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Background: Metastatic uveal melanoma (mUM) is rare. Immune checkpoint inhibitors (ICIs) have shown modest efficacy in mUM. Tebentafusp prolonged overall survival (OS) in a phase 3 study. We aimed to investigate the efficacy and safety of the sequence of tebentafusp and ICIs., Methods: Patients with HLA-A * 02:01 positive mUM, or metastatic GNA11/GNAQ mutant melanocytic tumors treated with tebentafusp followed by ICIs (group 1) or the inverse sequence (group 2) at any treatment line were retrospectively identified. The primary objective was OS rate at 2 years., Results: 131 patients were included; 51 in group 1 and 80 in group 2. 30 % in group 1 % and 40 % in group 2 had normal baseline lactate dehydrogenase (LDH, p = 0.05). 94 % in group 1 % and 77 % in group 2 had multilobular liver disease (p = 0.02). Median OS was 22.4 months (95 % CI 19-24.8) in group 1 and 33.6 months (95 % CI 28.9-43) in group 2 (p = 0.004). Total median PFS was 12 months (95 % CI 10.7-18.8) in group 1 and 20.3 months (95 % CI 17.2-27.3) in group 2 (p = 0.04). The frequency of cytokine release syndrome was higher in group 2 (15 % vs 27 %). Other clinical factors were associated with short total PFS in the multivariable analysis., Conclusions: Both treatment sequences are clinically feasible. A clinical benefit was noted in the sequential combination of ICIs followed by tebentafusp. This observation is limited by the retrospective nature of the study and merits further investigation in prospective clinical trials., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FD receives/received honoraria and travel support from Merck Sharp & Dohme, Bristol Myers Squibb, Pierre Fabre and Sun Pharma. EKH reports: advisory role; Novartis, MSD; speaker´s Bureau: Novartis, MSD; research Funding: funding paid to Dr. Koch Hein Institution for support of a melanoma registry in Chile; travel, accommodations, expenses: Pfizer, Novartis, Roche Pharma AG. CGM receives/received honoraria for lectures/advisory board and travel support from Pierre Fabre, BMS, MSD. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IOBiotech, Immunocore, Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR Ltd, Pierre Fabre, Regeneron, Scancell, SkylineDX B.V. O.M. has consulting/advisory roles for Bristol Myers Squibb, MSD, Roche, Novartis, Amgen, Pierre Fabre, and Neracare; has received research grants from Bristol Myers Squibb, MSD, and Amgen; is a consultant advisor or a paid speaker for Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Amgen, and Nektar; has received research funding from Bristol Myers Squibb and Pierre Fabre; and is the cofounder of a cell therapy company called Cellula. DBJ has served on advisory boards or as a consultant for BMS, Catalyst Biopharma, Iovance, The Jackson Laboratory, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte. EK has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Pierre Fabre, Immunocore and Lilly, and received research grants from Bristol Myers Squibb, Delcath, Novartis and Pierre-Fabre. Not related to current work and paid to institute. AMJ has received research funding (institution) from Immunocore, Merck Sharp and Dohme, Bristol Myers Squibb. RD declares financial interests from Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable., Methods: In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57)., Results: In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively)., Conclusions: This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens., Competing Interests: AG speaker´s honoraria from Allmirall, Amgen, Bristol-Myers Squibb, Immunocore, MSD Sharp & Dohme and Roche; intermittent advisory board relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, Delcath Systems Inc, GSK, Novartis, MSD Sharp & Dohme, Pfizer, and Roche. CB declares speaker´s and/or consultancy honoraria from Almirall, Bristol-Myers Squibb, Delcath, Immunocore, Leo Pharma, Miltenyi, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals, Regeneron, and Sanofi-Aventis outside the submitted work. CP received honoraria speaker honoraria or honoraria as a consultant and travel support from Novartis, Bristol-Myers Squibb, Roche, Merck Serono, MSD Sharp & Dohme, Celgene, AbbVie, Sun Pharma, UCB, Allergy Therapeutics, and LEO. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, Bristol-Myers Squibb, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Sanofi, and Immunocore and research funding from Novartis and Roche. FZ declares speakers and advisory board honoraria and/or travel support from Bristol-Myers Squibb, MSD Sharp & Dohme, Roche, Novartis, Pierre Fabre Pharmaceuticals, and Sanofi-Aventis outside the submitted work. JCH declares research support from Bristol Myers Squibb, Sanofi, and Sunpharma, advisory board honoraria from GSK, Pierre Fabre Pharmaceuticals, Sun Pharma, speaker honoraria from Amgen, Bristol-Myers Squibb, Delcath, GSK, Immuno core, MSD Sharp & Dohme, Novartis, Sanofi and Sun Pharma and travel support from Bristol-Myers Squibb, Iovance and Sun Pharma. SH declares speakers and advisory board honoraria from Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, Sanofi, Sun Pharma, and Pierre Fabre Pharmaceuticals. JUl: Speakers and advisory board honoraria from Bristol-Myers Squibb, Kyowa-Kirin, Merck Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Sanofi, and travel support from Pierre Fabre Pharmaceuticals. JUt is on the advisory board or has received honoraria and travel support from Amgen, Bristol-Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre Pharmaceuticals, Roche, Sanofi outside the submitted work. KCK serves as a consultant to Philogen, Bristol-Myers Squibb, MSD Sharp & Dohme, Sanofi Aventis, and Immunocore and received travel grants and speaker fees from Philogen, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb, MSD Sharp & Dohme, Sun Pharma, Sanofi Aventis, Novartis, Medac and has received research support by Novartis. K-MT received speaker or consultant honoraria and travel support from Bristol-Myers Squibb, MSD Sharp & Dohme, Roche, Novartis, Pierre Fabre Pharmaceuticals, Sanofi Genzyme, Sun Pharma, Amgen, LEO Pharma, Galderma, Almirall, and Candela. ME declares honoraria and travel support from Bristol-Myers Squibb, Immunocore, Novartis, Pierre Fabre Pharmaceuticals, and Sanofi, outside the submitted work. MVH: Honoraria from MSD Sharp & Dohme, Bristol-Myers Squibb, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma. PM Research support: Novartis, Bristol-Myers Squibb, MSD Sharp & Dohme. Honoraria for lectures: Roche, Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Merck-Serono, Pierre Fabre Pharmaceuticals, Sanofi, Sun Pharma, Baiersdorf; Honoraria for advisory boards: Roche Pharma, Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme, Immunocore, Sun Pharma, Sanofi. PT: Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, CureVac, Roche, Kyowa Kirin, Biofrontera, Invited Speaker, Personal BMS, Novartis, Pierre Fabre Pharmaceuticals, Merck Serono, Sanofi, Roche, Kyowa Kirin, Advisory Board, Personal BMS, Pierre Fabre Pharmaceuticals, Other, Personal, Travel support. RG Research support: Amgen, MSD Sharp & Dohme, Sun Pharma, Sanofi/Regeneron, Almirall, Kyowa Kirin. Honoraria for lectures: Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, MSD Sharp & Dohme, Sun, Pierre Fabre Pharmaceuticals, Sanofi/Regeneron, Sun Pharma Honoraria for advisory boards: Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme, 4SC, Immunocore, Sun Pharma, Sanofi/Regeneron, Delcath. SU declares research support from Bristol-Myers Squibb and MSD Sharp & Dohme; speakers and advisory board honoraria from Bristol-Myers Squibb, MSD Sharp & Dohme, Merck Serono, Novartis, and Roche, and travel support from Bristol-Myers Squibb, and MSD Sharp & Dohme. UL declares research support from MSD Sharp & Dohme; speakers and advisory board honoraria from MSD Sharp & Dohme, Novartis, Sanofi, and Sun Pharma, and travel support from Pierre Fabre Pharmaceuticals and Sun Pharma. BS Speakers honoria and/or travel support from Amgen, Bristol-Myers Squibb, MSD Sharp & Dohme, Jansen, Novartis, Roche, Sun Pharma, abbvie, Sanofi, Pierre Fabre Pharmaceuticals, Boehringer Ingelheim and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AT declared a past co-authorship with the author RG, JH, SH, KCK, CL, FM, MM, PT, K-MT, FZ, and MVH to the handling editor., (Copyright © 2024 Koch, Petzold, Dippel, Erdmann, Gesierich, Gutzmer, Hassel, Haferkamp, Kähler, Kreuzberg, Leiter, Loquai, Meier, Meissner, Mohr, Pföhler, Rahimi, Schell, Terheyden, Thoms, Ugurel, Ulrich, Utikal, Weichenthal, Ziller, Berking and Heppt.)

Background: Immune checkpoint inhibitors (ICIs) such as PD(L)1 and CTLA4 antibodies as well as targeted therapies such as BRAF and MEK inhibitors have significantly improved the systemic treatment of skin cancer in adjuvant and advanced therapy settings. All these drugs differ in their spectrum of side effects., Materials and Methods: The aim of this article is to provide an overview of the spectrum of side effects of dermato-oncological therapies and their management, taking into account the current literature., Results: The most important side effects of ICIs, the CCR4 inhibitor mogamulizumab, the ImmTAC tebentafusp, the BRAF and MEK inhibitors and the multityrosine kinase inhibitor imatinib are considered., Conclusions: Side effects can manifest themselves in all organ systems. Chronic side effects and long-term harm are possible, especially with ICIs, and require close therapy monitoring and patient education. Knowledge of the side effects and the temporal, sometimes delayed course of their occurrence are essential for diagnosis and prompt initiation of therapy., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: Adjuvant treatment with immune checkpoint inhibitors, such as PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT), has shown a significant improvement in disease-free survival (DFS) for high-risk melanoma patients. However, due to specific side effects, the choice of treatment is often influenced by the risk of toxicity. Therefore, the role of physicians in treatment decisions of patients is crucial. This study investigated for the first time in a multicenter setting the attitudes and preferences of dermatooncologists in Germany and Switzerland regarding adjuvant treatment with (c)ICI and TT., Methods: In the GERMELATOX-A study, 108 physicians (median age: 32 yrs, 67.6% female) from 11 skin cancer centers were surveyed to rate typical side effect scenarios of (c)ICI and TT treatments and then compared to patients' ratings evaluated in a previous analysis from the same centers. The scenarios described mild-to-moderate or severe toxicity and included melanoma relapse leading to death. The physicians were asked about the level of side effects they would tolerate in exchange for a reduction in melanoma relapse and an increase in survival at 5 years., Results: The preferences of physicians and patients revealed significant differences regarding adjuvant melanoma treatment with (c)ICI and TT (p < 0.05). Compared to patients, physicians tend to value a melanoma relapse less severe, according to a visual analog scale. They were also less threatened by all scenarios of side effects during adjuvant treatment with (c)ICI or TT, compared to patients. Physicians required lower risk reductions for disease-free survival (DFS) and overall survival (OS) for both ICI and TT and their drug-related side effects to accept these treatments. In case of severe side effects, physicians required similar 5-year DFS rates for ICI and TT (60-65%), while patients needed a 15% improvement of 5-year DFS for ICI compared to TT (80%/65%). For survival, physicians expected an OS improvement of + 10% for all three treatment modalities, whereas patients required a higher increase: + 18-22% for ICI and + 15% for TT., Conclusion: Our study highlights the importance of understanding the patient's perspective and a potential difference to the doctor's view when making decisions about adjuvant melanoma treatment with (c)ICI and TT, especially as these treatments are increasingly being implemented in earlier stages., (© 2024. The Author(s).)

