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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.

Aim Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear. Patients and methods Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres. Results We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1–181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of ICI resulted in decrease of lipase after reinduction of ICI lipase levels increased again in 12 of 24 patients. In 18 patients (27%), ICI was continued unchanged, and in 12 (67%) of them, lipase levels normalised. Twenty-two patients were identified with newly diagnosed type I diabetes mellitus related to ICI, and 12 (55%) thereof had also lipase elevation mainly shortly before or after the diagnosis of diabetes. Fourteen (64%) patients had other irAE, mainly thyroiditis. Irrespective of lipase elevation, patients frequently showed a rapid onset with ketoacidosis, decreased c-peptide, and strongly increased blood glucose levels. Conclusion Increased serum lipase during ICI is often not associated with pancreatitis but with other irAE as possible cause. Therefore, it might be sufficient to regularly monitor blood glucose levels and perform further workup only in case of signs or symptoms of pancreatitis and/or exocrine pancreas insufficiency.

Purpose Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. Methods A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. Results 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. Conclusion Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.

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.

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.

Cutaneous melanoma is one of the most aggressive forms of skin neoplasms and represents a major cause of neoplastic or cancer death in Europe. Without adequate therapy, the 5-year survival rate is 15% when the disease metastasizes to distant organs. The objective of our study was to evaluate the status quo of the current treatment standards in stage IV melanoma and rationale for therapy decisions in Germany and Austria between January 2016 and September 2018. In this retrospective, anonymized registry, data of male and female patients with unresectable advanced/metastatic BRAF-positive cutaneous melanoma treated in the first, second, and third line with registered substances were analyzed using descriptive statistics. Ninety-nine patients (50.5% male) received a total of 172 treatment lines. The first (99 patients), second (56 patients), and third (17 patients) treatment lines were documented. Within the 80.8% of patients with stage IV melanoma, targeted therapy (TT) was more frequently administered as a first-line treatment than immunotherapy (IO) with checkpoint inhibitors (59.6% TT vs. 40.4% IO). Across all lines, patients received TT in 54.7% and IO in 43.0% of the cases. As targeted agents, dabrafenib plus trametinib was predominantly prescribed (72.3%), whereas the monotherapy with anti-programmed cell death protein 1 and anti-cytotoxic T lymphocyte-associated protein 4 antibodies or their combination was prescribed similarly often (50.0% vs. 47.3%). Most commonly, the treatment type was switched from TT to IO or vice versa upon disease progression. The most frequent rationales for prescribing either TT or IO were remission pressure (72.9%) or physician’s preference (45.0%), respectively. Disease progression was a more frequent cause of treatment discontinuation than undesired events. Patients in Germany and Austria with unresectable advanced or metastatic BRAF-mutant melanoma predominantly receive guideline-recommended treatments. TT was more frequently administered than IO while the rationale for prescribing a specific treatment type differed between the two.

Wegen seiner fruhzeitigen Metastasierung ist beim malignen Melanom eine rasche Diagnosestellung von zentraler Bedeutung. Ist der „schwarze Hautkrebs“ erst erkannt, sind weitere diagnostische und therapeutische Schritte notwendig, die sich an genau definierten Algorithmen orientieren. Auf den Gebieten der adjuvanten und metastasierten Situation haben in den letzten Jahren neue Erkenntnisse zu grundlegenden Anderungen des Therapieregimes gefuhrt. Mit diesem Artikel soll eine Ubersicht uber das aktuelle leitlinienorientierte Vorgehen beim malignen Melanom gegeben werden.

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.

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.

Introduction Afatinib is a tyrosine kinase inhibitor (TKI), that has been approved for treating patients with epidermal growth factor receptor (EGFR) mutated advanced non-small-cell lung cancer (NSCLC). Stevens-Johnson syndrome (SJS) related to EGFR directed TKIs is a rare adverse event. Case presentation We report a case of a 79-year-old white female with EGFR-mutated, metastatic non-small-cell lung cancer treated with afatinib as first-line palliative treatment, who developed a SJS after two months of treatment. Discontinuation of the TKI and systemic glucocorticoid treatment led to improvement of symptoms and recovery. Conclusion Severe adverse cutaneous drug reactions that predominantly involve the skin and mucous membranes during treatment with afatinib should alert clinicians to suspect SJS and react appropriately.

In der Phase-III-Studie KEYNOTE-006 wurde Pembrolizumab mit Ipilimumab, der bisherigen Standardtherapie bei fortgeschrittenem Melanom, verglichen.

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease affecting the skin and mucous membranes. Autoreactive CD4(+) T helper (Th) lymphocytes are crucial for the autoantibody response against the desmosomal adhesion molecules, desmoglein (dsg)-3 and dsg1. Eleven patients with extensive PV were treated with the anti-CD20 antibody, rituximab (375 mg per m(2) body surface area once weekly for 4 weeks). Frequencies of autoreactive CD4(+) Th cells in the peripheral blood of the PV patients were determined 0, 1, 3, 6, and 12 months after rituximab treatment. Additionally, the clinical response was evaluated and serum autoantibody titers were quantified by ELISA. Rituximab induced peripheral B-cell depletion for 6-12 months, leading to a dramatic decline of serum autoantibodies and significant clinical improvement in all PV patients. The frequencies of dsg3-specific CD4(+) Th1 and Th2 cells decreased significantly for 6 and 12 months, respectively, while the overall count of CD3(+)CD4(+) T lymphocytes and the frequency of tetanus toxoid-reactive CD4(+) Th cells remained unaffected. Our findings indicate that the response to rituximab in PV involves two mechanisms: (1) the depletion of autoreactive B cells and (2) the herein demonstrated, presumably specific downregulation of dsg3-specific CD4(+) Th cells.