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Metastatic uveal melanoma (UM) is a rare form of melanoma differing from cutaneous melanoma by etiology, prognosis, driver mutations, pattern of metastases and poor response rate to immune checkpoint inhibitors (ICI). Recently, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, tebentafusp, has been approved for the treatment of HLA-A*02:01 metastatic or unresectable UM. While the treatment regime is complex with weekly administrations and close monitoring, the response rate is limited. Only a few data exist on combined ICI in UM after previous progression on tebentafusp. In this case report, we present a patient with metastatic UM who first suffered extensive progression under treatment with tebentafusp but in the following had an excellent response to combined ICI. We discuss possible interactions that could explain responsiveness to ICI after pretreatment with tebentafusp in advanced UM.

Background High tumor mutational burden (TMB) is associated with a favorable outcome in metastatic melanoma patients treated with immune checkpoint inhibitors. However, data are limited in the adjuvant setting. As BRAF mutated patients have an alternative with targeted adjuvant therapy, it is important to identify predictive factors for relapse and recurrence-free survival (RFS) in patients receiving adjuvant anti-PD-1 antibodies. Methods We evaluated 165 melanoma patients who started adjuvant anti-PD-1 antibody therapy at our center between March 2018 and September 2019. The initial tumor stage was assessed at the beginning of therapy according to the 8th edition of the AJCC Cancer Staging Manual. Tumor and normal tissue of the high-risk stages IIIC/D/IV were sequenced using a 700 gene NGS panel. Results The tumor stages at the beginning of adjuvant anti-PD-1 therapy were as follows: N = 80 stage IIIA/B (48%), N = 85 stage IIIC/D/IV (52%). 72/165 patients (44%) suffered a relapse, 44/72 (61%) with only loco regional and 28/72 (39%) with distant metastases. Sequencing results were available from 83 to 85 patients with stage IIIC/D/IV. BRAF mutation status (HR 2.12, 95% CI 1.12–4.08; p = 0.022) and TMB (HR 7.11, 95% CI 2.19–23.11; p = 0.001) were significant and independent predictive factors for relapse-free survival (RFS). Conclusion BRAF mutation status and TMB were independent predictive factors for RFS. Patients with BRAF V600E/K mutation and TMB high had the best outcome. A classification based on BRAF mutation status and TMB is proposed to predict RFS in melanoma patients with adjuvant anti-PD-1 therapy.

BackgroundDespite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.MethodsPatients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).ResultsOf 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwtpatients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmutpatients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmutpatients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmutpatients. In BRAFwtpatients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwtpatients. For BRAFmutpatients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.ConclusionsIn BRAFmutpatients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwtpatients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1.

BackgroundThe clinical utility of molecular profiling and targeted therapies for neuro-oncology patients outside of clinical trials is not established. We aimed at investigating feasibility and clinical utility of molecular profiling and targeted therapy in adult patients with advanced tumors in the nervous system within a prospective observational study.Methodsmolecular tumor board (MTB)@ZPM (NCT03503149) is a prospective observational precision medicine study for patients with advanced tumors. After inclusion of patients, we performed comprehensive molecular profiling, formulated ranked biomarker-guided therapy recommendations based on consensus by the MTB, and collected prospective clinical outcome data.ResultsHere, we present initial data of 661 adult patients with tumors of the nervous system enrolled by December 31, 2021. Of these, 408 patients were presented at the MTB. Molecular-instructed therapy recommendations could be made in 380/408 (93.1%) cases and were prioritized by evidence levels. Therapies were initiated in 86/380 (22.6%) cases until data cutoff. We observed a progression-free survival ratio >1.3 in 31.3% of patients.ConclusionsOur study supports the clinical utility of biomarker-guided therapies for neuro-oncology patients and indicates clinical benefit in a subset of patients. Our data might inform future clinical trials, translational studies, and even clinical care.

Background Despite impressive response rates, most patients with advanced melanoma ultimately progress following therapy with B-Raf proto-oncogene (BRAF) inhibitors (BRAFi). Therefore, frequent radiologic assessments are necessary, and reliable serum biomarkers would be beneficial for disease monitoring. Objective This study investigated the ability of lactate dehydrogenase (LDH) and S100 calcium-binding protein B (S100B) to detect response and disease progression during treatment with BRAFi. Patients and Methods Baseline levels of LDH and S100B and repeated measurements during therapy were recorded retrospectively in 191 patients with metastatic melanoma. LDH and S100B levels were compared between distinct time points (baseline, first follow-up visit [FV], best objective response [BR], and progressive disease [PD]). The prognostic ability of the serum biomarkers in relation to disease-specific survival (DSS) was assessed with univariable and multivariable Cox regression analysis. Results Elevated baseline LDH and S100B correlated with impaired DSS. In contrast with LDH (P = 0.12), S100B levels at FV correlated with response (P = 0.0030). Both markers significantly decreased during the first weeks of BRAFi treatment (LDH, P = 0.00034; S100B, P < 0.0001) and increased between BR and PD (LDH, P = 0.016; S100B, P < 0.0001). Patients with elevated S100B (P = 0.00062) but not with elevated LDH (P = 0.067) at the time point of radiologically confirmed PD showed significantly impaired DSS after PD. Interestingly, DSS after PD differed significantly according to S100B levels determined as early as 8 weeks (median) before PD (P = 0.0024). Conclusions LDH and S100B are suitable serum biomarkers during therapy with BRAFi. S100B shows stronger correlation with response and exhibits more accuracy in predicting PD. Close biomarker monitoring with S100B is recommended during treatment with BRAFi to detect PD early. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00792-8.

Sequencing of tumour tissue with comprehensive gene panels is increasingly used to guide treatment in precision oncology. Analysis of tumour-normal pairs allows in contrast to tumour-only assessment direct discrimination between somatic and germline alterations, which might have important implications not only for the patients but also their families.We performed tumour normal sequencing with a large gene panel in 1048 patients with advanced cancer to support treatment decision. Sequencing results were correlated with clinical and family data.We identified 156 likely pathogenic or pathogenic (LP/P) germline variants in cancer predisposition genes (CPGs) in 144 cases (13.7%). Of all patients, 8.8% had a LP/P variant in autosomal-dominant cancer predisposition genes (AD-CPGs), most of them being genes with high or moderate penetrance (ATM, BRCA2, CHEK2 and BRCA1). In 48 cases, the P/LP variant matched the expected tumour spectrum. A second variant in tumour tissue was found in 31 patients with AD-CPG variants. Low frequency mutations in either TP53, ATM or DNMT3A in the normal sample indicated clonal haematopoiesis in five cases.Tumour-normal testing for personalised treatment identifies germline LP/P variants in a relevant proportion of patients with cancer. The majority of them would not have been referred to genetic counselling based on family history. Indirect functional readouts of tumour-normal sequencing can provide novel links between CPGs and unexpected cancers. The interpretation of increasingly complex datasets in precision oncology is challenging and concepts of interdisciplinary personalised cancer prevention are needed to support patients and their families.