Purpose: The interaction of gut microbiome and immune system is being studied with increasing interest. Disturbing factors, such as antibiotics may impact the immune system via gut and interfere with tumor response to immune checkpoint blockade (ICB)., Methods: In this multicenter retrospective cohort study exclusively treatment-naïve patients with cutaneous or mucosal melanoma treated with first-line anti-PD-1 based ICB for advanced, non-resectable disease between 06/2013 and 09/2018 were included. Progression-free (PFS), and overall survival (OS) according to antibiotic exposure (within 60 days prior to ICB and after the start of ICB vs. no antibiotic exposure) were analyzed. To account for immortal time bias, data from patients with antibiotics during ICB were analyzed separately in the time periods before and after start of antibiotics., Results: Among 578 patients with first-line anti-PD1 based ICB, 7% of patients received antibiotics within 60 days prior to ICB and 19% after starting ICB. Antibiotic exposure prior to ICB was associated with worse PFS (adjusted HR 1.75 [95% CI 1.22-2.52]) and OS (adjusted HR 1.64 [95% CI 1.04-2.58]) by multivariate analysis adjusting for potential confounders. The use of antibiotics after the start of ICB had no effect on either PFS (adjusted HR 1.19; 95% CI 0.89-1.60) or OS (adjusted HR 1.08; 95% CI 0.75-1.57)., Conclusions: Antibiotic exposure within 60 days prior to ICB seems to be associated with worse PFS and OS in melanoma patients receiving first-line anti-PD1 based therapy, whereas antibiotics after the start of ICB do not appear to affect PFS or OS., Competing Interests: Declaration of Competing Interest E.C. received travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, UCB and Almirall outside the submitted work. B.S. Honoraria from MSD, BMS, SUN Pharma, Allmiral, Novartis; Advisory Board for MSD, BMS, Pierre Fabre Pharma, Sanofi; travel support from BMS, Novartis, Pierre Fabre Pharma; Research Funding from Novartis; all outside the submitted work. M.S. received speaker honoraria from Novartis and advisory board honoraria from Sanofi Genzyme. R.G. declares research support from Novartis, Amgen, Sanofi, Merck-Serono, Admiral, SUN Pharma and Kyowa-Kirin; honoraria for lectures from Roche Pharma, Bristol-Myers Scuibb, Novartis, MSD. Almirall, Amgen, Merck-Serono, SUN Pharma, Pierre-Fabre, and Sanofi; advisory honoraria from Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Admiral, Amgen, Pierre-Fabre, Merck-Serono, 4SC, Sun Pharma, Merck-Serono, Sanofi, Delcath and Immunocore. C.L. receives personal fees and travel reimbursement from MSD, BMS, Merck, Sanofi, Almirall Hermal, Kyowa Kirin, Biontech, Pierre Fabre, Novartis and Sun Pharma outside the submitted work. K.K. has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. A.Z.M. received travel support from Novartis, Genzyme, and Bristol-Myers Squibb, outside the submitted work. J.M.P. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis, Sanofi and received travel support from Bristol-Myers Squibb, Novartis, Pierre Fabre and Therakos. E.G. received travel support from Pierre-Fabre, outside the submitted work. A.M. received travel support from Novartis, outside the submitted work. A.R. received grants, personal fees, and non-financial support from Novartis; grants and non-financial support from Bristol-Myers Squibb; personal fees and non-financial support from Roche; personal fees from Merck Sharp & Dohme; and non-financial support from Amgen, outside the submitted work. S.U. declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis; and meeting and travel support from Almirall, Bristol-Myers Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sun Pharma; outside the submitted work. D.S. received grants and other support from Bristol-Myers Squibb, personal fees from Bristol-Myers Squibb during the conduct of the study; personal fees from Amgen; personal fees from Boehringer Ingelheim; personal fees from InFlarX; personal fees and other support from Roche; grants, personal fees and other support from Novartis; personal fees from Incyte; personal fees and other support from Regeneron; personal fees from 4SC; personal fees from Sanofi; personal fees from Neracare; personal fees from Pierre-Fabre; personal fees and other support from Merck-EMD; personal fees from Pfizer; personal fees and other support from Philiogen; personal fees from Array, personal fees and other support from MSD Sharp & Dohme, outside the submitted work. E.L. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, Sunpharma, Takeda and travel support from Bristol-Myers Squibb, Pierre- Fabre, Sunpharma and Novartis, outside the submitted work.A.S. L.Z. served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, and Sanofi; and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, and Novartis, outside the submitted work. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM., (© 2023. The Author(s).)

Monoclonal antibodies (mAbs) acting as immune checkpoint inhibitors (ICIs) are among the most frequently used immunotherapies in oncology. However, precision medicine approaches to adapt the treatment to the patient are still poorly exploited. Given the risk of severe adverse reactions, predicting patient eligibility for ICI therapy represents a great asset for precision medicine. Today, the extended panel of mass spectrometric approaches, accompanied by newly developed sample preparation methods is a strategy of choice for responder and non-responder stratification on a molecular basis, and early detection of resistance. In this perspective article, we review the biodisposition of mAbs, the interest in molecular stratification of patients treated with these mAbs, and the possible analytical strategies to achieve this goal, with a major emphasis on mass spectrometric approaches., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Immune checkpoint inhibitors (ICI) are now being used in a number of dermato-oncological indications. In particular, the approval for adjuvant therapy of high-risk stage IIB/C and III melanoma means that more patients of fertile age receive ICI., Objectives: This raises the question of how ICIs affect male and female fertility and whether they are teratogenic., Materials and Methods: Compilation of current data from the summary of product characteristics (SmPCs) and by literature search (PubMed)., Results: Immune-related adverse events of ICI can impair fertility in the acute stage, and especially in the case of endocrine side effects, also in the long term. These include hypothyroidism, as well as adrenal and pituitary insufficiency. However, fertility can usually be restored with hormone replacement. Direct autoimmune effects on the reproductive organs are probably very rare, although immune-related orchitis has been described. Reliable contraception should be used in women of childbearing age. Pregnant women should only receive ICI in urgent exceptional cases, because the miscarriage rate is probably significantly increased., Conclusions: Unfortunately, the current data on patient counselling is still very sparse. Scientific studies on the influence of ICI on fertility and teratogenicity are urgently needed., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Based on its viral-associated or UV-associated carcinogenesis, Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer. Thus, clinically evident MCC occurs either in immuno-compromised patients or based on tumor-intrinsic immune escape mechanisms. This notion may explain that although advanced MCC can be effectively restrained by treatment with PD-1/PD-L1 immune checkpoint inhibitors (ICIs), a considerable percentage of patients does not benefit from ICI therapy. Biomarkers predicting ICI treatment response are currently not available., Methods: The present multicenter retrospective study investigated clinical and molecular characteristics in 114 patients with unresectable MCC at baseline before treatment with ICI for their association with therapy response (best overall response, BOR). In a subset of 21 patients, pretreatment tumor tissue was analyzed for activation, differentiation and spatial distribution of tumor infiltrating lymphocytes (TIL)., Results: Of the 114 patients, n=74 (65%) achieved disease control (BOR=complete response/partial response/stable disease) on ICI. A Bayesian cumulative ordinal regression model revealed absence of immunosuppression and a limited number of tumor-involved organ systems was highly associated with a favorable therapy response. Unimpaired overall performance status, high age, normal serum lactate dehydrogenase and normal serum C reactive protein were moderately associated with disease control. While neither tumor Merkel cell polyomavirus nor tumor PD-L1 status showed a correlation with therapy response, treatment with anti-PD-1 antibodies was associated with a higher probability of disease control than treatment with anti-PD-L1 antibodies. Multiplexed immunohistochemistry demonstrated the predominance of CD8 + effector and central memory T cells (T CM ) in close proximity to tumor cells in patients with a favorable therapy response., Conclusions: Our findings indicate the absence of immunosuppression, a limited number of tumor-affected organs, and a predominance of CD8 + T CM among TIL, as baseline parameters associated with a favorable response to PD-1/PD-L1 ICI therapy of advanced MCC. These factors should be considered when making treatment decisions in MCC patients., Competing Interests: Competing interests: SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp & Dohme. LZ served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, and Novartis, outside the submitted work. PT declares invited speaker's honoraria from Bristol-Myers Squibb, Novartis, MSD, Pierre-Fabre, CureVac, Roche, Kyowa Kirin, Biofrontera, advisory board honoraria from Bristol-Myers Squibb, Novartis, Pierre-Fabre, Merck Serono, Sanofi, Roche, Kyowa Kirin, and travel support from Bristol-Myers Squibb, and Pierre-Fabre. UL declares advisory board honoraria from MSD, Roche, Sanofi, Novartis, Sun Pharma, Almirall Hermal. TE declares consulting fees from BMS, Novartis, Roche, Pierre Fabre, Sanofi; board membership and payment for lectures in speakers bureau from Pierre Fabre, MSD, Roche, BMS, Novartis and Sanofi. CL reports advisory board honoraria from MSD, BMS, Roche, Pierre Fabre, Novartis, Sun Pharma, Sanofi, Kyowa Kirin, Almiral Hermal, Biontech, Merc; speakers fee from MSD, BMS, Roche, Pierre Fabre, Novartis, Sun Pharma, Sanofi, Merck; travel reimbusment from MSD, BMS, Roche, Pierre Fabre, Novartis, Sun Pharma, Sanofi, Kyowa Kirin, Almiral Hermal, Biontech and Merck. JCH declares research support from Bristol Myers Squibb; advisory board honoraria from Pierre Fabre, Sanofi, Sun Pharma and Merck Sharp & Dome; speakers honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Sanofi and Almirall and travel support from Pierre Fabre. TG reports receiving speakers and/or advisory board honoraria from BMS, Sanofi-Grenzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen Lilly, Pfizer, Pierre Fabre; speakers and/or advisory board honoraria from BMS, Sanofi-Grenzyme, MSD, Novartis, Pharma, Roche, Abbvie, Almirall, Janssen Lillly, Pfizer, Pierre Fabre. SH declares advisory boards honoraria from Pierre Fabre, MSD, BMS, Novartis, Sanofi. PM reports board membership and payment for lectures in speakers bureau from Pierre Fabre, GSK, MSD, Merck Germany, Roche, BMS, Novartis, Sanofi. P. Mohr reports research support (to institution): Bristol-MyersSquibb, Novartis, MSD. Honoraria for lectures (personally): Pierre Fabre, GSK, MSD, Merck Germany, Roche, BMS, Novartis, Sanofi, Amgen, SUN-Pharma, Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, Bayer, Pierre-Fabre, Sanofi. Honoraria for advisory boards: Pierre Fabre, GSK, MSD, Merck Germany, Roche, BMS, Novartis, Sanofi, Beiersdorf, Almiral-Hermal, AmgenBayersdorf, Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, SUN-Pharma, SUN, Merck-Serono, Sanofi. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, AMGEN, SUNPHARMA, Allergy Therapeutics and LEO. LMH served as consultant and/or has received honoraria from Amgen, BMS, Curevac, MSD, Novartis, Pierre-Fabre, Roche, Sanofi and Sun Pharma, outside the submitted work. Research funding to institution: Novartis. R. Gutzmer reports research support from Pfizer, Johnson & Johnson, Novartis, Amgen, MerckSerono, SUN Pharma; honoraria for lectures from Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, SUN, Pierre-Fabre, Sanofi, SUN Pharma, Bayer; honoraria for advice from Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, 4SC, Incyte, SUN Pharma, Sanofi, Pfizer. JSU is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. H-US is an employee of Targos Molecular Pathology Inc. and reports research support from Novartis Oncology and received honoraria from MSD, BMS, Roche Pharma, Novartis Oncology, AstraZeneca, Eisai, Takeda, Molecular Health, outside of the submitted work. DS reports personal fees from Amgen, GSK, BMS, Novartis, Roche, Merck, Astra Zeneca, Merck-Serono, Pfizer, Incyte, Array Pierre Fabre, Sanofi Genzyme, Regeneron, 4Sc, InFlaRx, Neracare, Ultimovacs, SunPharma, Philogen, Immunocore, Sandoz-Hexal outside the submitted work. JCB is receiving speaker's bureau honoraria from Amgen, Pfizer, MerckSerono, Recordati and Sanofi; is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group receives research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Immune checkpoint inhibitors (ICIs) are approved to treat multiple cancers. Retrospective analyses demonstrate acceptable safety of ICIs in most patients with autoimmune disease, although disease exacerbation may occur. Psoriasis vulgaris is a common, immune-mediated disease, and outcomes of ICI treatment in patients with psoriasis are not well described. Thus we sought to define the safety profile and effectiveness of ICIs in patients with pre-existing psoriasis., Methods: In this retrospective cohort study, patients from eight academic centers with pre-existing psoriasis who received ICI treatment for cancer were evaluated. Main safety outcomes were psoriasis exacerbation and immune-related adverse events (irAEs). We also assessed progression-free survival (PFS) and overall survival., Results: Of 76 patients studied (50 (66%) male; median age 67 years; 62 (82%) with melanoma, 5 (7%) with lung cancer, 2 (3%) with head and neck cancer, and 7 (9%) with other cancers; median follow-up 25.1 months (range=0.2-99 months)), 51 (67%) received anti-PD-1 antibodies, 8 (11%) anti-CTLA-4, and 17 (22%) combination of anti-PD-1/CTLA-4. All patients had pre-existing psoriasis, most frequently plaque psoriasis (46 patients (61%)) and 15 (20%) with psoriatic arthritis. Forty-one patients (54%) had received any prior therapy for psoriasis although only two (3%) were on systemic immunosuppression at ICI initiation. With ICI treatment, 43 patients (57%) experienced a psoriasis flare of cutaneous and/or extracutaneous disease after a median of 44 days of receiving ICI. Of those who experienced a flare, 23 patients (53%) were managed with topical therapy only; 16 (21%) needed systemic therapy. Only five patients (7%) required immunotherapy discontinuation for psoriasis flare. Forty-five patients (59%) experienced other irAEs, 17 (22%) of which were grade 3/4. PFS with landmark analysis was significantly longer in patients with a psoriasis flare versus those without (39 vs 8.7 months, p=0.049)., Conclusions: In this multicenter study, ICI therapy was associated with frequent psoriasis exacerbation, although flares were manageable with standard psoriasis treatments and few required ICI discontinuation. Patients who experienced disease exacerbation performed at least as well as those who did not. Thus, pre-existing psoriasis should not prevent patients from receiving ICIs for treatment of malignancy., Competing Interests: Competing interests: DBJ has served on advisory boards for BMS, Catalyst Biopharma, Iovance, Jansen, Merck, Novartis, Oncosec, and Pfizer; and received research funding from BMS and Incyte. JCH declares research support from Bristol Myers Squibb; advisory board honoraria from Pierre Fabre, Sanofi, Sun Pharma and Merck Sharp & Dome; speakers honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Sanofi and Almirall; and travel support from Pierre Fabre. AM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre and QBiotics. GL is consultant advisor for Aduro Biotech, Amgen, Array Biopharma, Boehringer Ingelheim International, Bristol-Myers Squibb, Highlight Therapeutics, Merck Sharpe & Dohme, Novartis Pharma, Pierre Fabre, QBiotics Group Limited, and Regeneron Pharmaceuticals. PB declares travel support from MSD; and advisory board honoraria from Novartis. MC is a consultant advisor for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Provectus and Sanofi. AH has served on advisory boards for BMS, MSD, Novartis, Pierre-Fabre and QBiotics. MEL consults with Johnson and Johnson, Novocure, QED, Bicara, Janssen, Novartis, F Hoffmann-La Roche, EMD Serono, AstraZeneca, Innovaderm, Deciphera, DFB, Azitra, Kintara, RBC/La Roche Posay, Trifecta, Varsona, Genentech, Loxo, Seattle Genetics, Lutris, OnQuality, Azitra, Roche, Oncoderm, NCODA, and Apricity. MEL receives research funding from Lutris, Paxman, Novocure, J&J, US Biotest, OQL, Novartis and AZ; and is funded in part through NIH/NCI Cancer Center Support Grant P30 CA008748. MJM has served as a consultant and/or received honorarium from AstraZeneca Pharmaceuticals, Catalyst Pharmaceuticals, Nektar Therapeutics and Immunai. STC serves on the Pfizer Advisory Board on digital media and the BOD for Medical Dermatology Society and is the Chair for Organisational Structure Committee of the AAD. ABW and VMR are supported by the NIH/NCI Cancer Center Support Grant P30 CA008748. VMR is funded by the Melanoma Research Alliance Young Investigator Award 614197 and an expert advisor for Inhabit Brands, Inc., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Leptomeningeal disease (LMD) is a complication of metastasized melanoma, with poor prognosis even in the era of immunotherapy. We present the case of a 37-year-old man who was diagnosed with stage IV melanoma with lymphonodular, splenic and pulmonary metastases. Treatment with dabrafenib and trametinib led to a complete remission, but subsequent symptomatic LMD. Treatment was changed to intrathecal methotrexate, leading to aseptic meningitis, but also a remission of LMD. Followed by ipilimumab monotherapy, a durable, complete remission was observed. Symptomatic LMD may not be amenable to immunotherapy alone, as quick responses may be needed. With little evidence and few retrospective trials demonstrating the challenging treatment of LMD, intrathecal chemotherapy, potentially in combination, may still be considered a viable option.

