inhibition (ICI) with anti-PD-1 antibodies in high-risk resected melanoma has been shown to improve recurrence-free survival. It is unclear whether prior adjuvant anti-PD-1 therapy is associated with altered response to subsequent ICI treatment in the metastatic setting. METHODS:Using data from the European Melanoma Registry (EUMelaReg), we analyzed the efficiency of first-line (1L) ICI in non-resectable or metastatic melanoma after failure from prior adjuvant anti-PD-1 treatment. Both single-agent anti-PD-1 and combined anti-PD-1/CTLA-4 (Ipi/Nivo) 1L regimes were included in the analysis. We identified 389 patients receiving 1L ICI with prior adjuvant anti-PD-1 treatment. The control population was selected from a pool of 3390 PD-1-naive cases by 1:1 matching for the type of 1L ICI and various prognostic factors. As outcome measure, overall remission rates (ORR) were calculated and progression-free survival (PFS) was evaluated by Kaplan-Meier and Cox regression analysis. RESULTS:Out of 389 patients, 303 (77.9 %) received Ipi/Nivo and 86 (22.1 %) anti-PD-1 in 1L. ORR was significantly lower in pre-treated patients (31.4 %) as compared to anti-PD-1 naive patients (48.8 %; p < 0.0001). Kaplan-Meier analysis showed significantly shorter median PFS for pre-treated patients. This applied to both anti-PD-1 and Ipi/Nivo treatment. Patients with early recurrence from adjuvant treatment (during or up to 12 weeks after end of treatment) showed lower ORR (28.5 %) and shorter PFS (3.1 months) than those who recurred later (37.7 % and 6.1 months, respectively). CONCLUSIONS:Patients with metastatic melanoma, previously exposed to anti-PD-1 ICI in the adjuvant setting showed significantly lower ORR and shorter PFS to 1L ICI with either Ipi/Nivo or single-agent anti-PD-1 retreatment.