Hepatic immune-related adverse events (irAE) including elevated liver function tests (transaminases) occur in 1.4–22.3% of melanoma patients receiving immune checkpoint inhibitors (ICPI) and constitute a potentially serious toxicity that is challenging to treat. In contrast to the liver transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST), only little is known about the frequency and impact of gamma-glutamyl transferase (GGT) elevations. GGT determined prior to and during therapy of metastatic melanoma patients treated with ICPI were retrospectively assessed in two independent cohorts (PD-1: n = 218, Ipi + Nivo: n = 148). Overall survival (OS) and best objective response were analyzed according to baseline and immune-related GGT (irGGT) elevations during treatment. In multivariate analysis, OS was reduced in patients with elevated baseline GGT (PD-1 group: hazard ratio [HR] 1.76, p = .0073; Ipi + Nivo group: HR 1.77, p = .032). Immune-related GGT elevation was recorded in 17% (PD-1 group) and 38.5% (Ipi + Nivo group). Of these patients, the majority (81 and 68%, respectively) had normal ALT and AST and showed no clinical signs of hepatotoxicity. Patients who experienced irGGT elevation had superior response (PD-1 group: odds ratio [OR] 3.57, p = .00072; Ipi + Nivo group: OR 1.74, p = .12) and OS (PD-1 group: HR 0.37, p = .0016; Ipi + Nivo group: HR 0.33, p = .00050). The frequency of hepatic irAE is currently underestimated. The addition of the sensitive enzyme GGT to the laboratory panel before and during therapy with ICPI allows to detect two to three times more patients developing hepatic or hepatobiliary toxicity than known so far. Immune-related GGT elevations correlate with response and favorable survival. Precis for use in the Table of Contents The frequency of hepatotoxicity under immune checkpoint blockade is currently underestimated. We suggest the addition of gamma-glutamyl transferase to the laboratory panel in checkpoint inhibitor patients for the detection of hepatobiliary toxicity.

Background: mucosal melanoma is a rare malignancy which represents approximately 1% of all melanomas. It is shown that mucosal melanomas have a different biology and less favourable prognosis than its cutaneous counterpart. Objectives: predictive and prognostic factors of survival for mucosal melanoma have not yet been elucidated. The aim of this study was to investigate risk factors affecting the course of mucosal melanoma patients followed in our clinic. Methods: one hundred and sixty-one patients with mucosal melanoma prospectively documented in the German Central Malignant Melanoma Registry (CMMR) were included in this study. Gender, age, localization, stage at first medical examination, tumour thickness and mutational status were documented. The American Joint Committee on Cancer (AJCC), 7th edition was used to define tumour stage. Kaplan-Meier survival curves were evaluated compared with the log-rank test. Multivariate Cox proportional hazard models were used to identify significant independent prognostic factors. Results: according to the localization, patients were categorized in 44.7% oral-nasal, 28.6% genital, 20.5% anorectal and 6.2% visceral. Genital mucosal melanomas had the most favourable 5-year OS rate (58.6%) followed by visceral (58.3%) and oral-nasal (39.3%). Anorectal melanomas had the worst OS time (median: 21 +/- 4.8 months) and 5-year survival rate (22.7%). Patients, NA

Objectives: Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30–40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes. Methods: Patients with advanced (non-resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG. Results: We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy-three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival (PFS) on ICI was 2.6 (95% CI 2.2–2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4–7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2–20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response. Conclusions: BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy. Rates of long-term benefit and survival in our study were similar to those reported for treatment-naïve patients receiving first-line MAPKi.

Simple Summary Our aim was to check for possible associations between clinical parameters or NGS-based genetic alterations and the occurrence of immune-related adverse events (IRAE) in melanoma patients with immune checkpoint inhibitors (ICI). We analyzed 95 melanoma patients with ICI and were able to identify several biomarkers associated with the development of IRAE. Female sex was significantly associated with the development of hepatitis, increased total and relative monocytes at ICI initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Furthermore, the following genetic alterations were identified being associated with IRAE: SMAD3 (pancreatitis); CD274, SLCO1B1 (hepatitis); PRDM1, CD274 (encephalitis); PRDM1, CD274, TSHR, FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. Our findings can help to assess the risk for the development of IRAE in melanoma patients with ICI. Abstract Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE would be desirable. In the literature, there is only little data available and furthermore mostly speculative, especially in view of genetic alterations. Our major aim was to check for possible associations between NGS-based genetic alterations and IRAE. We therefore analyzed 95 melanoma patients with ICI and evaluated their NGS results. We checked the data in view of potential associations between copy number variations (CNVs), small variations (VARs), human leucocyte antigen (HLA), sex, blood count parameters, pre-existing autoimmune diseases and the occurrence of IRAE. We conducted a literature research on genetic alterations hypothesized to be associated with the occurrence of IRAE. In total, we identified 39 genes that have been discussed as hypothetical biomarkers. We compared the list of these 39 genes with the tumor panel that our patients had received and focused our study on those 16 genes that were also included in the tumor panel used for NGS. Therefore, we focused our analyses on the following genes: AIRE, TERT, SH2B3, LRRK2, IKZF1, SMAD3, JAK2, PRDM1, CTLA4, TSHR, FAN1, SLCO1B1, PDCD1, IL1RN, CD274, UNG. We obtained relevant results: female sex was significantly associated with the development of hepatitis, combined immunotherapy with colitis, increased total and relative monocytes at therapy initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Further significant associations were as follows: HLA homozygosity (hepatitis), and VARs on SMAD3 (pancreatitis). Regarding CNVs, significant markers included PRDM1 deletions and IL1RN (IRAE), CD274 duplications and SLCO1B1 (hepatitis), PRDM1 and CD274 (encephalitis), and PRDM1, CD274, TSHR, and FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. The association between HLA homozygosity and IRAE was clarified by finding HLA-A homozygosity as determining factor. We identified several genetic alterations hypothesized in the literature to be associated with the development of IRAE and found significant results concerning pre-existing autoimmune diseases and specific blood count parameters. Our findings can help to better understand the development of IRAE in melanoma patients. NGS might be a useful screening tool, however, our findings have yet to be confirmed in larger studies.

BackgroundDespite of various therapeutic strategies, treatment of patients with melanoma brain metastasis (MBM) still is a major challenge. This study aimed at investigating the impact of type and sequence of immune checkpoint blockade (ICB) and targeted therapy (TT), radiotherapy, and surgery on the survival outcome of patients with MBM.MethodWe assessed data of 450 patients collected within the prospective multicenter real-world skin cancer registry ADOREG who were diagnosed with MBM before start of the first non-adjuvant systemic therapy. Study endpoints were progression-free survival (PFS) and overall survival (OS).ResultsOf 450 MBM patients, 175 (38.9%) received CTLA-4+PD-1 ICB, 161 (35.8%) PD-1 ICB, and 114 (25.3%) BRAF+MEK TT as first-line treatment. Additional to systemic therapy, 67.3% of the patients received radiotherapy (stereotactic radiosurgery (SRS); conventional radiotherapy (CRT)) and 24.4% had surgery of MBM. 199 patients (42.2%) received a second-line systemic therapy. Multivariate Cox regression analysis revealed the application of radiotherapy (HR for SRS: 0.213, 95% CI 0.094 to 0.485, p1 cm: 1.977, 95% CI 1.117 to 3.500, p=0.019), age (HR for age >65 years: 1.802, 95% CI 1.016 to 3.197, p=0.044), and ECOG performance status (HR for ECOG ≥2: HR: 2.615, 95% CI 1.024 to 6.676, p=0.044) as independent prognostic factors of OS on first-line therapy. The type of first-line therapy (ICB vs TT) was not independently prognostic. As second-line therapy BRAF+MEK showed the best survival outcome compared with ICB and other therapies (HR for CTLA-4+PD-1 compared with BRAF+MEK: 13.964, 95% CI 3.6 to 54.4, pConclusionsIn patients with MBM, the addition of radiotherapy resulted in a favorable OS on systemic therapy. In BRAF-mutated MBM patients, ICB as first-line therapy and BRAF+MEK as second-line therapy were associated with a significantly prolonged OS.