Background: Immune checkpoint inhibitors (ICIs) are widely used and may induce long-term survival in various types of cancer. Yet, there is scarce evidence on potential effects on patient fertility and the necessity of cryopreservation before treatment onset. The aim of our study was to assess the prevalence of male infertility after initiation of ICI treatment., Methods: This is a monocenter, cross-sectional pilot study. Fertility was investigated by spermiogram, analysis of sexual hormones and questionnaires on sexual function and sexual activity. Male patients under the age of 60 years previously or currently treated with ICI for cutaneous malignancies or uveal melanoma were included., Results: Twenty-five patients were included, with a median age of 49 years. Eighteen of 22 (82%) available spermiograms showed no pathologies, all patients reported a normal sexual function and sexual activity. Of four patients with pathological spermiogram, three patients were diagnosed with azoospermia and one with oligoasthenoteratozoospermia. Three patients had significant confounding factors (previous inguinal radiotherapy, chemotherapy and chronic alcohol abuse, and bacterial orchitis). One patient with normal spermiogram before ICI treatment presented 1 year after initiation with azoospermia, showing an asymptomatic, inflammatory infiltrate with predominantly neutrophil granulocytes, macrophages and T-lymphocytes in the ejaculate. Infectious causes were ruled out; andrological examination was unremarkable. A second case with reduced sperm counts during treatment may be ICI-induced also., Conclusions: Most patients had no restrictions in fertility, yet an inflammatory loss of spermatogenesis seems possible. Cryopreservation should be discussed with all patients with potential future desire for children before treatment., Competing Interests: Conflict of interest statement M.S.: honoraria and/or travel grants from Abbvie, Bristol-Myers Squibb (BMS), Merck, Merck Sharp & Dohme (MSD), Novartis and Pfizer. G.T.: advisory honoraria from Merck and Boston Scientific. M.He.: No conflict of interest to declare. D.S.: grants, personal fees, non-financial support and/or other from Novartis, BMS, Merck Serono, Amgen, Immunocore, Incyte, 4SC, Pierre Fabre, Sanofi/Regeneron, Array BioPharma, InFlarX, Philogen, Regeneron, Merck/MSD, Sandoz/Hexal, NeraCare, Roche/Genentech; outside the submitted work. I.M.: No conflict of interest to declare. A.H.E.: advisory honoraria from Biotest AG, MSD Oncology, Galderma, Janssen Cilag, AbbVie as well as speaker's honoraria from Roche Pharma. M.Ha.: No conflict of interest to declare. J.C.H.: honoraria for talks from BMS, MSD, Roche, Novartis; advisory board member for MSD, Pierre Fabre; scientific grant support from BMS; travel grants from BMS, Pierre Fabre., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients., Methods: In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast (<6 months) distant progression) were analysed separately., Results: Median follow-up time was 30.5 (range 0.8-154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40-0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45-1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%., Conclusion: Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.Z.: received travel support from Novartis, Sanofi Genzyme, and Bristol Myers Squibb, outside the submitted work. M.P.: No relevant conflicts of interest. J.C.H.: received honoraria from talks: BMS, MSD, Roche, Novartis, Sun Pharma, Almirall, Sanofi, honoraria from adboards: Sun Pharma, Sanofi, Pierre Fabre, scientific grant: BMS. V.G.: received honoraria from Bristol Myers Squibb (BMS) and reports travel support from Novartis, Pierre Fabre Pharmaceuticals, BMS, Merck Sharp & Dohme (MSD), Sanofi Genzyme and SUN Pharmaceutical Industries outside the submitted work. Z.F.: No relevant conflicts of interest. C.L.: served as consult and and/or has received honoraria and or received travel support from Roche, Novartis, Pierre Fabre, MDS, Merck, BMS, Sanofi, Sun Pharma, Biontech, Kyowa Kirin, Almirall Hermal outside the submitted work. D. R.-S. has received honoraria for talks from Roche and Pierre Fabre and has received travel grants from Novartis, Pierre Fabre and Sanofi Genzyme. R. G.: received honoraria: Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre Fabr; consultant or advisory role: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre Fabre, Merck Serono, Bayer, Pfizer; Funding: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck Serono, SUN Pharma, Sanofi; travel, accommodations, expenses: Roche, BMS, SUN, Merck Serono, Pierre Fabre. J. U. is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. Se.H.: served as consultant and/or has received honoraria from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Sun Pharma outside the submitted work. L.R.: No relevant conflicts of interest. K.C.K.: served as consultant and/or has received honoraria from Amgen, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sun Pharma and travel support from Amgen, Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Sun pharma and Novartis, outside the submitted work. C.W.: served as consultant and/or has received honoraria from Amgen, Roche, Bristol Myers Squibb, Kyowa Kirin, Merck Sharp & Dohme, Novartis, Sanofi, Takeda and travel support from Amgen, Bristol Myers Squibb, Curevac, Pierre Fabre and Novartis, outside the submitted work. A.M.: has received speaker or consultant fees from AbbVie, Almirall, Novartis, Bristol Myers Squibb, Pfizer, and Roche, outside of the submitted work; A.M. is employed by Novartis; the work described in this publication was completed prior to his employment at Novartis. K. M.T.: served as consultant and/or has received honoraria from Bristol Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Sanofi, Sun Pharma, LEO, Galderma, and Candela and travel support from Bristol Myers Squibb, Roche, Novartis, Pierre Fabre, and Candela, outside the submitted work. T.W.: received honoraria and travel support from Amgen, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, outside the submitted work. C.P.: received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, Sanofi ‘Genzyme, Sun Pharma, Amgen and LEO. A. R.: reports non-financial support from Amgen, non-financial support from Roche, personal fees and non-financial support from Merck/MSD, grants and non-financial support from Novartis, grants and non-financial support from BMS, non-financial support from TEVA, grants from Adtec, outside the submitted work. S. U.: declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp & Dohme. L.Z.: served as consultant and/or has received honoraria from Roche, Bristol Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Sanofi, and Sun Pharma and travel support from MSD, BMS, Amgen, Pierre Fabre, Sun Pharma, Sanofi and Novartis, outside the submitted work. N.S.: No relevant conflicts of interest. A.S.: No relevant conflicts of interest. F.K.: No relevant conflicts of interest. L.H.: served as consultant and/or has received honoraria from Amgen, Roche, Bristol Myers Squibb, Curevac, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sun Pharma and a research grant from Novartis, outside the submitted work. Fri.M.: has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. Fra.M.: served as consultant and/or has received honoraria from Novartis, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi Genzyme and travel support from Novartis, Sun Pharma and Bristol Myers Squibb, outside the submitted work. M.S.: participated in advisory boards of Bristol Myers Squibb, Novartis, MSD, Roche, Pierre Fabre, Kyowa Kirin, Immunocore and Sanofi Genzyme. M.S. received travel accommodation and expenses by Novartis, Pierre Fabre, and Sun Pharma, outside the submitted work. B.S.: received personal honoraria from Bristol Myers Squibb, Merck Sharpe & Dome, Novartis, Pfizer/EMD Serono, Pierre Fabre and Roche; has an advisory role for Bristol Myers Squibb, Merck Sharpe & Dome, Novartis, Pierre Fabre and Roche; and has received research funding from Bristol Myers Squibb, Merck Sharpe & Dome, and Pierre Fabre, all paid to the institute. Su.H.: No relevant conflicts of interest. D.S: reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sun Pharma, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. E.L.: served as consultant and/or has received honoraria from Amgen, Actelion, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Janssen, Medac, Sanofi, Sun Pharma and travel support from Amgen, Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Sun Pharma and Novartis, outside the submitted work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Conflict of interest statement Honoraria: R.G. (Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre Fabre), C.P. (Roche, BMS, MSD, Novartis, Merck Serono, Celgene, AbbVie, LEO), L.Z. (Roche, BMS, MSD, Novartis, Sanofi, Pierre Fabre), K.-M.T. (Roche, BMS, MSD, Novartis, Pierre Fabre, LEO, Galderma, Candela, CSL Behring), K.C.K. (Merck sharp and Dohme, Novartis and Bristol Myers Squibb and travel support from Novartis), J.C.H. (BMS, MSD, Roche, Novartis, Sanofi), S.U. (BMS, MSD, Merck Serono, Novartis and Roche), C.B. (Roche, BMS, MSD, Novartis, Sanofi-Aventis), D.D. (MSD, Novartis, Roche, Sanofi), J.U. (Amgen, Bristol Myers Squibb, GSK, LEO Pharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi), R.H. (Roche, BMS, MSD, Novartis, Pierre Fabre), L.H. (BMS, Roche, Novartis, MSD, Amgen, CureVac, Sanofi, Pierre Fabre), C.L. (Roche, Pierre Fabre, Novartis, BMS, MSD, Merck, Almirall Hermall, Sun Pharma, Sanofi, BioNTech, Kyowa Kirin), F.M. (Novartis, Roche, BMS, MSD, Pierre Fabre), I.G. (Novartis, Roche, BMS, MSD, Sanofi), T.K.E. (Roche, Pierre Fabre, Novartis, BMS, MSD, Sanofi). Consultant or Advisory Role: R.G. (BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre Fabre, Merck Serono, Bayer, Pfizer), C.P. (Roche, Novartis, Merck Serono), L.Z. (MSD, BMS, Novartis, Pierre Fabre, Sanofi), K.-M.T. (Roche, BMS, MSD, Novartis, Pierre Fabre, LEO, CSL Behring) K.C.K. (BMS, MSD, Novartis, Pierre Fabre), J.C.H. (MSD, Sun Pharma, Pierre Fabre), S.U. (BMS, MSD, Merck Serono, Novartis and Roche), C.B. (Roche, BMS, MSD, Novartis, Merck Serono, Sanofi-Aventis, Pierre Fabre), D.D. (Novartis, Roche, Sanofi), J.U. (Amgen, Bristol Myers Squibb, GSK, Leo Pharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi), R.H. (Roche, BMS, Novartis, Pierre Fabre), L.H. (BMS, Roche, Novartis, MSD, Amgen, Curevac, Sanofi, Pierre Fabre), C.L. (Roche, Pierre Fabre, Novartis, BMS, MSD, Merck, Almirall Hermal, Sun Pharma, Sanofi, BioNTech, Kyowa Kirin), F.M. (Novartis, Roche, BMS, MSD, Pierre Fabre), I.G. (Novartis, Roche, BMS, MSD, Sanofi), T.K.E. (Roche, Pierre Fabre, Novartis, BMS, MSD, Sanofi). Research Funding: R.G. (Novartis, Pfizer, Johnson & Johnson, Amgen, Merck Serono, SUN Pharma, Sanofi), L.Z. (Novartis), K.C.K. (Novartis, Merck Sharp and Dohme), J.C.H. (BMS), S.U. (BMS, Merck Serono), J.U. (Apogenix, NOXXON Pharma, Elsalys Biotech, TILT Biotherapeutics, BioNTech RNA Pharmaceuticals, RHEACELL, Merck), L.H. (Novartis), F.M. (Novartis, Roche), I.G. (Roche, Pfizer, Novartis). Travel, Accommodations, Expenses: R.G. (Roche, BMS, SUN, Merck Serono, Pierre Fabre), C.P. (Roche, BMS, MSD, Novartis, Merck Serono, Celgene, AbbVie, LEO), L.Z. (BMS, Pierre Fabre, Amgen, Sanofi, Sun Pharma, Novartis), K.-M.T. (Roche, BMS, MSD, Novartis, Pierre-Fabre, LEO, Candela) K.C.K. (MSD, Novartis and Bristol Myers Squibb, Novartis), J.C.H. (Pierre Fabre, BMS), S.U. (BMS, MSD), D.D. (Amgen, BMS, MSD, Mylan, Novartis, Pierre Fabre, Roche, Sanofi), J.U. (Amgen, Bristol Myers Squibb, GSK, Leo Pharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi), C.L. (Roche, Pierre Fabre, Novartis, BMS, MSD, Merck, Almirall Hermall, Sun Pharma, Sanofi, BioNTech, Kyowa Kirin), F.M. (Novartis, Roche, BMS, MSD, Pierre Fabre), I. G. (Novartis, Roche, BMS, MSD). Stock ownership: none. Patent application/registration: none. Employment: none. No conflict of interest: C.R. and C.K. had no conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Anti-PD1-based immunotherapy is currently used in most patients with advanced melanoma. Despite the remarkable data regarding overall survival, the optimal treatment duration is still unknown., Methods: We evaluated the outcome of 125 patients with advanced melanoma with and without brain metastases (MBM), treated either with anti-PD1 monotherapy (N = 97) or combined with anti-CTLA4 (N = 28) after elective treatment discontinuation due to complete response (CR) (group A, N = 86), or treatment-limiting toxicity (N = 33) and investigator's decision (ID, N = 6) (group B) with subsequent CR., Results: For group A, median duration of treatment (mDoT) was 22 months (range 5-49) and median time to CR 9 months (range 2-47). Accordingly, mDoT for group B was 3 months (range 0-36) and median time to CR 7 months (range 1-32). Seven patients from group A and three from group B experienced disease recurrence. Off-treatment survival was not reached. Median off-treatment response time (mOTRt) was 19 months (range 0-42) and 25 months (range 0-66), respectively. For MBM, mOTRt was 17 months (range 7-41) and 28 months (range 9-39), respectively. After a median follow-up of 38 months (range 9-70), seven (5.6%) patients had deceased, one (0.8%) due to melanoma., Conclusions: Treatment discontinuation is feasible also in patients with MBM. Efficacy outcomes seemed to be similar in both groups of patients who achieved CR, regardless of reason for discontinuation. In patients who experienced disease relapse, treatment re-challenge with anti-PD1 resulted in subsequent renewed response., Competing Interests: Conflict of interest statement FD receives intermittent travel support from Pierre Fabre outside of the submitted work. AZ has received travel grants from Novartis and BMS outside of the submitted work. AC receives meeting, accommodation and travel support from Roche, Amgen and BMS. KCK serves as consultant to Roche, BMS, MSD and received travel grants and speaker fees from Roche, BMS, MSD, GSK, Amgen. LF reports grants from Novartis, grants from BMS, grants from MSD, outside the submitted work; FT received travel support from Novartis and Abbvie. LH receives fees for consultant/advisory role: Amgen, Bristol-Myers Squibb, Curevac, Roche Pharma, MSD Sharp & Dohme Sharp & Dohme, Novartis, Sanofi, Pierre Fabre. Research funding: Novartis. JH has intermittent project focused consultant or advisory relationships with Merck Sharp & Dohme, Pierre Fabre and Sunpharma and has received speaker honoraria from Novartis, BMS and travel support from Pierre Fabre and BMS outside of the submitted work. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, AstraZeneca, Syndax, SunPharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim. He also received research funds from Bristol Myers Squibb, Roche-Genentech, Array and travel support from MSD. OM reports grants and personal fees from Bristol Myers Squibb (BMS), grants and personal fees from MSD, personal fees from Roche, outside the submitted work. AH received consultancy and speaker honoraria from the following companies: Amgen, BMS, MerckPfizer, MSD, Novartis, Philogen, Pierre Fabre, Provectus, Regeneron and Roche. CL received consultancy and speaker honoraria from the following companies: Amgen, BMS, MerckPfizer, MSD, Novartis, Pierre Fabre and Roche. EL served as consultant or/and has received honoraria from Amgen, Actelion, Roche, Bristol Myers Squibb (BMS), Merck Sharp & Dohme (MSD, Novartis, Janssen, Medac and travel support from Amgen, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Amgen, Pierre Fabre, Sunpharma and Novartis. ER reports personal fees from Amgen, personal fees from Sanofi, outside the submitted work. RD has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre outside the submitted work. JM has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb und Pierre Fabre outside of the submitted work. CG, SSch and PFC have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking., Methods: This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting., Results: Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4-1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2-2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3-1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8-2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6-1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5-1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding., Conclusions: Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone., Competing Interests: Conflicts of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sarah Knispel: Travel support from Bristol-Myers Squibb and Amgen. Maximilian Gassenmaier: Consultant or Advisory Role: Novartis; Research funding: Novartis. Carmen Loquai: Advisory role/Speakers fee/Travel support: BMS, MSD, Merck, Novartis, Pierre Fabre, Sunpharma, Sanofi, Roche, Almirall Hermal, Biontech, Kyowa Kirin. Cindy Franklin: Advisory board or received honoraria of BMS and Novartis and received travel grants from BMS, Novartis and Pierre Fabre. Ralf Gutzmer: Personal Honoraria from Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Consultant or advisory role: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, MerckSerono, Bayer, Pfizer. Research funding: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi, all paid to the institution. Travel, accommodations, expenses: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre. Bastian Schilling: Personal honoraria from Bristol-Myers Squibb, Merck Sharpe and Dome, Novartis, Pfizer/EMD Serono, Pierre Fabre and Roche; has an advisory role for Bristol-Myers Squibb, Merck Sharpe and Dome, Novartis, Pierre Fabre and Roche; and has received research funding from Bristol-Myers Squibb, Merck Sharpe and Dome, and Pierre Fabre, all paid to the institute. Andreas Stang: Speaker honoraria from Merck Serono. Selma Ugurel: Research support from Bristol-Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and Travel support from Bristol-Myers Squibb, and Merck Sharp & Dohme. Lisa Zimmer: Honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre; Consultant or advisory role: BMS, Novartis, Pierre Fabre, Sunpharma, Sanofi, MSD; Research funding to institution: Novartis; Travel support: BMS, Pierre Fabre, Sanofi, Amgen, Novartis, Sunpharma. Carina N Owen: Travel support from Merck Sharp Dohme. Jessica C Hassel: Honoraria from BMS, MSD, Novartis, Roche, Pierre Fabre, Sanofi; Consultant or advisory role: MSD, Pierre Fabre, Sunpharma; Research funding: BMS; Travel support: Pierre Fabre. Friedegund Meier has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. Carola Berking: Honoraria from BMS, Immunocore, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi-Aventis for consultancy and/or presentations on scientific symposia. Douglas B Johnson: Advisory boards for Array Biopharma, BMS, Iovance, Jansen, Merck and Novartis and research funding from BMS and Incyte. Elisabeth Livingstone: Intermittent advisory board relationships with Roche, BMS, Novartis, Sanofi and Actelion and has received travel grants and honoraria from Roche, BMS, MSD, Amgen, Pierre Fabre, SunPharma, Novartis, Boehringer-Ingelheim, medac. Alexander M Menzies: Advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. Simone M Goldinger: past advisory boards for BMS, MSD, Roche and Novartis. Kai-Martin Thoms: Honoraria from BMS, MSD, Roche, Novartis, Pierre Fabre, Sun Pharma, LEO, Candela; Consultant or advisory role: BMS, MSD, Roche, Novartis, Pierre Fabre, Sun Pharma, LEO; Travel support: BMS, MSD, Roche, Novartis, Pierre Fabre, LEO. Dirk Schadendorf: Has/had a consultant/advisory role in the last 2 years for Bristol-Myers Squibb (BMS), Roche-Genentech, Merck Sharp & Dohme (MSD), Array, Immunocore, InFlaRX, Nektar, Novartis, Merck Serono, Pierre Fabre, Pfizer, Philogen, Regeneron, SunPharma, Sandoz, Sanofi, Ultimovacs and 4SC. He also received research funds from Bristol-MyersSquibb, Roche, Amgen and Novartis. Travel support: BMS, Pierre Fabre, Sanofi, Nektar, Novartis, Roche, Merck Serono and Sunpharma. Dennis Niebel: Has received speakers’ honoraria or travel expense reimbursements from BMS, Novartis, GSK, Celgene and MSD. Judith Sirokay: Honoraria from Roche, BMS, MSD, Novartis, Consultant or advisory role: Novartis, MSD; Travel support: BMS, Pierre Fabre. Peter Mohr: Has/had a consultant/advisory role in the last 2 years for Amgen, Bristol-Myers Squibb (BMS), Roche-Genentech, Merck Sharp & Dohme (MSD), Novartis, Merck Serono, Pierre Fabre, Pfizer, Philogen, Sanofi. He also received research funds from Bristol-Myers Squibb, Merck Sharp & Dohme (MSD) and Novartis. Travel support: Amgen, BMS, Merck Sharp & Dohme (MSD), Pierre Fabre, Sanofi, Novartis, Roche and Sunpharma. Laura Susok: Collaboration with BMS, Novartis, Sunpharma, MSD, Roche, Pierre Fabre. Paolo Ascierto: Has/had a consultant/advisory role for Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Array, Merck Serono, Pierre-Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Array and travel support from MSD. Claudia Pföhler: Consultancy, speaker fees, travel grants: BMS, MSD, Merck Serono, Roche, Amgen, GSK, Novartis, Sanofi Genzyme, Pierre Fabre, LEO, UCB, Sunpharma. Clinical studies: Novartis, BMS. Lucie Heinzerling: Consultant or advisory role: Amgen, BMS, Curevac, Novartis, Pierre Fabre, Roche, Sanofi, MSD; research funding (to institution): Novartis. Patrick Schummer: honoraria: Bristol-Myers Squibb (BMS); institutional research grant: Novartis; Travel support: Novartis, Lilly and BMS. Thomas Eigentler: Has/had a consultant/advisory role in the last 2 years for Bristol-Myers Squibb (BMS), Roche-Genentech, Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Philogen, Sanofi. He also received research funds from Bristol-Myers Squibb, Merck Sharp & Dohme (MSD) and Novartis. Katharina C. Kähler: Serves as consultant to Roche, BMS, MSD, Pierre Fabre and received travel grants and speaker fees from Roche, BMS, MSD, Amgen, Pierre Fabre and Philogen. Julia Tietze: Honoraria from Roche, BMS, MSD, Amgen, Sanofi, Travel support: Pierre Fabre, Novartis, BMS. Georgina V. Long: Is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V. All other authors (Felix Kiecker, Raphael Reinhard, Konstantin Drexler, Christopher Cann, Lydia Reinhardt, Carsten Weishaupt, Maria I Fleischer, Leonie Bluhm) declared to have no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes., Patients and Methods: Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres., Results: In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1-128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis)., Conclusion: Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Rafaela Kramer: NoneZaremba Anne: Received travel support from Novartis, Genzyme and Bristol-Myers Squibb. Alvaro Moreira: Speaker's honoraria from AbbVie, Novartis, Bristol-Myers Squibb, Pfizer and Roche; consultant's honoraria from Almirall. Selma Ugurel: Selma Ugurel declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp and Dohme. Douglas Johnson: Advisory boards for Array Biopharma, BMS, Catalyst, Iovance, Jansen, Merck, Novartis, and research funding from BMS and Incyte. Jessica C. Hassel: honoraria from BMS, MSD, Roche, Novartis, Pfizer, Sanofi; consultant's honoraria from Pierre Faber, MSD, Sunpharma; science grant from BMS. Martin Salzmann: honoraria and travel grants from Abbvie, Bristol-Myers Squibb (BMS), Merck, Merck Sharp & Dohme (MSD), Novartis and Pfizer. Anja Gesierich: speaker's honoraria from Bristol-Myers Squibb, MSD Sharp and Dohme and Roche; Consultant's honoraria from Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp and Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel support from Bristol-Myers Squibb, MSD Sharp and Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, GSK, Novartis, Merck, MSD Sharp and Dohme, Pfizer and Roche. Alisonn Weppler: none. Lavinia Spain: Honoraria from Bristol-Myers Squibb for Advisory Boards Carmen Loquai: Advisory board, speakers fee, travel reimbursement: Roche, Pierre Fabre, Novartis, BMS, Merck, MSD, Biontech, Almiral Hermal, Kyowa Kirin, Sun Pharma, Sanofi Milena Dudda: none. Claudia Pföhler: Consultancy, speaker fees, travel grants: BMS, MSD, Merck, Roche, Amgen, GSK, Novartis, Sanofi Genzyme, Pierre Fabre, LEO. Clinical studies: Novartis, BMS. Adriana Hepner: AH is employee of AstraZeneca with stock options in the company, has received honoraria from Novartis and travel expenses from Roche. Georgina V. Long: consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., Merck Sharpe and Dohme, Novartis Pharma AG, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V. Alexander Menzies: advisory board BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics Matteo S. Carlino: MSC has served on advisory boards for Bristol-Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, Sanofi, Merck, Ideaya, Regeneron, Nektar, Eisai and honoraria from Bristol-Myers Squibb, MSD, Novartis Michael M. Sachse: Speaker fees: Roche, MSD, Novartis Céleste Lebbé: Consultancy, speaker fees, travel grants or research funding: BMS, MSD, Merck, Roche, Amgen, Novartis, Sanofi, Pierre Fabre. Clinical studies: BMS, MSD, Merck, Sanofi, Incyrte, Roche, Amgen, GSK, Curevac, Genentech and Novartis Barouyr Baroudjian: Consultancy, speaker fees, travel grants: BMS, MSD, Novartis, Pierre Fabre Tomohiro Enokida: none. Makoto Tahara: reports grants and personal fees from Ono Pharmaceutical, grants and personal fees from MSD, grants and personal fees from BMS, during the conduct of the study; grants and personal fees from Bayer, grants and personal fees from Eisai, grants and personal fees from Merck serono, personal fees from LOXO, grants and personal fees from Pfizer, grants and personal fees from Rakuten Medical, personal fees from Celgene, personal fees from Amgen, grants and personal fees from Novartis, outside the submitted work. Max Schlaak: Consultancy, speaker fees or travel grants: BMS, MSD, Roche, Kyowa Kirin, Novartis, Sanofi Genzyme, Pierre Fabre, Sun Pharma Kinan Hayani: none. Paul Bröckelmann: PJB declares honoraria and non-financial support by Bristol-Myers Squibb and research funding by Bristol-Myers Squibb and MSD Sharp and Dohme. Friedegund Meier: F.M. has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. Lydia Reinhardt: none. Philip Friedlander: none. Thomas Eigentler: received fees for advisory boards from Roche, Novartis, MSD, BMS, Sanofi and Philogen Katharina C. Kähler: serves as consultant to Roche, BMS, MSD, Pierre Fabre and received travel grants and speaker fees from Roche, BMS, MSD, Amgen, Pierre Fabre and Philogen. Lisa Zimmer: LZ has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp and Dohme, Novartis, Pierre Fabre, research funding from Novartis and has served on advisory boards for Bristol-Myers Squibb, Novartis, Pierre Fabre, Sunpharma, Sanofi, Merck Sharp and Dohme; travel support: Bristol-Myers Squibb, Pierre Fabre, Sanofi, Amgen, Novartis, Sunpharma Lucie Heinzerling: Consultancy, speaker fees, travel grants or research funding: BMS, MSD, Merck, Roche, Amgen, Curevac, Novartis, Sanofi, Pierre Fabre. Clinical studies: BMS, MSD, Merck, Roche, Amgen, GSK, Curevac and Novartis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Skin cancers are known for their strong immunogenicity, which may contribute to a high treatment efficacy of immune checkpoint inhibition (ICI). However, a considerable proportion of patients with skin cancer is immuno-compromised by concomitant diseases. Due to their previous exclusion from clinical trials, the ICI treatment efficacy is poorly investigated in these patients. The present study analyzed the ICI treatment outcome in advanced patients with skin cancer with a concomitant hematological malignancy., Methods: This retrospective multicenter study included patients who were treated with ICI for locally advanced or metastatic melanoma (MM), cutaneous squamous cell carcinoma (cSCC), or Merkel cell carcinoma (MCC), and had a previous diagnosis of a hematological malignancy irrespective of disease activity or need of therapy at ICI treatment start. Comparator patient cohorts without concomitant hematological malignancy were extracted from the prospective multicenter skin cancer registry ADOREG. Treatment outcome was measured as best overall response, progression-free (PFS), and overall survival (OS)., Results: 84 patients (MM, n=52; cSCC, n=15; MCC, n=17) with concomitant hematological malignancy were identified at 20 skin cancer centers. The most frequent concomitant hematological malignancies were non-Hodgkin's lymphoma (n=70), with chronic lymphocytic leukemia (n=32) being the largest entity. While 9 patients received ICI in an adjuvant setting, 75 patients were treated for advanced non-resectable disease (55 anti-PD-1; 8 anti-PD-L1; 5 anti-CTLA-4; 7 combinations). In the latter 75 patients, best objective response (complete response+partial response) was 28.0%, disease stabilization was 25.3%, and 38.6% showed progressive disease (PD). Subdivided by skin cancer entity, best objective response was 31.1% (MM), 26.7% (cSCC), and 18.8% (MCC). Median PFS was 8.4 months (MM), 4.0 months (cSCC), and 5.7 months (MCC). 1-year OS rates were 78.4% (MM), 65.8% (cSCC), and 47.4% (MCC). Comparison with respective ADOREG patient cohorts without hematological malignancy (n=392) revealed no relevant differences in ICI therapy outcome for MM and MCC, but a significantly reduced PFS for cSCC (p=0.002)., Conclusions: ICI therapy showed efficacy in advanced patients with skin cancer with a concomitant hematological malignancy. Compared with patients without hematological malignancy, the observed ICI therapy outcome was impaired in cSCC, but not in MM or MCC patients., Competing Interests: Competing interests: UL: relevant financial activities (research support from Merck Sharp and Dohme; speakers and advisory board honoraria from Merck Sharp and Dohme, Novartis and Roche, Sanofi Aventis and travel support from Sun Pharma). CL: relevant financial activities (speakers, advisory board honoraria and travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis, Roche, Pierre Fabre, Sun Pharma, Kiowa Kirin, Sanofi, Biontech, Allmiral Hermal). DR-S: relevant financial activities (speakers and advisory board honoraria from Novartis and Roche; travel support from Sanofy Genzyme, Roche and Novartis). JCH: relevant financial activities (research support from Bristol Myers Squibb; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Roche, Pierre Fabre and Sanofi Aventis, and travel support from Bristol Myers Squibb and Pierre Fabre). VG: relevant financial activities (honoraria from Bristol-Myers Squibb, advisory board honoraria from Novartis and reports travel support from Novartis, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb, Merck Sharp & Dohme and Sanofi Genzyme). JS: relevant financial activities (speakers’ honoraria and/or travel expense reimbursements from Novartis, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre and Roche). AR: relevant financial activities (travel grants and lecture fees from Bristol-Myers Squibb, Amgen and Roche). RG: relevant financial activities (personal fees and non-financial support from Bristol Myers Squibb, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Merck Serono, grants, personal fees and non-financial support from Amgen, personal fees and non-financial support from Pierre Fabre, personal fees and non-financial support from Sanofi Regeneron, personal fees from Merck Sharp and Dohme, grants, personal fees and non-financial support from Novartis, personal fees from Almirall Hermal, grants and personal fees from Pfizer, personal fees from SUN Pharma, personal fees from 4SC, grants from Johnson&Johnson). KCK: relevant financial activities (research support, travel grants and honoraria from Bristol Myers Squibb and Merck Sharp and Dohme).TG: relevant financial activities (speakers and/or advisory board honoraria from Bristol Myers Squibb, Sanofi-Genzyme, Merck Sharp and Dohme, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono). KS: relevant financial activities (speakers and advisory board honoraria from AMGEN Oncology, Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Pierre Fabre and Roche, and travel support from Bristol Myers Squibb, Novartis, Pierre Fabre and TEVA/Cephalon Pharma). CP: relevant financial activities (speaker honoraria or honoraria as a consultant and travel support from Novartis, Bristol Myers Squibb, Roche, Merck Serono, Merck Sharp and Dohme, Celgene, AbbVie, Lilly and LEO). CF: relevant financial activities (travel support from Bristol Myers Squibb and Pierre Fabre; advisory board or honararia from Bristol Myers Squibb and Novartis). PT: relevant financial activities (speaker's honoraria from Bristol Myers Squibb, Novartis, Merck Sharp and Dohme, Pierre-Fabre, CureVac and Roche, consultant's honoraria from Bristol Myers Squibb, Novartis, Pierre-Fabre, Merck Serono, Sanofi und Roche and travel support from Bristol Myers Squibb, Pierre-Fabre and Roche). SH: relevant financial activities (research support from Bristol Myers Squibb; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Sanofi and Roche). PM: relevant financial activities (honoraria from Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Pierre Fabre, Novartis, Sanofi and Roche). LH: relevant financial activities (speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis, Amgen, Curevac, Pierre Fabre, Sanofi and Roche). EL: relevant financial activities (served as consultant or/and has received honoraria from Amgen, Actelion, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Janssen, Medac, and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre Fabre, Sunpharma and Novartis). DS: relevant financial activities (Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Sanofi, Regeneron, Array, Pierre Fabre, 4SC, Helsinn, Philogen, InFlarX, Merck-Serono, SunPharma, Ultimovacs, Sandoz). CG: relevant financial activities (personal fees from Amgen, personal fees from Merck Sharp & Dohme, grants and personal fees from Novartis, grants and personal fees from NeraCare, grants and personal fees from Bristol-Myers Squibb, personal fees from Pierre Fabre, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi). JCB: relevant financial activities (speaker honoraria from Amgen, MerckSerono, Pfizer, Sanofi; advisory board honoraria from 4SC, Amgen, CureVac, eTheRNA, MerckSerono, Novartis and InProTher; research funding from Alcedis, Boehringer Ingelheim, Bristol-Myers Squibb, IQVIA, and MerckSerono; travel support from 4SC and Incyte). SU: relevant financial activities (research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp and Dohme). All other authors (Lena Bischof, Ulrike Keim, Andreas Meiwes, Lydia Reinhardt, Nora Schlecht) declared to have no conflicts of interest., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies of the skin. Even though most patients are sufficiently treated by surgical resection, some will eventually metastasize and need systemic therapy. Phase I and II studies have shown efficacy for programmed cell death protein 1 (PD-1) inhibitors, but cohort sizes are low and real-world data especially on long-term outcome are pending., Methods: Patients from six German skin cancer centers treated with PD-1 inhibitors (pembrolizumab, nivolumab or cemiplimab) for advanced cSCC were retrospectively studied. Internal patient records were analyzed for clinical outcome including response, progression-free survival (PFS), overall survival (OS) and toxicity., Results: Of 46 evaluable patients (median age: 76 years), the overall response rate (RR) was 58.7%, including 15.2% with complete response. The disease control rate was 80.4%. Both median PFS and OS were not reached, Kaplan-Meier estimated 1-year PFS was 58.8%. Patients responding to therapy showed durable remission. Response was independent of the PD-1 inhibitor used and also independent of the presence of distant metastases vs. locally advanced disease. Two predictive factors were found: Patients with primaries located on the leg had a poorer therapy outcome and patients with high lactate dehydrogenase serum levels at baseline. Treatment was overall tolerated well, with less than 10% of patients discontinuing therapy due to toxicity., Conclusions: PD-1 inhibitors fulfill the need for an efficient systemic therapy for advanced cSCC and should be the new standard of care. With high RRs and durable disease control, neoadjuvant and adjuvant regimens should be evaluated., Competing Interests: Conflict of interest statement M.S. received honoraria and travel grants from Abbvie, Bristol-Myers Squibb (BMS), Merck, Merck Sharp & Dohme (MSD) and Novartis and Pfizer. U.L. has received honoraria from Roche, Merck Sharp and Dohme, Novartis, SUN, Sanofi; has received speaker fees and advisory Board honoraria from Roche, Novartis, Sun, Sanofi; has received research funding from MSD. C.L. has been a member of the advisory board of BMS, MSD, Merck, Sanofi, Roche, Pierre Fabre, Sun Pharma, Amgen, Biontech, Almirall Hermal, Kiowa Kirin, Novartis; has received speaker fees and travel reimbursement from BMS, MSD, Merck, Sanofi, Roche, Pierre Fabre, Sun Pharma, Amgen, Biontech, Almirall Hermal, Kiowa Kirin, and Novartis. L.Z. has received honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre; has been a consultant or a member of the advisory role from BMS, Novartis, Pierre Fabre, Sunpharma, Sanofi, MSD; has received research funding from Novartis; has received travel support from BMS, Pierre Fabre, Sanofi, Amgen, Novartis, and Sunpharma. S.U. has received research support from Bristol Myers Squibb and Merck Serono; has received speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis and Roche; has received travel support from Bristol Myers Squibb, Merck Sharp and Dohme. R.G. has received honoraria from Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre Fabre; has been as a consultant or a member of the advisory role from BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre Fabre, 4SC; has received research Funding from Novartis, Pfizer, Johnson & Johnson, Amgen, Merck Serono; has received travel fees, accommodation fees and expenses from Roche, BMS, SUN, Merck Serono and Pierre Fabre. K.M.T. has received honoraria from BMS, Roche, MSD, Novartis, Pierre Fabre, LEO, AbbVie, Galderma, Candela; has been as a consultant or a member of the advisory role from BMS, Roche, MSD, Novartis, Pierre Fabre, LEO, Sun Pharma, AbbVie; has received travel grants from BMS, Roche, Novartis and Pierre Fabre. A.H.E has received advisory honoraria from Biotest AG, MSD Oncology, Galderma, Janssen Cilag, AbbVie, as well as speaker's honoraria from Roche Pharma. J.C.H. has received honoraria for talks from BMS, MSD, Roche, Novartis; has been an advisory board member for MSD and Pierre Fabre; has received scientific grant support from BMS; has received travel grants from BMS and Pierre Fabre., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aim: To evaluate changes in health-related quality of life (HRQoL) in a Phase II trial (NCT02155647) of treatment-naive patients with metastatic Merkel cell carcinoma treated with avelumab (15-month follow-up). Materials & methods: Mixed-effect Models for Repeated Measures were applied to HRQoL data (FACT-M; EQ-5D-5L) to assess changes over time. Clinically derived progression-free survival was compared with HRQoL deterioration-free survival. Results: Overall, we saw relative stability in HRQoL among 116 included patients, with nonprogression associated with statistically and clinically meaningful better HRQoL compared with progressive disease. Deterioration-free survival rates (49-72% at 6 months, 40-58% at 12 months) were consistently higher/better compared with progression-free survival rates (41/31% at 6/12 months). Conclusion: These findings show unique longitudinal HRQoL data for treatment-naive metastatic Merkel cell carcinoma patients treated with avelumab. Clinical trial registration : NCT02155647 (ClinicalTrials.gov).