Conjunctival melanoma is a rare type of ocular melanoma, which is prone to local recurrence and metastasis and can lead to patient death. Novel therapeutic strategies have revolutionized cutaneous melanoma management. The efficacy of these therapies in conjunctival melanoma, however, has not been evaluated in larger patient cohorts.In this multi-center retrospective cohort study with additional screening of the ADOREG database, data were collected from 34 patients with metastatic conjunctival melanoma who received targeted therapy (TT) (BRAF ± MEK inhibitors) or immune checkpoint inhibitors (ICI) (anti-PD-1 ± anti-CTLA4). In 15 cases, tissue was available for targeted next-generation-sequencing (611 genes) and RNA sequencing. Driver mutations, tumor mutational burden, copy number variations and inflammatory/IFNγ gene expression signatures were determined.Genetic characterization identified frequent BRAF (46.7%, 7/15), NRAS (26.7%, 4/15), NF1 (20%, 3/15), and TERT promoter (46.7%, 7/15) mutations. UV associated CT and CCTT mutations were common. Median follow-up time after start of first TT or ICI therapy was 13.2 months. In 26 patients receiving first-line ICI, estimated one-year progression-free survival (PFS) rate was 42.0%, PFS and overall survival (OS) 6.2 and 18.0 months, respectively. First-line TT was given to 8 patients, estimated one-year PFS rate was 54.7%, median PFS and OS 12.6 and 29.1 months, respectively.Our findings support the role of UV irradiation in conjunctival melanoma and the genetic similarity with cutaneous melanoma. Conjunctival melanoma patients with advanced disease benefit from both targeted therapies (BRAF ± MEK inhibitors) and immune checkpoint inhibitors.

Background Cutaneous melanoma is an aggressive malignancy that is proposed to account for 90% of skin cancer–related mortality. Individuals with melanoma experience both physical and psychological impacts associated with their diagnosis and treatment. Health-related information is being increasingly accessed and shared by stakeholders on social media platforms. Objective This study aimed to assess how individuals living with melanoma across 14 European countries use social media to discuss their needs and provide their perceptions of the disease. Methods Social media sources including Twitter, forums, and blogs were searched using predefined search strings of keywords relating to melanoma. Manual and automated relevancy approaches filtered the extracted data for content that provided patient-centric insights. This contextualized data was then mined for insightful concepts around the symptoms, diagnosis, treatment, impacts, and lived experiences of melanoma. Results A total of 182,400 posts related to melanoma were identified between November 2018 and November 2020. Following exclusion of irrelevant posts and using random sampling methodology, 864 posts were identified as relevant to the study objectives. Of the social media channels included, Twitter was the most commonly used, followed by forums and blogs. Most posts originated from the United Kingdom (n=328, 38%) and Spain (n=138, 16%). Of the relevant posts, 62% (n=536) were categorized as originating from individuals with melanoma. The most frequently discussed melanoma-related topics were treatment (436/792, 55%), diagnosis and tests (261/792, 33%), and remission (190/792, 24%). The majority of treatment discussions were about surgery (292/436, 67%), followed by immunotherapy (52/436, 12%). In total, 255 posts discussed the impacts of melanoma, which included emotional burden (n=179, 70%), physical impacts (n=61, 24%), effects on social life (n=43, 17%), and financial impacts (n=10, 4%). Conclusions Findings from this study highlight how melanoma stakeholders discuss key concepts associated with the condition on social media, adding to the conceptual model of the patient journey. This social media listening approach is a powerful tool for exploring melanoma stakeholder perspectives, providing insights that can be used to corroborate existing data and inform future studies.

Comprehensive genomic profiling and biomarker-based therapeutic strategies are currently used in clinical trials and in innovative health care systems including the center for personalized medicine network. Systematic assessments of patient-reported outcomes are warranted to gain insight into the perspective of patients and their relatives during biomarker-based therapies. In the present study, we focused on health-related quality of life (HRQoL), psychosocial situation, and physical symptoms in patients treated at the Center for Personalized Medicine Tübingen. First, we retrospectively evaluated symptom burden of n=265 (neuro-)oncological patients in the Molecular Tumor Board (MTB). Sixty percent of patients reported at least 1 neurological symptom, and psychosocial burden/unmet needs were high (overall 156/265; 59%, patients with malignant tumors n=86/106; 81%, Fisher’s exact, p < 0.0001). We therefore developed an app by 14 expert rounds and pretesting including validated assessments of HRoL, symptom und psychological burden and tested it in a pilot study. We conducted a structured interview with users 3 months afterwards to assess the app’s usability and feasibility. The interview was transcribed and analyzed according to a qualitative content analysis. So far, a total of 10 patients and caregivers have been enrolled in this pilot study. They reported that (i) the app is compatible with their daily routine (median 9.3, range 0-10), that (ii) they are more aware of their health status, which was rated as positive, and that (iii) completing app-based questionnaires was easier compared to paper questionnaires. Two patients reported technical problems, which were resolved timely. The pilot study proved feasibility and acceptance of the app. The app might optimize symptom burden assessment, adapted to the patients’ profiles. The next step is to prospectively compare HRQoL before and after start of targeted therapy in a multicenter study.

Simple Summary Melanoma is the most aggressive form of skin cancer, with a rapidly increasing incidence rate. Due to ineffective treatment options in the late stage melanoma, patients have an overall poor prognosis. Over the last decades, the role of the immune system in the control of tumor progression has been established and immune checkpoint inhibitors (ICi) have shown remarkable clinical activity. While current trials suggest durable responses in patient under ICi therapy, there is increasing evidence pointing towards existence of innate and acquired resistance to ICi therapy; and it is now clear that personalized medicine will be critical for effective patient therapy. Proteogenomics is a powerful tool to study the mode of action of disease-associated mutations at the genome, transcriptome, proteome and PTM level. Here, we applied a proteogenomic workflow to study melanoma samples from human tumors. Such workflow may be applicable to other patient-derived samples and different cancer types. Abstract Immune checkpoint inhibitors are used to restore or augment antitumor immune responses and show great promise in the treatment of melanoma and other types of cancers. However, only a small percentage of patients are fully responsive to immune checkpoint inhibition, mostly due to tumor heterogeneity and primary resistance to therapy. Both of these features are largely driven by the accumulation of patient-specific mutations, pointing to the need for personalized approaches in diagnostics and immunotherapy. Proteogenomics integrates patient-specific genomic and proteomic data to study cancer development, tumor heterogeneity and resistance mechanisms. Using this approach, we characterized the mutational landscape of four clinical melanoma patients. This enabled the quantification of hundreds of sample-specific amino acid variants, among them many that were previously not reported in melanoma. Changes in abundance at the protein and phosphorylation site levels revealed patient-specific over-represented pathways, notably linked to melanoma development (MAPK1 activation) or immunotherapy (NLRP1 inflammasome). Personalized data integration resulted in the prediction of protein drug targets, such as the drugs vandetanib and bosutinib, which were experimentally validated and led to a reduction in the viability of tumor cells. Our study emphasizes the potential of proteogenomic approaches to study personalized mutational landscapes, signaling networks and therapy options.

Despite remarkably improved outcomes with immune checkpoint inhibition, many patients with metastatic melanoma will eventually require further therapy. Chemotherapy has limited activity when used first-line but can alter the tumour microenvironment and does improve efficacy when used in combination with immunotherapy in lung cancer. Whether chemotherapy after checkpoint inhibitor failure has relevant activity in patients with metastatic melanoma is unknown.Patients with metastatic melanoma treated with chemotherapy after progression on immunotherapy with checkpoint inhibitors were identified retrospectively from 24 melanoma centres. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety were examined.In total, 463 patients were treated between 2007 and 2017. Fifty-six per cent had received PD-1-based therapy before chemotherapy. Chemotherapy regimens included carboplatin + paclitaxel (32%), dacarbazine (25%), temozolomide (15%), taxanes (9%, nab-paclitaxel 4%), fotemustine (6%) and others (13%). Median duration of therapy was 7.9 weeks (0-108). Responses included 0.4% complete response (CR), 12% partial response (PR), 21% stable disease (SD) and 67% progressive disease (PD). Median PFS was 2.6 months (2.2, 3.0), and median PFS in responders was 8.7 months (6.3, 16.3), respectively. Twelve-month PFS was 12% (95% CI 2-15%). In patients who had received anti-PD-1 before chemotherapy, the ORR was 11%, and median PFS was 2.5 months (2.1, 2.8). The highest activity was achieved with single-agent taxanes (N = 40), with ORR 25% and median PFS 3.9 months (2.1, 6.2). Median OS from chemotherapy start was 7.1 months (6.5, 8.0). Subsequent treatment with checkpoint inhibitors achieved a response rate of 16% with a median PFS of 19.1 months (2.0-43.1 months). No unexpected toxicities were observed.Chemotherapy has a low response rate and short PFS in patients with metastatic melanoma who have failed checkpoint inhibitor therapy, although activity varied between regimens. Chemotherapy has a limited role in the management of metastatic melanoma.