CTLA-4 and PD-1 play a key role in tumor-induced downregulation of lymphocytic immune responses. Immune checkpoint inhibitors have been shown to alter the immune response to various cancer types. Anti-CTLA-4 and anti-PD-1 antibodies affect the interaction between tumor, antigen-presenting cells and T lymphocytes. Clinical studies of the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab have provided evidence of their positive effects on overall survival in melanoma patients. Combined treatment using ipilimumab and nivolumab has been shown to achieve five-year survival rates of 52 %. Such enhancement of the immune response is inevitably associated with adverse events. Knowledge of the spectrum of side effects is essential, both in terms of prevention and management. Adverse events include colitis, dermatitis, hypophysitis, thyroiditis, hepatitis and other, less common autoimmune phenomena. In recent years, considerable progress has been made in the detection and treatment of the aforementioned immune-related adverse events. However, early diagnosis of rare neurological or cardiac side effects, which may be associated with increased mortality, frequently pose a challenge. The present update highlights our current understanding as well as new insights into the spectrum of side effects associated with checkpoint inhibitors and their management., (© 2020 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Purpose: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer, which can be effectively controlled by immunotherapy with PD-1/PD-L1 checkpoint inhibitors. However, a significant proportion of patients are characterized by primary therapy resistance. Predictive biomarkers for response to immunotherapy are lacking., Experimental Design: We applied Bayesian inference analyses on 41 patients with MCC testing various clinical and biomolecular characteristics to predict treatment response. Further, we performed a comprehensive analysis of tumor tissue-based immunologic parameters including multiplexed immunofluorescence for T-cell activation and differentiation markers, expression of immune-related genes and T-cell receptor (TCR) repertoire analyses in 18 patients, seven objective responders, and 11 nonresponders., Results: Bayesian inference analyses demonstrated that among currently discussed biomarkers only unimpaired overall performance status and absence of immunosuppression were associated with response to therapy. However, in responders, a predominance of central memory T cells and expression of genes associated with lymphocyte attraction and activation was evident. In addition, TCR repertoire usage of tumor-infiltrating lymphocytes (TILs) demonstrated low T-cell clonality, but high TCR diversity in responding patients. In nonresponders, terminally differentiated effector T cells with a constrained TCR repertoire prevailed. Sequential analyses of tumor tissue obtained during immunotherapy revealed a more pronounced and diverse clonal expansion of TILs in responders indicating an impaired proliferative capacity among TILs of nonresponders upon checkpoint blockade., Conclusions: Our explorative study identified new tumor tissue-based molecular characteristics associated with response to anti-PD-1/PD-L1 therapy in MCC. These observations warrant further investigations in larger patient cohorts to confirm their potential value as predictive markers., (©2020 American Association for Cancer Research.)