Introduction Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. Methods & results Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor–pretreated compared with MAPK-inhibitor–naive intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1Bhigh cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death. Conclusion The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.

Aim: Melanoma brain metastases (MBM) are associated with a dismal prognosis. Few clinical trials evaluated the impact of immunotherapy (IT) and targeted therapy (TT) alone or in combination with surgery and radiotherapy in this population. Patients & methods: Retrospective analysis of data from 163 patients diagnosed with MBM between January 2014 and December 2016. Prognostic factors of overall survival were analyzed using Kaplan–Meier survival curves, classification and regression tree and multivariate Cox regression analysis. Results: The median follow-up was 25 months; median overall survival (mOS) for all patients was 7 months. For patients receiving IT, the mOS was 13 months and 7 months for patients receiving TT or chemotherapy (CT). The mOS for patients treated with surgery/radiosurgery in combination with IT, TT and CT was 25, 14 and 11 months, respectively. Conclusion: New systemic therapies, especially IT, improve mOS in patients with MBM, particularly when combined with surgery/radiosurgery upfront.

Background Patients with hepatic metastatic uveal melanoma still have a poor outcome. Purpose To evaluate overall survival (OS), progression-free survival (PFS), and response predictors in these patients treated with chemosaturation by percutaneous hepatic perfusion with melphalan (CS-PHP). Material and Methods Between June 2015 and March 2020, a total of 29 patients (median age 69.7 years; age range 30–81 years; 60% women; median BMI 25.7 kg/m2; range 18.7–35.3kg/m2; 1–6 procedures per patient) were treated with 53 CS-PHPs. All patients received cross-sectional imaging for initial and follow-up examinations. Baseline tumor load, extrahepatic tumor load, tumor response, PFS, and OS were assessed. Non-parametric statistics were used. Results After the initial CS-PHP, a partial response was observed in 11 patients (41%), stable disease in 12 patients (44%) and progressive disease in 4 patients (15%); two patients died before the response was evaluated. After initial CS-PHP, median OS was 12.9 ± 7.4 months and median PFS was 7.1 ± 7.4 months. OS after one year was 50%. After the second CS-PHP, median PFS was 7.9 ± 5.7 months. Seven patients had a liver tumor burden >25%, associated with a significantly shorter OS (6.0 ± 2.4 vs. 14.1 ± 12.7 months; P = 0.008). At the time of first CS-PHP, 41% (12/29) of the patients had extrahepatic metastases that did not affect OS (11.1 ± 8.4 months vs. 12.9 ± 13.6 months; P = 0.66). Conclusion CS-PHP is a safe and effective treatment for the hepatic metastatic uveal melanoma, especially for patients with a hepatic tumor burden

Checkpoint inhibitors have revolutionized the treatment of patients with metastasized melanoma. However, it remains unclear when to stop treatment. We retrospectively analyzed 45 patients (median age 64 years, 58% male) with metastasized melanoma from 3 cancer centers that received checkpoint inhibitors and discontinued therapy due to either immune-related adverse events or patient decision after an (18F)2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with a low-dose CT scan (FDG-PET-CT) scan without signs for disease progression. After a median of 21 (range 1–42) months of immunotherapy an FDG-PET-CT scan was performed to evaluate disease activity. In these, 32 patients (71%) showed a complete metabolic response (CMR) and 13 were classified as non-CMR. After a median follow-up of 34 (range 1–70) months, 3/32 (9%) of CMR patients and 6/13 (46%) of non-CMR patients had progressed (p = 0.007). Progression-free survival (PFS), as estimated from the date of last drug administration, was significantly longer among CMR patients than non-CMR (log-rank: p = 0.001, hazard ratio: 0.127, 95% CI: 0.032–0.511). Two-year PFS was 94% among CMR patients and 62% among non-CMR patients. Univariable Cox regression showed that metabolic response was the only parameter which predicted PFS (p = 0.004). Multivariate analysis revealed that metabolic response predicted disease progression (p = 0.008). In conclusion, our findings suggest that patients with CMR in an FDG-PET-CT scan may have a favorable outcome even if checkpoint inhibition is discontinued.

CD8+ cytotoxic T cells are key players in anti-cancer immune responses as they destroy MHC class I-dependent tumor cells. Therefore, the spatial distribution of CD8+ cytotoxic T cells might represent an important surrogate for the response to cancer immunotherapy including immune checkpoint inhibitor therapy ICT. The radiolabeled minibody [89Zr]Zr-Df-IAB22M2C is characterized by a high affinity to human CD8 and was already investigated in a phase I study. Here, we present our first experience with the non invasive in vivo assessment of the whole body CD8 T cell distribution in cancer patients using clinical [89Zr]Zr-Df-IAB22M2C PET/MRI. In total 8 patients with metastasized cancers (5 x malignant melanoma; 1 x choroidal melanoma, 1 x NSCLC and 1 x sarcoma) were studied before (n = 3) or during (n = 5) ICT. Multiparametric PET/MRI was performed 24 h after injection of 74.2±17.9 MBq [89Zr]Zr-Df-IAB22M2C (1.1 - 1.8 mg Df-IAB22M2C) on a Siemens Biograph mMR System (SiemensHealthineers, Erlangen, Germany). The whole body distribution of the [89Zr]Zr-Df-IAB22M2C tracer was analyzed with a special focus on tumors/metastases as well as primary and secondary lymphatic organs. The PET tracer [89Zr]Zr-Df-IAB22M2C was well tolerated without any reported side effects. The PET/MRI acquisitions 24h p.i. of [89Zr]Zr-Df-IAB22M2C revealed a comparably low background signal with only a minor blood pool and unspecific tissue retention. Regarding the primary and secondary lymphoid organs we observed a high interpatient variability of the tracer uptake. Four out of five patients with previous ICT exhibited a relatively high [89Zr]Zr-Df-IAB22M2C uptake in the bone marrow. Also a large number of non metastatic lymph nodes yielded a pronounced [89Zr]Zr-Df-IAB22M2C uptake in four patients. Strikingly, a low [89Zr]Zr-Df-IAB22M2C uptake in the spleen compared to the liver (liver/spleen ratio < 10) was observed in 4 out of the 5 patients with cancer progression during ICT. Interestingly, only one metastasis with an intense tracer was detected in this patient cohort. This first clinical experiences revealed the feasibility to assess potential immune-related changes by [89Zr]Zr-Df-IAB22M2C PET/MRI. Considering these results we hypothesize that the whole body distribution of CD8+ cytotoxic T-cells assessed by non-invasive in vivo [89Zr]Zr-Df-IAB22M2C PET/MRI might be associated with the response to cancer immunotherapy which needs to be investigated in subsequent prospective trials. Citation Format: Johannes Schwenck, Dominik Sonanini, Walter Ehrlichmann, Gabriele Kienzle, Gerald Reischl, Pascal Krezer, Ian Wilson, Ron Korn, Irene Gonzalez-Menendez, Leticia Quintanilla-Martinez, Ferdinand Seith, Andrea Forschner, Thomas Eigentler, Lars Zender, Martin Röcken, Bernd Pichler, Lukas Flatz, Manfred Kneilling, Christian la Fougere. Imaging of CD8+ cytotoxic T-cells by Zr-89-Df-IAB22M2C PET/MRI: First clinical experience in patients with metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB058.

9564 Background: AJCC v8 includes Breslow thickness and ulceration to subdivide stage I and II CM pts into risk groups. In light of the results from adjuvant therapy in stage II CM, it has been discussed that pts’ follow-up and eventually treatment should consider additional markers, namely CP-GEP, to further refine the risk classification provided by the AJCC v8. The aim of this single center study was to clinically validate a prognostic CP-GEP-based risk score for stage I/II CMs combining Breslow, age and the expression of 8 genes SERPINE2, GDF15, ITGB3, CXCL8, LOXL4, TGFBR1, PLAT and MLANA. Methods: All obtainable formalin-fixed paraffin-embedded primaries of stage I/II CMs with negative sentinel lymph node (SLN) from the Central Malignant Melanoma Registry of Germany diagnosed between 2000-2017 and archived in Tuebingen were included. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome. Quantitative reverse transcription polymerase chain reaction of the 8 genes was performed and combined with age and tumor thickness to define CP-GEP low- vs. high-score groups. Relapse-free survival (RFS), distant metastasis free survival (DMFS) and overall survival (OS) were evaluated using Kaplan-Meier curves. CP-GEP score performance was tested using multivariate Cox regression adjusted for tumor thickness, ulceration and age. Results: We included 543 pts with Stage IA (n=78); IB (n=223); IIA (n= 123); IIB (n=73); IIC (n=46). 43% were females, median Breslow was 1.7mm and 25% of tumors had ulceration. The median follow-up was 78 months (IQR 47-116). 311 (57%) patients had a high-risk CP-GEP score. The 5-y RFS rate was 71% and 92% (HR 4.2; p

9526 Background: For the treatment of advanced BRAFV600-mutated melanoma, targeted BRAF/MEK-inhibition is a standard of care. Encorafenib + binimetinib (EB) were approved 2018 in the EU and 2019 in Switzerland, based on positive results from COLUMBUS (NCT01909453), median progression-free survival (PFS) 14.9 mo (5-yr PFS: 23%), overall survival (OS) 33.6 mo (5-yr OS: 35%). As data from controlled trials are based on selected populations, BERINGMELANOMA investigates EB-use under real-world conditions in a broader population. Methods: BERINGMELANOMA (NCT04045691) is an ongoing, multi-national, prospective, longitudinal, non-interventional study. It analyzes the effectiveness (prim. endpoint: 1-yr PFS-rate), QoL and safety of EB-therapy in the unresectable advanced or metastatic setting under real-world conditions, focusing on the first- (1L) and second-line setting including an evaluation of the impact of prognostic factors. The project aims to enroll up to 750 patients (pts) in a total of 80 German, Austrian and Swiss sites (study duration: 8 yrs). So far (10/2019-01/2022), 280 pts have been included. Pts with prior BRAF-/MEK-inhibition (except adjuvant use completed > 6 mo) and > 1 prior therapy line with CPI in the palliative setting were excluded (adjuvant CPI allowed). Results: Here we present the 2nd planned interim snapshot based on the initial 200 enrolled pts (186 treated / 182 evaluable; median FU: 14.2 mo). This analysis set shows a median age of 60.5 yrs (range 20.0-89.0), 45% of pts were female. 87% presented with distant metastases (brain: 30%), with an involvement of ≥3 organ systems in 51% and elevated LDH in 43%. 54% of pts underwent any prior systemic therapy (adjuvant: 30%; 1L CPI palliative: 24%, mainly with ipilimumab + nivolumab). EB was mainly administered in the 1L-setting (60%). Main reasons for EB-selection were: efficacy (44%), physician's preference (34%), QoL (17%). Median estimated EB treatment duration was 11.6 mo (95%CI 8.8-18.6), median relative dose intensity for both drugs: 100%, main reasons EB-discontinuation: PD (55%), toxicity (16%). Treatment adaptations were required in 40% of pts (interruption E 26%, B 29%), toxicity as main reason (E 26%, B 29%). Adverse events were reported in 86% of pts (grade 3/4: 34%), mainly (≥10%, all grades): diarrhea, nausea, fatigue (each 17%), CK increase (16%), GGT increase (11%). No fatal toxicities were observed. Conclusions: This 2nd interim snapshot shows an investigation of EB in a real-world population with advanced disease. Despite the poorer prognosis configuration as compared to the pivotal study, the observed tolerability profile is largely consistent with data derived from COLUMBUS without any new safety signals. The 3rd interim snapshot will be performed after enrollment of 300 pts.

The advent of BRAF/MEK inhibitors (BRAFi/MEKi) has significantly improved progression-free (PFS) and overall survival (OS) for patients with advanced BRAF-V600-mutant melanoma. Long-term survivors have been identified particularly among patients with a complete response (CR) to BRAF/MEK-directed targeted therapy (TT). However, it remains unclear which patients who achieved a CR maintain a durable response and whether treatment cessation might be a safe option in these patients. Therefore, this study investigated the impact of treatment cessation on the clinical course of patients with a CR upon BRAF/MEK-directed-TT. We retrospectively selected patients with BRAF-V600-mutant advanced non-resectable melanoma who had been treated with BRAFi ± MEKi therapy and achieved a CR upon treatment out of the multicentric skin cancer registry ADOReg. Data on baseline patient characteristics, duration of TT, treatment cessation, tumor progression (TP) and response to second-line treatments were collected and analyzed. Of 461 patients who received BRAF/MEK-directed TT 37 achieved a CR. TP after initial CR was observed in 22 patients (60%) mainly affecting patients who discontinued TT (n = 22/26), whereas all patients with ongoing TT (n = 11) maintained their CR. Accordingly, patients who discontinued TT had a higher risk of TP compared to patients with ongoing treatment (p &lt, 0.001). However, our data also show that patients who received TT for more than 16 months and who discontinued TT for other reasons than TP or toxicity did not have a shorter PFS compared to patients with ongoing treatment. Response rates to second-line treatment being initiated in 21 patients, varied between 27% for immune-checkpoint inhibitors (ICI) and 60% for BRAFi/MEKi rechallenge. In summary, we identified a considerable number of patients who achieved a CR upon BRAF/MEK-directed TT in this contemporary real-world cohort of patients with BRAF-V600-mutant melanoma. Sustained PFS was not restricted to ongoing TT but was also found in patients who discontinued TT.

BackgroundCheckpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies.MethodsMGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB–IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR.ResultsPretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, pConclusionsHigh pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens.

Response assessment or prediction to checkpoint inhibitor therapy (CIT) is an unsolved problem in current routine diagnostics of patients with melanoma. Here, we evaluated very early changes of primary and secondary lymphoid organs under CIT in multiparametric [18F]-labeled fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)/MRI as possible predictors of treatment response and investigated their correlation with baseline blood immune biomarkers. Between October 2014 and November 2017, 17 patients with unresectable melanoma (8 females; 65±11 years) undergoing CIT were prospectively evaluated using whole-body 18F-FDG-PET/MRI before CIT start (t0), 2 weeks (t1) and 3 months after CIT initiation (t2). At each time point, the volume, the 18F-FDG-uptake and the mean apparent diffusion coefficient (ADC) of the spleen as well as the 18F-FDG uptake of the bone marrow were assessed. Relative lymphocyte count (RLC), relative eosinophil count (REC) and neutrophil-lymphocyte ratio (NLR) were assessed at baseline. Response Evaluation Criteria in Solid Tumours modified for immune-based therapeutics (iRECIST) and decisions from an interdisciplinary tumor board were used for treatment response evaluation at t2. iRECIST was compared with PET response criteria in solid tumors for image-based response evaluation at different time points. Comparative analysis was conducted with Mann-Whitney U test with false discovery rate correction for multiple testing and correlation coefficients were computed. In lymphoid organs, significant differences (p18F-FDG-uptake in the spleen at t1 and the increase of the uptake t1-t0 (responders/non-responders: standardized uptake value lean body mass 1.19/0.93; +49%/−1%). The best correlation coefficients to baseline biomarkers were found for the 18F-FDG-uptake in the spleen at t1: NLR, r=−0.46; RLC, r=0.43; REC, r=0.58 (p18F-FDG-uptake of bone marrow (+31%/−9%) at t1 and the ADCmean at t2 (+46%/+15%) compared with t0, however, not reaching significance. Our findings indicate that an effective systemic immune response in patients undergoing CIT can be detected as a significantly increased spleen activity in 18F-FDG-PET as early as 2 weeks after treatment initiation.Trial registration numberNCT03132090, DRKS00013925.