Immune checkpoint blockers have substantially improved prognosis of melanoma patients, nevertheless, resistance remains a significant problem. Here, intrinsic and extrinsic factors in the tumor microenvironment are discussed, including the expression of alternative immune checkpoints such as lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3). While most studies focus on immune cell expression of these proteins, we investigated their melanoma cell intrinsic expression by immunohistochemistry in melanoma metastases of 60 patients treated with anti-programmed cell death protein 1 (PD-1) and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy, and correlated it with the expression of potential ligands, RNA sequencing data and clinical outcome. LAG-3 and TIM-3 were commonly expressed in melanoma cells. In the stage IV cohort, expression of LAG-3 was associated with M1 stage ( p  < 0.001) and previous exposure to immune checkpoint inhibitors ( p  = 0.029). Moreover, in the anti-PD-1 monotherapy treatment group patients with high LAG-3 expression by tumor cells tended to have a shorter progression-free survival ( p  = 0.088), whereas high expression of TIM-3 was associated with a significantly longer overall survival ( p  = 0.007). In conclusion, we provide a systematic analysis of melanoma cell intrinsic LAG-3 and TIM-3 expression, highlighting potential implications of their expression on patient survival.

Tissue-resident memory T cells (TRM cells) have become an interesting subject of study for antitumor immunity in melanoma and other solid tumors. In the initial phases of antitumor immunity, they maintain an immune equilibrium and protect against challenges with tumor cells and the formation of primary melanomas. In metastatic settings, they are a prime target cell population for immune checkpoint inhibition (ICI) because they highly express inhibitory checkpoint molecules such as PD-1, CTLA-4, or LAG-3. Once melanoma patients are treated with ICI, TRM cells residing in the tumor are reactivated and expand. Tumor killing is achieved by secreting effector molecules such as IFN-g. However, off-target effects are also observed. Immune-related adverse events, such as those affecting barrier organs like the skin, can be mediated by ICI-induced TRM cells. Therefore, a detailed understanding of this memory T-cell type is obligatory to better guide and improve immunotherapy regimens. [ABSTRACT FROM AUTHOR]

Simple Summary: The effects of immune checkpoint inhibitor (ICI) therapy on 40 melanoma patients who developed immune-related hypophysitis were examined in this study. These patients were compared to 40 matched ones who did not develop hypophysitis. The onset of hypophysitis varied depending on the type of ICI used. Symptoms commonly included fatigue, headaches, and digestive problems. Patients with hypophysitis had low T4 hormone levels regardless of ICI type. However, low T3 and TSH hormone levels were only observed in patients who developed hypophysitis from ipilimumab. A rapid drop in blood sodium levels was also noted at the time of hypophysitis diagnosis. Additionally, the number of eosinophils and lymphocytes in the blood increased consistently in hypophysitis patients. Early diagnosis of hypophysitis is important because of its potential complications. Monitoring patients for specific symptoms and blood value changes could aid in early detection, allowing for prompt intervention and management. Background: Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activities and are widely used for the treatment of advanced cancers. However, they may lead to immune-related adverse events (irAEs) and some of them, such as hypophysitis, can be life-threatening. Here, early diagnosis is critical. Methods: We retrospectively analyzed 40 melanoma patients who developed hypophysitis during ICI treatment with either ipilimumab and/or anti-PD1 therapy and compared them to 40 control patients who did not develop hypophysitis during the ICI treatment, matched for age, gender, type of immunotherapy, and stage. Clinical data and blood values such as LDH, CRP, TSH, T3, T4, and absolute immune cell counts were retrieved from the medical records. Patient characteristics, laboratory values, progression-free survival, and overall survival were compared between the two groups. Results: Patients with ir-hypophysitis had a median age of 59 years, and most of them were male. Clinically, frequent symptoms were fatigue, headache, dizziness, and gastrointestinal symptoms such as nausea or abdominal pain. The onset of ir-hypophysitis differed much between ipilimumab- (median 8 weeks) and anti-PD1 (median 40 weeks)-induced hypophysitis (p < 0.001). At baseline, besides a slightly increased CRP level (p = 0.06), no differences were observed in patients who later developed hypophysitis compared to the control. After treatment started, hypophysitis patients showed a constant and significant decline in T4 levels from the start of therapy until diagnosis (p < 0.05), independent of the ICI treatment regime. However, a decline in T3 and TSH was only noted in patients with ipilimumab-induced ir-hypophysitis. Furthermore, serum sodium levels declined rapidly at the diagnosis of hypophysitis (p < 0.001). In addition, there was a constant increase in the absolute counts of eosinophils and lymphocytes from baseline in hypophysitis patients (p < 0.05). Conclusion: Ir-hypophysitis reveals different clinical pictures and onset times depending on the ICI regime used. Whereas a drop in T4 levels was indicative of developing hypophysitis independent of the ICI regime, TSH levels only declined in patients under ipilimumab-based ICI regimes. To best monitor our patients, it is important to recognize these differences. [ABSTRACT FROM AUTHOR]

Aim: The development of biomarkers that can reliably and early predict response to immune checkpoint inhibitors (ICIs) is crucial in melanoma. In recent years, the gut microbiome has emerged as an important regulator of immunotherapy response, which may, moreover, serve as a surrogate marker and prognosticator in oncological patients under immunotherapy. Aim of the present study is to investigate if physiologic colonic [18F]FDG uptake in PET/CT before start of ICIs correlates with clinical outcome of metastatic melanoma patients. The relation between [18F]FDG uptake in lymphoid cell-rich organs and long-term patient outcome is also assessed. Methodology: One hundred nineteen stage IV melanoma patients scheduled for immunotherapy with ipilimumab, applied either as monotherapy or in combination with nivolumab, underwent baseline [18F]FDG PET/CT. PET/CT data analysis consisted of standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) calculations in the colon as well as measurements of the colon-to-liver SUV ratios (CLRmean, CLRmax). Visual grading of colon uptake based on a four-point scale was also performed. Moreover, the spleen-to-liver SUV ratios (SLRmean, SLRmax) and the bone marrow-to-liver SUV ratios (BLRmean, BLRmax) were calculated. We also measured serum lipopolysaccharide (LPS) levels as a marker for bacterial translocation and surrogate for mucosal defense homeostasis. The results were correlated with patients' best clinical response, progression-free survival (PFS), and overall survival (OS) as well as clinical signs of colitis. Results: Median follow-up [95%CI] from the beginning of immunotherapy was 64.6 months [61.0–68.6 months]. Best response to treatment was progressive disease (PD) for 60 patients, stable disease (SD) for 37 patients, partial response (PR) for 18 patients, and complete response (CR) for 4 patients. Kaplan–Meier curves demonstrated a trend for longer PFS and OS in patients with lower colonic SUV and CLR values; however, no statistical significance for these parameters as prognostic factors was demonstrated. On the other hand, patients showing disease control as best response to treatment (SD, PR, CR) had significantly lower colonic MTV and TLG than those showing PD. With regard to lymphoid cell-rich organs, significantly lower baseline SLRmax and BLRmax were observed in patients responding with disease control than progression to treatment. Furthermore, patients with lower SLRmax and BLRmax values had a significantly longer OS when dichotomized at their median. In multivariate analysis, PET parameters that were found to significantly adversely correlate with patient survival were colonic MTV for PFS, colonic TLG for PFS, and BLRmax for PFS and OS. Conclusions: Physiologic colonic [18F]FDG uptake in PET/CT, as assessed by means of SUV, before start of ipilimumab-based treatment does not seem to independently predict patient survival of metastatic melanoma. On the other hand, volumetric PET parameters, such as MTV and TLG, derived from the normal gut may identify patients showing disease control to immunotherapy and significantly correlate with PFS. Moreover, the investigation of glucose metabolism in the spleen and the bone marrow may offer prognostic information. [ABSTRACT FROM AUTHOR]