Background: Primary resistance to immunotherapy can be observed in approximately 40&ndash, 65% of the stage IV melanoma patients treated with immune checkpoint inhibitors. A minority of the patients receive a second-line therapy, and the clinical benefit is small. Patients and methods: Stage IV melanoma patients treated with first-line PD-1-based immunotherapy between January 2015 and December 2018 were investigated. Primary resistance was defined as progressive disease (PD) at the time of the first tumor assessment after starting immunotherapy. Patients with complete response, partial response, and stable disease were classified as having disease control (DC). Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan&ndash, Meier estimator. Univariate and multivariate logistic regression analyses were performed to determine prognostic factors associated with OS. Results: Three hundred and nineteen patients were included, and 40% had primary resistance to immunotherapy. The median follow-up time was 22 months. Patients with primary resistance had 1-, 2-, and 3-year OS rates of 41%, 15%, and 10%, respectively, compared to 91%, 81%, and 65% for the patients who achieved DC. The following independently significant prognostic factors for OS were identified: protein S100B level and primary tumor localization. There was a statistically significant difference for OS (p &lt, 0.0001) but not for PFS (p = 0.230) when analyzing risk groups formed with a combination of these two variables (low-, intermediate-, and high-risk subgroups). Conclusions: Melanoma patients with primary resistance to immunotherapy have a dismal prognosis. Response at the first tumor assessment after starting immunotherapy is a stronger prognostic factor for the further course of the disease than pretreatment risk factors.

Purpose BRAF and MEK inhibitors significantly improved the prognosis of metastatic melanoma. Nevertheless, initial treatment response may be only temporary. Liquid biopsies (LB) offer a possibility to monitor patients by measuring circulating tumor DNA (ctDNA). We sought to find out whether ctDNA can be used to reliably determine progressive disease under targeted therapy. In addition, we wanted to check whether ctDNA may represent a possible prognostic marker for survival. Patients and methods We included 19 melanoma patients with BRAF and MEK inhibitor therapy. For each patient, a 710 gene panel was analyzed on the latest available tumor tissue before the start of therapy. Repetitive LB were collected in which BRAF V600E/K mutations were monitored using digital droplet PCR (ddPCR). We correlated radiological staging results and overall survival with ctDNA results. Results In 13 patients, ctDNA was detectable when starting targeted therapy, whereas in six patients, ddPCR was always negative, which we confirmed with ultra-deep sequencing. All patients with initially detectable ctDNA had ctDNA values declining to zero during follow-up, increasing again at the time of extracerebral progression or even slightly before detection by imaging. Survival was significantly worse for patients with elevated LDH (p=0.034) or detectable ctDNA (p=0.008) at the start of targeted therapy. Conclusion Therapy monitoring by ctDNA seems to be a reliable method for detecting extracranial progression, even more sensitive and specific than LDH or S100B. However, due to the small number of cases in our study, further studies are necessary.

// Katharina C. Kahler 1 , Christine Blome 2 , Andrea Forschner 3 , Ralf Gutzmer 4 , Axel Hauschild 1 , Lucie Heinzerling 5 , Elisabeth Livingstone 6 , Carmen Loquai 7 , Tina Muller-Brenne 7 , Dirk Schadendorf 6 , Jochen Utikal 8 , Tobias Wagner 2 and Matthias Augustin 2 1 Department of Dermatology, Skin Cancer Center, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany 2 Institute for Health Services Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg, Hamburg, Germany 3 Department of Dermatology, Eberhard-Karls University of Tubingen, Tubingen, Germany 4 Department of Dermatology, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany 5 Department of Dermatology, University Hospital Erlangen, Erlangen, Germany 6 Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany 7 Department of Dermatology, University of Mainz, Mainz, Germany 8 Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Mannheim, Germany Correspondence to: Katharina C. Kahler, email: kkaehler@dermatology.uni-kiel.de Keywords: melanoma; patient preferences; interferon Received: March 27, 2018 Accepted: April 28, 2018 Published: May 25, 2018 ABSTRACT After more than two decades with interferon alfa-2a and 2b (IFN) as the only approved drugs in the adjuvant setting for melanoma, new treatment approaches like immune checkpoint inhibitors and BRAF-MEK inhibitors improve the progression free survival (PFS) and also the overall survival (OS). We compared physicians’ preferences (“utilities”) for health states associated with IFN therapy to their patients’ preferences. Utilities describe a preference for a specific health state on a scale of 0 (as bad as death) to 1.0 (perfect health). Setting: We assessed utilities for health states associated with adjuvant IFN using the standard gamble technique in 108 physicians and 130 melanoma patients. Four IFN toxicity scenarios and three outcome scenarios were given to the participants. Both groups were asked for the 5-year disease free survival (DFS) they would need to accept the described IFN-related side effects. Results: In both groups, utilities for melanoma relapse were significantly lower than for IFN side effects, showing that toxicity was more acceptable than relapse. Physicians indicated higher utilities for each scenario and needed lower 5-year DFS both in case of mild-to-moderate and severe side effects. Patients were willing to tolerate mild-to-moderate and severe toxicity for a 50% and 75% chance of 5-year DFS, while physicians only required a chance of 40% and 50%, respectively. Conclusion: Both physicians and patients rated melanoma recurrence much lower than even severe IFN side effects. In direct comparison, physicians rated cancer-related scenarios more positively and accepted IFN toxicity for an even lower treatment benefit.

Background: Concomitant radiation with BRAF inhibitor (BRAFi) therapy may increase radiation-induced side effects but also potentially improve tumour control in melanoma patients. Methods: A total of 155 patients with BRAF-mutated melanoma from 17 European skin cancer centres were retrospectively analysed. Out of these, 87 patients received concomitant radiotherapy and BRAFi (59 vemurafenib, 28 dabrafenib), while in 68 patients BRAFi therapy was interrupted during radiation (51 vemurafenib, 17 dabrafenib). Overall survival was calculated from the first radiation (OSRT) and from start of BRAFi therapy (OSBRAFi). Results: The median duration of BRAFi treatment interruption prior to radiotherapy was 4 days and lasted for 17 days. Median OSRT and OSBRAFi in the entire cohort were 9.8 and 12.6 months in the interrupted group and 7.3 and 11.5 months in the concomitant group (P=0.075/P=0.217), respectively. Interrupted vemurafenib treatment with a median OSRT and OSBRAFi of 10.1 and 13.1 months, respectively, was superior to concomitant vemurafenib treatment with a median OSRT and OSBRAFi of 6.6 and 10.9 months (P=0.004/P=0.067). Interrupted dabrafenib treatment with a median OSRT and OSBRAFi of 7.7 and 9.8 months, respectively, did not differ from concomitant dabrafenib treatment with a median OSRT and OSBRAFi of 9.9 and 11.6 months (P=0.132/P=0.404). Median local control of the irradiated area did not differ in the interrupted and concomitant BRAFi treatment groups (P=0.619). Skin toxicity of grade ≥2 (CTCAE) was significantly increased in patients with concomitant vemurafenib compared to the group with treatment interruption (P=0.002). Conclusions: Interruption of vemurafenib treatment during radiation was associated with better survival and less toxicity compared to concomitant treatment. Due to lower number of patients, the relevance of treatment interruption in dabrafenib treated patients should be further investigated. The results of this analysis indicate that treatment with the BRAFi vemurafenib should be interrupted during radiotherapy. Prospective studies are desperately needed.