Purpose : To investigate the prognostic value of [18F]FDG PET/CT as part of response monitoring in metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs). Methods: Sixty-seven patients underwent [18F]FDG PET/CT before start of treatment (baseline PET/CT), after two cycles (interim PET/CT) and after four cycles of ICIs administration (late PET/CT). Metabolic response evaluation was based on the conventional EORTC and PERCIST criteria, as well as the newly introduced, immunotherapy-modified PERCIMT, imPERCIST5 and iPERCIST criteria. Metabolic response to immunotherapy was classified according to four response groups (complete metabolic response [CMR], partial metabolic response [PMR], stable metabolic disease [SMD], progressive metabolic disease [PMD]), and further dichotomized by response rate (responders = [CMR] + [PMR] vs. non-responders = [PMD] + [SMD]), and disease control rate (disease control = [CMR] + [PMR] + [SMD] vs. [PMD]). The spleen-to-liver SUV ratios (SLRmean, SLRmax) and bone marrow-to-liver SUV ratios (BLRmean, BLRmax) were also calculated. The results of PET/CT were correlated with patients' overall survival (OS). Results: Median patient follow up [95% CI] was 61.5 months [45.3 – 66.7 months]. On interim PET/CT, the application of the novel PERCIMT demonstrated significantly longer survival for metabolic responders, while the rest criteria revealed no significant survival differences between the different response groups. Respectively on late PET/CT, both a trend for longer OS and significantly longer OS were observed in patients responding to ICIs with metabolic response and disease control after application of various criteria, both conventional and immunotherapy-modified. Moreover, patients with lower SLRmean values demonstrated significantly longer OS. Conclusion: In patients with metastatic melanoma PET/CT-based response assessment after four ICIs cycles is significantly associated with OS after application of different metabolic criteria. The prognostic performance of the modality is also high after the first two ICIs cycles, especially with employment of novel criteria. In addition, investigation of spleen glucose metabolism may provide further prognostic information. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint blockade has dramatically improved the outcomes of patients with melanoma. Available long-term updates of clinical studies show a sustained clinical benefit for patients treated with PD-1 inhibitors such as nivolumab or pembrolizumab or for those treated with a combination of nivolumab and ipilimumab. However, about 40–50% of patients acquire resistance to therapy within five years from the start of anti-PD-1 therapy. This review assesses available definitions of the resistance and patterns of response to PD-1 immunotherapy and summarizes the potential underlying mechanisms. The available data on resistance to PD-1 therapy, medical needs and therapeutic options for melanoma patients resistant to ICI are discussed for the metastatic setting, including brain metastases, as well as for the adjuvant and neo-adjuvant settings. Available 4- and 5-year updates for progression-free and for overall survival demonstrate a lasting clinical benefit for melanoma patients receiving anti-PD-directed immune checkpoint inhibitor therapy. However, at least one-half of the patients either do not respond to therapy or relapse early or late following the initial response to therapy. Little is known about the reasons for primary and/or secondary resistance to immunotherapy and the patterns of relapse. This review, prepared by an interdisciplinary expert panel, describes the assessment of the response and classification of resistance to PD-1 therapy, briefly summarizes the potential mechanisms of resistance, and analyzes the medical needs of and therapeutic options for melanoma patients resistant to immune checkpoint inhibitors. We appraised clinical data from trials in the metastatic, adjuvant and neo-adjuvant settings to tabulate frequencies of resistance. For these three settings, the role of predictive biomarkers for resistance is critically discussed, as well as are multimodal therapeutic options or novel immunotherapeutic approaches which may help patients overcome resistance to immune checkpoint therapy. The lack of suitable biomarkers and the currently modest outcomes of novel therapeutic regimens for overcoming resistance, most of them with a PD-1 backbone, support our recommendation to include as many patients as possible in novel or ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Background: Choosing the adequate systemic treatment for melanoma is driven by clinical parameters and personal preferences. Objective: Evaluation of the impact of disease and treatment on the daily life of patients receiving systemic therapy for melanoma. Methods: A German‐wide, cross‐sectional comparative study was conducted at 13 specialized skin cancer centres from 08/2020 to 03/2021. A questionnaire was distributed to assess patients' perception of disease and symptoms, the impact of their current treatment on quality of life (QOL) and activities, adverse events (AEs), therapeutic visits, as well as believe in and satisfaction with their current systemic melanoma treatment. Patient‐reported outcomes (PROs) were rated on a continuous numerical rating scale or selected from a given list. Results: Four hundred and fourteen patients with systemic melanoma therapy were included. 359 (87%) received immune checkpoint inhibition (ICI) and 55 (13%) targeted therapy (TT). About 1/3 of patients were adjuvantly treated, the remaining because of unresectable/metastatic melanoma. In subgroup analyses, only in the adjuvant setting, TT patients reported a significant decrease in their treatment associated QOL compared to patients with ICI (p = 0.02). Patients with TT were 1.9 times more likely to report AEs than patients with ICI, a difference being significant just for the adjuvant setting (p = 0.01). ICI treatment intervals differed significantly between adjuvant and unresectable/metastatic setting (p = 0.04), though all patients, regardless of their specific ICI drug, evaluated their treatment frequency as adequate. TT patients with dabrafenib/trametinib (n = 37) or encorafenib/binimetinib (n = 15) did not differ regarding the strain of daily pill intake. Patients older than 63 years rated various PROs better than younger patients. Conclusions: Patients evaluated their treatment mainly positively. ICI might be preferred over TT regarding QOL and patient‐reported AEs in the adjuvant setting. Older melanoma patients appeared to be less impacted by their disease and more satisfied with their treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: For patients with advanced basal cell carcinoma (aBCC) limited treatment options are available. In this situation, hedgehog inhibitors (HHIs) are approved as first-line treatment. Upon treatment failure or intolerance, a second-line treatment with PD1 inhibitors (PD1i) is an option. However, no third-line treatment is established. Therefore, we collected data of patients with aBCC, who received HHI reinduction following PD1i-failure. In our cohort of 12 patients, initial HHI treatment led to partial response in 8 and disease stabilization in 4 patients. Eventual HHI discontinuation was mostly due to tumor progression. Second-line PD1i resulted in a partial response in only one patient. Four out of the twelve patients responded to HHI reinduction, with the longest follow-up period being 29 months. Thus, a sequential treatment with HHI reinduction can be a feasible treatment option in a subgroup of patients with aBCC after treatment failure of first-line HHIs as well as of second-line PD1i. For patients with advanced basal cell carcinoma (aBCC) first-line treatment with hedgehog inhibitors (HHIs) and second-line treatment with PD1 inhibitors (PD1i) is available, offering combination and sequencing options. Here, we focus on the efficacy and safety of HHI reinduction after PD1i failure. Retrospective data analysis was performed with 12 patients with aBCC (locally advanced (n = 8)/metastatic (n = 4)). These patients (male:female 6:6, median age 68 years) initially received HHIs, leading to complete/partial response (66%) or stable disease (33%). Median treatment duration was 20.8 (2–64.5) months until discontinuation due to progression (n = 8), adverse events (n = 3), or patient request (n = 1). Subsequent PD1 inhibition (pembrolizumab 42%, cemiplimab 58%) yielded a partial response (8%), stable disease (33%), or progression (59%). Median treatment duration was 4.1 (0.8–16.3) months until discontinuation due to progression (n = 9), adverse events (n = 1), patient request (n = 1), or missing drug approval (n = 1). HHI reinduction resulted in complete/partial response (33%), stable disease (50%), or progression (17%). Median treatment duration was 3.6 (1–29) months. Response duration in the four responding patients was 2–29+ months. Thus, a subgroup of patients with aBCC responded to reinduction of HHI following PD1i failure. Therefore, this sequential treatment represents a feasible treatment option. [ABSTRACT FROM AUTHOR]

To date, few data are available regarding Adverse events (AEs) in cancer patients who are vaccinated for coronavirus disease 2019 (COVID-19) while being actively treated with Immune-checkpoint inhibitors (ICIs). We aimed to assess the safety of COVID-19 vaccines approved in Germany. Specifically, we investigated the frequency of general side effects and immune-related AEs of COVID-19 vaccination. A triage survey was used to collect the following information for patients with metastatic skin cancer: vaccine type, date of receipt of each dose of vaccine, and self-reported side effects. Clinical data were retrieved from the patients' medical records. Of 130 patients with metastatic skin cancer, 89 patients were on immunotherapy and received COVID-19 vaccination. Of these 89 patients (median age: 64 years; 57 [64%] men), 89% had melanoma, and 71% received ICI therapy with a PD-1 antibody. Eighty-eight percent received an mRNA-based COVID-19 vaccination. The median follow-up time was 125 days after the first vaccination, and 84 days after the second. The most common observed side effects were mild to moderate pain at the injection site (40%), followed by fatigue (24%). Grade 3 irAEs were reported in eight patients, seven of whom were on nivolumab plus ipilimumab combination treatment. Of the 19 patients vaccinated within 72 h before/after ICI, five developed irAEs within 17 days (1–17 days). This small cohort study suggests that approved COVID-19 vaccinations are safe for use in cancer patients receiving ICIs. However, some precautions should be taken, especially regarding the timing of vaccination and ICI treatment. [ABSTRACT FROM AUTHOR]

In patients with melanoma brain metastases (MBM), a combination of radiotherapy (RT) with immune checkpoint inhibitors (ICI) is routinely used. However, the best sequence of radio-immunotherapy (RIT) remains unclear. In an exploratory phase 2 trial, MBM patients received RT (stereotactic or whole-brain radiotherapy depending on the number of MBM) combined with ipilimumab (ipi) ± nivolumab (nivo) in different sequencing (Rad-ICI or ICI-Rad). Comparators arms included patients treated with ipi-free systemic treatment or without RT (in MBM-free patients). The primary endpoints were radiological and immunological responses in the peripheral blood. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Of 106 screened, 92 patients were included in the study. Multivariate analysis revealed an advantage for patients starting with RT (Rad-ICI) for overall response rate (RR: p = .007; HR: 7.88 (95%CI: 1.76-35.27)) and disease control rate (DCR: p = .036; HR: 6.26 (95%CI: 1.13-34.71)) with a trend for a better PFS (p = .162; HR: 1.64 (95%CI: 0.8-3.3)). After RT plus two cycles of ipi-based ICI in both RIT sequences, increased frequencies of activated CD4, CD8 T cells and an increase in melanoma-specific T cell responses were observed in the peripheral blood. Lasso regression analysis revealed a significant clinical benefit for patients treated with Rad-ICI sequence and immunological features, including high frequencies of memory T cells and activated CD8 T cells in the blood. This study supports increasing evidence that sequencing RT followed by ICI treatment may have better effects on the immunological responses and clinical outcomes in MBM patients. [ABSTRACT FROM AUTHOR]

Background: The usage of immune checkpoint inhibitors (ICIs) is the standard practice for the treatment of metastatic melanoma. However, a significant amount of patients show no response to immunotherapy, while issues on its reliable response interpretation exist. Aim of this study was to investigate the phenomenon of early disease progression in 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in melanoma patients treated with ICIs. Methods: Thirty-one patients under ICIs serially monitored with 18F-FDG PET/CT were enrolled. All patients exhibited progressive metabolic disease (PMD) after two ICIs' cycles according to the European Organization for Research and Treatment of Cancer (EORTC) criteria, and were characterized as unconfirmed PMD (uPMD). They were further followed with at least one PET/CT for either confirmation of PMD (cPMD) or demonstration of pseudoprogression remission. Patients were also evaluated with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT). Moreover, in an attempt to investigate immune activation, the spleen to liver ratios (SLRmean, SLRmax) of 18F-FDG uptake were measured. Results: Median follow up was 69.7 months [64.6–NA]. According to EORTC, 26/31 patients with uPMD eventually showed cPMD (83.9%) and 5/31 patients showed pseudoprogression (16.1%). Patients with cPMD (n = 26) had a median OS of 10.9 months [8.5–NA], while those with pseudoprogression (n = 5) did not reach a median OS [40.9–NA]. Respectively, after application of PERCIMT, 2/5 patients of the pseudoprogression group were correctly classified as non-PMD, reducing the uPMD cohort to 29 patients; eventually, 26/29 patients demonstrated cPMD (89.7%) and 3/29 pseudoprogression (10.3%). One further patient with pseudoprogression exhibited transient, sarcoid-like, mediastinal/hilar lymphadenopathy, a known immune-related adverse event (irAE). Finally, patients eventually showing cPMD exhibited a significantly higher SLRmean than those showing pseudoprogression after two ICIs' cycles (p = 0.038). Conclusion: PET/CT, performed already after administration of two ICIs' cycles, can identify the majority of non-responders in melanoma immunotherapy. In order to tackle however, the non-negligible phenomenon of pseudoprogression, another follow-up PET/CT, the usage of novel response criteria and vigilance over emergence of radiological irAEs are recommended. Moreover, the investigation of spleen glucose metabolism may offer further prognostic information in melanoma patients under ICIs. [ABSTRACT FROM AUTHOR]

Different mechanisms lead to immune checkpoint inhibitor (ICI) resistance. Identifying clinically useful biomarkers might improve drug selection and patients' therapy. We analyzed the soluble immune checkpoints sPD1, sPDL1, sLAG3, and sTIM3 using ELISA and their expression on circulating T cells using FACS in pre- and on-treatment blood samples of ICI treated melanoma patients. In addition, pre-treatment melanoma metastases were stained for TIM3 and LAG3 expression by IHC. Results were correlated with treatment response and progression-free survival (PFS). Resistance to anti-PD1 treatment (n = 48) was associated with high pre-treatment serum levels of sLAG3 (DCR: p = .009; PFS: p = .018; ROC cutoff >148 pg/ml) but not sPD1, sPDL1 or sTIM3. In contrast, resistance to ipilimumab plus nivolumab (n = 42) was associated with high levels of sPD1 (DCR: p = .019, PFS: p = .046; ROC cutoff >167 pg/ml) but not sPDL1, sLAG3 or sTIM3. Both treatment regimens shared a profound increase of sPD1 serum levels with treatment (p < .0001). FACS analysis revealed reduced frequencies of CD3+ CD8+ PD1 + T cells (p = .028) in anti-PD1-resistant patients, whereas increased frequencies of CD3+ CD4+ LAG3 + T cells characterized patients resistant to ipilimumab plus nivolumab (p = .033). Unlike anti-PD1 monotherapy, combination blockade significantly increased proliferating T cells (CD3+ CD8+ Ki67 + T cells; p < .0001) and eosinophils (p = .001). In melanoma metastases, an increased infiltration with TIM3+ or LAG3 + T cells in the tumor microenvironment correlated with a shorter PFS under anti-PD1 treatment (TIM3: p = .019, LAG3: p = .07). Different soluble immune checkpoints characterized checkpoint inhibitor-resistant melanoma. Measuring these serum markers may have the potential to be used in clinical routine. [ABSTRACT FROM AUTHOR]

Immunotherapy with immune checkpoint inhibitors (ICIs) changed the treatment management in several solid metastatic tumors with very poor prognosis, in particular in melanoma stage IV since its introduction in 2011. However, it is not yet fully understood why some patients respond to ICIs and others not, and it is also unclear why melanomas are the most sensitive tumors to ICI treatment. Selection criteria for patient stratification are needed and several approaches are under evaluation. These include the PD-L1 expression in the tumor samples, assessment of the tumor mutational burden as well as radiological and molecular imaging techniques, such as positron emission tomography (PET)-CT and PET-MRI with 18F-fluorodeoxyglucose (FDG) or novel radiopharmaceuticals. In the near future, a more holistic approach based on the combination of imaging data and sequencing data and the development of radiogenomic signatures will be needed for a better characterization of immunotherapy response and selection of patients who will benefit from ICI therapy alone or in combination with chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Technical advances in immunotherapies have led to the development of novel T cell receptor (TCR)-based approaches to fight cancer. One of these therapies, tebentafusp, has shown a significant benefit in the overall survival of uveal melanoma patients for the first time. This review focuses on TCR-directed therapies in the treatment of uveal melanoma. Metastatic uveal melanoma (mUM) is one of the most rapidly progressing tumors, with a bad prognosis and no standard-of-care treatment. Immune checkpoint inhibitors have revolutionized cancer therapy and improved overall survival in patients with metastatic cutaneous melanoma (mCM). However, this approach has been largely unimpressive, with no significant impact on the survival of mUM patients. Technical advances in immunotherapies have led to the development of novel T cell receptor (TCR)-based approaches to fight cancer. For the first time in over 50 years, compelling evidence demonstrates the power of TCR-based approaches for survival in mUM patients. Hence, this review summarizes novel TCR-based immunotherapeutic strategies currently in clinical studies for mUM treatment. We also discuss the potential combinational treatments to these strategies to maximize the clinical benefits. [ABSTRACT FROM AUTHOR]

Melanoma, a highly aggressive form of skin cancer, has seen significant advancements in treatment through the introduction of immunotherapy. However, the variability in patient responses underscores the need for reliable biomarkers to guide treatment decisions. This article reviews key biomarkers in melanoma immunotherapy, such as PD-L1 expression, tumor mutational burden (TMB), and gene expression profiles (GEPs). It also explores emerging biomarkers, including LAG-3 expression, immune cell phenotyping in tissue and blood, gut microbiota, and circulating tumor DNA (ctDNA). Notably, ctDNA may offer valuable insights into the efficacy of T cell-engaging bispecific molecules, such as tebentafusp. The review provides a comprehensive overview of the evolving landscape of melanoma biomarkers, their role in personalizing treatment, and future research directions, including neoadjuvant immune checkpoint inhibition. [ABSTRACT FROM AUTHOR]

Simple Summary: The fractal dimension (FD) and the multifractal spectrum (MFS) are nonlinear quantitative measures which express the heterogeneity in the distribution of the tracer, F-18-fluorodeoxyglucose, (18F-FDG), in the body of patients suffering from metastatic melanoma. Given the well-documented, high accumulation of the tracer in tumor/metastatic sites, the measures expressing the tracer distribution also express the extent of metastases in the body. As such, FD and MFS can be employed to detect the presence of melanoma and to monitor the therapeutic outcome using the PET-CT follow-up digitized scans of the patients. In the present study, the FD and MFS measures of patients are evaluated before and during treatment with PD-1 inhibitors and are compared with the corresponding values of healthy controls. The MFS predictions agree with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while the FD agrees in 77% of all cases. Therefore, the quantitative MFS is proposed as an additional, alternative biomarker for monitoring the immunotherapy outcome in melanoma patients, after treatment with PD-1 inhibitors. Longitudinal whole-body PET-CT scans with F-18-fluorodeoxyglucose (18F-FDG) in patients suffering from metastatic melanoma were analyzed and the tracer distribution in patients was compared with that of healthy controls. Nineteen patients with metastatic melanoma were scanned before, after two and after four cycles of treatment with PD-1 inhibitors (pembrolizumab, nivolumab) applied as monotherapy or as combination treatment with ipilimumab. For comparison eight healthy controls were analyzed. As quantitative measures for the comparison between controls and patients, the nonlinear fractal dimension (FD) and multifractal spectrum (MFS) were calculated from the digitized PET-CT scans. The FD and MFS measures, which capture the dispersion of the tracer in the body, decreased with disease progression, since the tracer particles tended to accumulate around metastatic sites in patients, while the measures increased when the patients' clinical condition ameliorate. The MFS measure gave better predictions and were consistent with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while FD agreed in 77% of all cases. These results agree, qualitatively, with a previous study of our group when treatment with ipilimumab monotherapy was considered. [ABSTRACT FROM AUTHOR]

Simple Summary: This retrospective multicenter study examines the influence of hepatic and extrahepatic metastases on the response of immune checkpoint blockade (ICB) in patients with metastatic uveal melanoma. A better response to dual ICB was observed in the presence of extrahepatic metastases in two recently published phase II trials. Therefore, we investigated two cohorts with and without extrahepatic metastasis and have assembled a population of 178 patients treated with ICB. The survival of this large cohort of patients with advanced UM was more favorable than that reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only. Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy is the standard of care in patients harboring metastasized melanoma. However, once further tumor growth is stopped it remains unclear when immunotherapy can be safely ceased. This clinical question is increasingly raised especially in patients with a strong desire to discontinue therapy or in patients who are forced to pause treatment due to severe immune-related side effects. With our study we aim to provide data which may be helpful for clinicians and patients when treatment discontinuation is considered. Further prospective, multicenter studies are needed to further address this important clinical issue. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: The potential interference at the immune response level between COVID-19 and cancer therapy raises key clinical questions and points out scientific issues that need to be promptly addressed. Among the therapeutic strategies available in oncological clinics, major concerns are raised by immunomodulatory drugs and, particularly, by immune checkpoint inhibitors (ICIs), which currently constitute a crucial drug in the management of several types of advanced and metastatic solid tumors. To date, the debate about the real impact of ICIs on the clinical outcome of COVID infection is still open. Here, we report and review the results of pertinent studies designed to evaluate the relationships between ICI treatment and COVID-19. Since the start of the global spread of coronavirus disease (COVID-19) pandemic, cancer patients were identified as a specifically susceptible subgroup of the patient population. Several reports have shown that cancer patients have an increased risk of both contracting the infection and of experiencing a more severe disease course, with a rapidly evolving picture associated with higher mortality. The assumption of cancer patients as "COVID-19 vulnerable" has led, irretrievably, to profound changes in the decision making of oncological treatments. Potential justifications for such concerns encompass the cancer-dependent suppression of the immune response, as well as the influence of administration of systemic anticancer treatments, including chemotherapy and immunotherapy. Nevertheless, to date, it is not clear whether the use of immune checkpoint inhibitors (ICIs) in cancer patients is safe, given their modulating effects on the immune system, or that they may rather conceal detrimental consequences. Theoretically, on the one hand, ICIs may enhance the immunological control of viral infections through their immunostimulating mechanisms; on the other hand, they could contribute to the hyper-inflammatory phase of COVID-19, worsening its clinical outcomes. In this study, we report the foremost clinical observations on the safety of ICI administration in cancer patients affected by COVID-19. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition in completely resected MCC (ie, a setting without an established systemic standard-of-care treatment). In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0–1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1–2 vs stages 3–4), age (<65 vs ≥65 years), and sex. Landmark disease-free survival (DFS) at 12 and 24 months was the primary endpoint, assessed in the intention-to-treat populations. Overall survival and safety were secondary endpoints. This planned interim analysis was triggered when the last-patient-in was followed up for more than 1 year. This study is registered with ClinicalTrials.gov (NCT02196961) and with the EU Clinical Trials Register (2013-000043-78). Between Oct 1, 2014, and Aug 31, 2020, 179 patients were enrolled (116 [65%] stage 3–4, 122 [68%] ≥65 years, 111 [62%] male). Stratification factors (stage, age, sex) were balanced across the nivolumab (n=118) and internal control group (observation, n=61); adjuvant radiotherapy was more common in the control group. At a median follow-up of 24·3 months (IQR 19·2–33·4), median DFS was not reached (between-groups hazard ratio 0·58, 95% CI 0·30–1·12); DFS rates in the nivolumab group were 85% at 12 months and 84% at 24 months, and in the observation group were 77% at 12 months and 73% at 24 months. Overall survival results were not yet mature. Grade 3–4 adverse events occurred in 48 [42%] of 115 patients who received at least one dose of nivolumab and seven [11%] of 61 patients in the observation group. No treatment-related deaths were reported. Adjuvant therapy with nivolumab resulted in an absolute risk reduction of 9% (1-year DFS) and 10% (2-year DFS). The present interim analysis of ADMEC-O might suggest clinical use of nivolumab in this area of unmet medical need. However, overall survival events rates, with ten events in the active treatment group and six events in the half-the-size observation group, are not mature enough to draw conclusions. The explorative data of our trial support the continuation of ongoing, randomised trials in this area. ADMEC-O suggests that adjuvant immunotherapy is clinically feasible in this area of unmet medical need. Bristol Myers Squibb. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis. In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre. Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p =.007), confusion (83% vs. 43%; p =.02), disorientation (83% vs. 29%; p =.007) and aphasia (43% vs. 0%; p =.007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43). ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death. • Presentation of ICI-iE is variable and resembles that of HSV-1 encephalitis. • Abnormal MRI and antineuronal antibodies are less common than previously reported. • Analysis of cerebrospinal fluid has the highest diagnostic value in ICI-iE. • ICI-iE has a mortality of 10% and long-term sequelae occur in 47% of patients. • Early immunosuppressive treatment of ICI-iE is associated with full recovery. [ABSTRACT FROM AUTHOR]

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 C>T and CC>TT 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. • Our findings support the role of UV irradiation in conjunctival melanoma. • Oncogene mutation patterns are similar to cutaneous melanoma. • In contrast to uveal melanoma, lymph node metastasis is common. • Response to immune checkpoint inhibition (ICI) is better than in uveal melanoma. • Targeted therapy (TT) should be considered in BRAF mutated conjunctival melanoma. [ABSTRACT FROM AUTHOR]

Recent evidence suggests additional immunomodulatory properties of RANKL inhibition possibly boosting the clinical efficacy of immune checkpoint inhibitors (ICI). We conducted a prospective, multicentre clinical trial in unresectable stage IV melanoma patients with bone metastases who received denosumab in parallel with dual ICI (BONEMET) and performed comprehensive immune monitoring at baseline and 4, 12, and 24 weeks after initiation of therapy. Secondary endpoints included tolerability and efficacy. For comparison, biospecimens from melanoma patients treated with dual ICI without denosumab were analyzed accordingly and served as retrospective reference cohort. In both the BONEMET (n = 16) and the reference cohort (n = 18) serum levels of 17 cytokines, including IFNγ were significantly increased after 4 weeks of treatment. Patients who received ICI and denosumab showed a significantly higher increase in serum CXCL-13 and a significant decrease in VEGFc compared with the reference cohort. While no changes in T cell composition were observed at 4 weeks, patients in the BONEMET cohort showed a significant decrease in the peripheral naïve T-cell population and an increase in CD8+ effector cells after 12 weeks. Treatment-related adverse events occurred with comparable frequency (93.8% in the BONEMET cohort versus 83.3% in the reference cohort). 7/16 patients in the BONEMET cohort and 8/18 patients in the reference cohort achieved disease control. Denosumab in combination with dual ICI modulates cytokine expression and T-cell composition in peripheral blood. The upregulation of CXCL-13, a key factor for initiating tertiary lymphoid structures, strengthens the hypothesis that denosumab indeed boost immunological effects. • Clinical trial of immune checkpoint inhibitors (ICI) and RANKL inhibitor denosumab. • Denosumab combined with ICI modulates T-cell composition and cytokine expression. • Denosumab in combination with ICI might enhance anti-tumor immune response. • Study provides a rationale for controlled clinical trials focusing efficacy. [ABSTRACT FROM AUTHOR]

Effective treatment options are limited for patients with advanced melanoma who have progressed on immune checkpoint inhibitors (ICI) and targeted therapies (TT). Preclinical models support the combination of ICI with TT; however, clinical trials evaluating the efficacy of triplet combinations in first-line setting showed limited advantage compared to TT only. We conducted a retrospective, multicenter study, that included patients with advanced melanoma who were treated with BRAF/MEK inhibitors in combination with an anti-PD-(L)1 antibody (triplet therapy) after failure of at least one anti-PD-(L)1-based therapy and one TT in seven major melanoma centers between February 2016 and July 2022. A total of 48 patients were included, of which 32 patients, 66.7% had brain metastases, 37 patients (77.1%) had three or more metastatic organs and 21 patients (43.8%) had three or more treatment lines. The median follow-up time was 31.4 months (IQR, 22.27–40.45 months). The treatment with triplet therapy resulted in an ORR of 35.4% (n = 17) and a DCR of 47.9% (n = 23). The median DOR was 5.9 months (range, 3.39–14.27 months). Patients treated with BRAF/MEK inhibitors as the last treatment line showed a slightly lower ORR (29.6%) compared to patients who received ICI or chemotherapy last (ORR: 42.9%). Grade 3–4 treatment-related adverse events occurred in 25% of patients (n = 12), with seven patients (14.6%) requiring discontinuation of treatment with both or either drug. Triplet therapy has shown activity in heavily pretreated patients with advanced melanoma and may represent a potential treatment regimen after failure of ICI and TT. • Unmet need for advanced melanoma after failure of immune- and targeted therapy (TT) • Combination of BRAF/MEK inhibitors plus anti-PD-(L)1 as so-called triplet therapy • Triplet therapy showed efficacy after failure of anti-PD-1-based therapy and TT • Triplet therapy as a viable regimen after failure of immune- and targeted therapy [ABSTRACT FROM AUTHOR]