Background: Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date. Patients and methods: Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression. Results: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC)

The clinical availability of small molecule inhibitors specifically targeting mutated BRAF marked a significant breakthrough in melanoma therapy. Despite a dramatic anti-tumour activity and improved patient survival, rapidly emerging resistance, however, greatly limits the clinical benefit. The majority of the already described resistance mechanisms involve a reactivation of the MAPK signalling pathway. The p90 ribosomal S6 kinase (RSK), a downstream effector of the MAPK signalling cascade, has been reported to enhance survival of melanoma cells in response to chemotherapy. Here, we can show that RSK activity is significantly increased in human melanoma cells with acquired resistance to the BRAFV600E/K inhibitor vemurafenib. Interestingly, inhibition of RSK signalling markedly impairs the viability of vemurafenib resistant melanoma cells and is effective both in two-dimensional and in three-dimensional culture systems, especially in a chronic, long-term application. The effect of RSK inhibition can be partly replicated by downregulation of the well-known RSK target, Y-box binding protein 1 (YB-1). Intriguingly, RSK inhibition also retains its efficacy in melanoma cells with combined resistance to vemurafenib and the MEK inhibitor trametinib. These data suggest that active RSK signalling might be an attractive novel therapeutic target in melanoma with acquired resistance to MAPK pathway inhibitors.

Simple Summary A large proportion of patients with metastatic melanoma suffer from psychological distress. Early identification of these patients is important to be able to offer them adequate support. This longitudinal study aimed to investigate the extent to which the psychological distress of patients with malignant melanoma might change during their first three months of treatment with immune checkpoint inhibitors. We found a high proportion of distressed patients in a cohort of 113 patients at the beginning of immunotherapy, which decreased during therapy. A binary logistic regression analysis provided additional factors indicating an increased risk of developing distress—female gender and occurrence of adverse events correlated significantly with distress values above the threshold. The strongest factor was patients’ self-assessment. When initiating immunotherapy, it is also important to consider the needs of patients and offer them psycho-oncological support. Abstract Background: Immune checkpoint inhibitors (ICI) provide effective treatment options for advanced melanoma patients. However, they are associated with high rates of immune-related side effects. There are no data on the distress of melanoma patients during their ICI treatment. We, therefore, conducted a prospective longitudinal study to assess distress and the need for psycho-oncological support in these patients. Methods: Questionnaires were completed before initiation of ICI (T0), after 6–8 weeks (T1), and after 12–14 weeks (T2). We furthermore included the Hornheide Screening Instrument (HSI), distress thermometer (DT), and patients’ self-assessment. Binary logistic regression was performed to identify factors indicating a need for psychooncological support. Results: 36.3%/55.8% (HSI / DT) of the patients were above the threshold, indicating a need for psychooncological support at T0, and 7.8% of the patients reported practical problems. In contrast, at T2, the distress values had decreased to 29.0%/40.2% (HSI/DT), respectively. Female gender and occurrence of side effects significantly correlated to values above the threshold. The strongest factor was the patient’s self-assessment. Conclusion: With the beginning of ICI, psychooncological support should be offered. Furthermore, practical problems should be considered, e.g., transport to therapy. Female patients and patients with side effects should be given special attention, as well as the patient self-assessment.

9555 Background: For the treatment of advanced BRAFV600-mutated melanoma, targeted therapy (BRAF/MEK-inhibition) is a standard of care. Encorafenib + binimetinib (EB) were approved in the EU in Sep 2018 and in Switzerland in Nov 2019, based on positive results from COLUMBUS (NCT01909453), with a median progression-free survival (PFS) of 14.9 mo (4-year PFS: 26%) and overall survival (OS) of 33.6 mo (4-year OS: 39%). As data from controlled trials are based on selected populations, BERINGMELANOMA investigates the use of EB under real-world conditions in a broader population. Methods: BERINGMELANOMA is an ongoing, multi-national, multi-center, prospective, longitudinal, non-interventional study. It analyzes the effectiveness, quality of life and tolerability of EB-treatment under real-world conditions (primary endpoint: 1-year PFS-rate), focusing on the first- (1L) and second-line setting and including an evaluation of the impact of prognostic factors. The project aims to enroll up to 750 patients (pts) in a total of 80 German, Austrian and Swiss sites with a study duration of 8 yrs. So far, from Oct 2019 to Jan 2021, 153 pts have been included. Pts with prior BRAF-/MEK-inhibition (except adjuvant use completed > 6 mo) and > 1 prior treatment line were excluded. Results: Here we present the first planned interim analysis based on the initial 100 enrolled pts (91 treated / 89 evaluable; median follow-up: 8.1 mo). This analysis set shows a median age of 63.0 yrs (range 29.0-88.0), 52% of pts were female. 81% presented with distant metastases (brain: 31%), with an involvement of ≥3 organ systems in 51% and an elevated LDH in 42%. 54% of pts underwent prior systemic therapy (adjuvant: 28%; 1L: 24%, with ipilimumab + nivolumab as main 1L-treatment: 52%). EB was mainly administered in the 1L-setting (65%). Main reasons for EB-selection were: physician's preference (37%), efficacy (34%), quality of life (21%). Median estimated EB treatment duration was 12.7 mo (95%CI 8.3-NE), median relative dose intensity was 100% for both drugs. Treatment adaptations were required in 34% of pts. Adverse events (AE) were reported in 76% of pts (grade 3/4: 26%). Main AE (≥10%, all grades) were: nausea (18%), diarrhea (17%), CK increase (15%), fatigue (11%), gamma-GT increase (11%). No fatal toxicities were observed. Conclusions: This first interim analysis of BERINGMELANOMA shows an investigation of EB in a real-world population with advanced disease. Despite the poorer prognosis configuration as compared to the pivotal study, the observed treatment duration and tolerability profile are largely consistent with data derived from COLUMBUS without any new safety signals. The second interim analysis will be performed after enrollment of 200 pts and will include an initial analysis of effectiveness data. Clinical trial information: NCT04045691.

9524 Background: High tumor mutational burden (TMB) is associated with a favorable outcome in metastatic melanoma patients treated with immune checkpoint inhibitors. However, data are limited in the adjuvant setting. As BRAF mutated patients have an alternative with targeted adjuvant therapy, it is important to identify predictive factors for relapse and recurrence-free survival (RFS) in patients receiving adjuvant PD-1 antibodies. Methods: We systematically evaluated all melanoma patients who started adjuvant PD-1 antibody therapy at our center between March 2018 and September 2019 to identify predictive factors for outcome. The median follow-up time from start of adjuvant anti-PD-1 therapy was 22 months. Tumor and normal tissue of all stage IIIC/D/IV patients and of stage IIIA/B patients with relapse were sequenced using a 700 genes panel. Predictive factors for relapse and RFS were identified using univariate and multivariate logistic and Cox regression analysis. RFS was estimated by the Kaplan-Meier method. TMB high was defined as the top 20 % of the cohort, corresponding to TMB values ≥ 20 Var/Mb. Results: A total of 165 patients were included in this study. According to AJCC 8th the initial tumor stages at the beginning of adjuvant anti-PD-1 therapy were as follows: N = 80 stage IIIA/B (48 %), N = 85 stage IIIC/D/IV (52 %). 72/165 patients (44 %) suffered a relapse, 44/72 (61 %) with loco regional and 28/72 (39 %) with distant metastases. Sequencing results were available from 79 / 85 patients with stage IIIC/D/IV. Here we present the results of this cohort. TMB low (OR 17.46, 95%CI 4.03-75.55; p < 0.0001) or absence of BRAF V600E/K mutation (OR 4.13, 95%CI 1.36-12.53; p = 0.012) were statistically significant, independent predictive factors for relapse. Also, with regard to RFS, BRAF mutation status and TMB were statistically significant and independent predictive factors. In the table below we display results for the combined variables. Patients with BRAF V600E/K mutation and TMB high had the best outcome. Conclusions: We identified TMB high as positive predictive marker in stage IIIC/D/IVmelanoma patients with adjuvant PD-1 antibody therapy. In tumors with BRAF V600E/K mutation and concurrent low TMB, adjuvant targeted therapy with BRAF- and MEK-inhibitors may be an alternative. This is also supported by the data on adjuvant dabrafenib and trametinib, which showed a greater advantage in patients with low TMB, presumably due to less tumor heterogeneity.[Table: see text]

Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail.Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Objective Measuring the success of molecularly guided therapies is a major challenge in precision oncology trials. A commonly used endpoint is an intra-patient progression-free survival (PFS) ratio, defined as the PFS interval associated with molecularly guided therapy (PFS2) divided by the PFS interval associated with the last prior systemic therapy (PFS1), above 1.3 or, in some studies, above 1.33 or 1.5. Methods To investigate if the concept of PFS ratios is in agreement with actual response evaluations by physicians, we conducted a survey among members of the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Programme of the German Cancer Consortium who were asked to classify the success of molecularly guided therapies in 194 patients enrolled in the MOSCATO 01 trial based on PFS1 and PFS2 times. Results A comparison of classification profiles revealed three distinct clusters of PFS benefit assessments. Only 29% of assessments were consistent with a PFS ratio threshold of 1.3, whereas the remaining 71% of participants applied a different classification scheme that did not rely on the relation between PFS times alone, but also took into account absolute PFS1 intervals. Based on these community-driven insights, we developed a modified PFS ratio that incorporates the influence of absolute PFS1 intervals on the judgement of clinical benefit by physicians. Application of the modified PFS ratio to outcome data from two recent precision oncology trials, MOSCATO 01 and WINTHER, revealed significantly improved concordance with physician-perceived clinical benefit and identified comparable proportions of patients who benefited from molecularly guided therapies. Conclusions The modified PFS ratio may represent a meaningful clinical endpoint that could aid in the design and interpretation of future precision oncology trials.

Background Combining stereotactic radiosurgery (SRS) and active systemic therapies (STs) achieved favourable survival outcomes in patients with melanoma brain metastases (MBMs) in retrospective analyses. However, several aspects of this Treatment strategy remain poorly understood. We Report on the Overall survival (OS) of patients with MBM treated with a combination of radiotherapy (RT) and ST as well as the Impact of the v-Raf murine sarcoma viral oncogene homolog B (BRAF)-V600 Mutation (BRAFmut) status, types of RT and ST and their sequence. Patients and methods Data of 208 patients treated with SRS or whole brain Radiation therapy (WBRT) and either immunotherapy (IT) or targeted therapy (TT) within a 6-week- interval to RT were analysed retrospectively. OS was calculated from RT to death or last follow-up. Univariate- and multivariate Cox proportional hazard analyses were performed to determine prognostic Features associated with OS. Results The median follow-up was 7.3 months. 139 patients received IT, 67 received TT and 2 received IT and TT within 6 weeks to RT (WBRT 45%; SRS 55%). One-year Kaplan-Meier OS rates were 69%, 65%, 33% and 18% (P < .001) for SRS with IT, SRS with TT, WBRT with IT and WBRT with TT, respectively. Patients with a BRAF mut receiving IT combined with RT experienced higher OS rates (88%, 65%, 50% and 18%). TT following RT or started before and continued thereafter was associated with improved median OS compared with to TT solely before RT (12.2 [95% confidence interval {CI} 9.3–15.1]; 9.8 [95% CI 6.9–12.6] versus 5.1 [95% CI 2.7–7.5]; P = .03). Conclusion SRS and IT achieved the highest OS rates. A BRAFmut appears to be a favourable prognostic factor for OS. For the combination of RT and TT, the sequence appears to be crucial. Combinations of WBRT and ST achieved unprecedentedly high OS rates and Warrant further studies.

Prognostic factors of melanoma patients with distant metastases remain poorly established. This study aimed to compare the prognostic impact of putative serum biomarkers, namely S100B, YKL-40 or CCL17, in stage IV melanoma patients. Serum concentrations were analyzed by ELISA. Disease-specific survival of 80 patients according to S100B, YKL-40 or CCL17 and clinical factors were calculated by univariate Kaplan–Meier survival and multivariate analysis. Low serum levels of S100B, high concentrations of CCL17 and female gender correlated with improved survival. A trend for favorable prognosis was observed for the M categories M1a/b versus M1c according to the AJCC classification. No correlation with survival was evident for YKL-40 serum levels and age. In multivariate analysis, S100B (HR 2.1; p = 0.005) and CCL17 (HR 1.8; p = 0.029) had independent prognostic impact. Patients with a combination of normal S100B and high CCL17 had a high chance for long-term survival, which was 43 % after 3 years. Serum levels of CCL17 and S100B represent independent prognostic markers for melanoma patients with distant metastases. These biomarkers were more powerful than the M category according to the AJCC classification to indicate overall survival. CCL17 represents a promising biomarker upon immune checkpoint blockade in melanoma.

We aimed to determine the prevalence and importance of fear of cancer progression (FoP) in melanoma patients with stage IA tumours to assess psychosocial and demographic factors associated with severity of FoP and to determine the relationship of FoP and quality of life (QoL). One hundred and thirty-six patients with stage IA melanoma completed the short version of the Fear of Progression Questionnaire (FoP-Q-SF), the Hospital Anxiety and Depression Scale (HADS) and the EORTC-QLQ-C30. We found a mean FoP-Q-SF sum score of 30.2 points (±8.4 points SD). In this study, 33% of patients reported high FoP at or above the cutoff-value of 34 points. Higher FoP was found in women (p < 0.01), young (p = 0.03) and employed (p = 0.02) patients. Being confronted with a cancer diagnosis in closely related persons predicted higher FoP (p < 0.01). FoP correlated positively with the HADS anxiety (r = 0.50, p < 0.01) and depression scales (r = 0.26, p < 0.01) and negatively with the EORTC-QLQ-C30 global health state (r = -0.32, p < 0.01). FoP is considerably prevalent in low-risk melanoma patients and associated with reduced QoL, cancer in related persons, women sex and participation in working life. Considerably high levels of FoP, even in patients with low-risk malignancies, underline the need for psychosocial support and psychotherapeutic interventions for melanoma patients.

Malignant melanoma is potentially life-threatening but in most cases curable if detected early. Willingness to pay (WTP) is a preference-based construct that reflects burden of disease by assessment of the monetary value for a hypothetical cure from disease. Since WTP (directly as total amount of money) has not been assessed so far in patients with low risk melanoma, it was interesting to gain insights in this patient population and then, in a second step, compare it directly with the WTP of their treating dermato-oncologists. WTP was assessed in 125 patients with low-risk melanoma and additionally in 105 treating physicians, asking for the one-time and continuous payments they would be willing to make for a sustainable cure, both as absolute sums and as percentages of monthly income. The median WTP based on one-time payment was €10,000 for patients and €100,000 for physicians; relative numbers were 100% versus 300% of monthly income. For continuous monthly payments, WTP was €500 for patients and €1000 for physicians, relative numbers 25% and 50% of income, respectively. Even after controlling for income differences, there was a significantly higher WTP in physicians for all four questions. Compared to patients with chronic skin diseases such as vitiligo, rosacea, atopic eczema and psoriasis, patients with low-risk melanoma showed a significantly higher WTP. Our data suggest that there is a relevant burden of disease even in patients with low-risk tumors. Higher WTP of physicians underlines the prevalence of differences in disease perception. CA extern

Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates. To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent. We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab. Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR. Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient’s convenience.