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Purpose: We aimed to identify predictive clinical and CT imaging biomarkers and assess their predictive capacity regarding overall survival (OS) and treatment response in patients with metastatic melanoma undergoing immunotherapy., Methods: The local institutional ethics committee approved this retrospective study and waived informed patient consent. 103 patients with immunotherapy for metastatic melanoma were randomly divided into training (n = 69) and validation cohort (n = 34). Baseline tumor markers (LDH, S100B), baseline CT imaging biomarkers (tumor burden, Choi density) and CT texture parameters (Entropy, Kurtosis, Skewness, uniformity, MPP, UPP) of the largest target lesion were extracted. To identify treatment response predictors, binary logistic regression analysis was performed in the training cohort and tested in the validation cohort. For OS, Cox regression and Kaplan Maier analyses were performed in the training cohort. Bivariate and multivariate models were established. Goodness of fit was assessed with Harrell's C-index. Potential predictors were tested in the validation cohort also using Cox-regression and Kaplan-Meier analyses., Results: Baseline S100B (Hazard ratio(HR) = 2.543, p0.018), tumor burden (HR = 1.657, p = 0.002) and Kurtosis (HR = 2.484, p < 0.001) were independent predictors of OS and were confirmed in the validation cohort (p < 0.048). Tumor burden and Kurtosis showed incremental predictive capacity allowing a good predictive model when combined with baseline S100B levels (C-index = 0.720). Only S100B was predictive of treatment response (OR ≤ 0.630, p ≤ 0.022). Imaging biomarkers did not predict treatment response., Conclusion: We identified easily obtainable baseline clinical (S100B) and CT predictors (tumor burden and Kurtosis) of OS in patients with metastatic melanoma undergoing immunotherapy. However, imaging predictors did not predict treatment response., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date., Patients and Methods: Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression., Results: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p = 0.002) as independent risk factors for poor survival. Patients with elevated CRP and LDH and a REC <1.5% were at highest risk for disease progression and death (p = 0.001)., Conclusions: Blood markers predict survival in metastatic UM treated with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high REC may help identify patients with better prognosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune-related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.

Simple Summary: The incidence of metastatic melanoma is rising, making it imperative to identify patients who do not benefit from immunotherapy. This study aimed to develop a radiomic biomarker, using segmentations from 146 baseline and 146 first follow-up CT scans, to predict best overall response, progression-free survival, and overall survival across various immunotherapies. We volumetrically segmented the total tumour load, excluding cerebral metastases. This study also examined whether reducing the number of segmented metastases per patient affects predictive accuracy. The findings suggest that delta radiomics could enhance the prediction of best overall response, progression-free survival, and overall survival in metastatic melanoma patients undergoing first-line immunotherapy. Although volumetric whole tumour load segmentation is complex, it may provide predictive benefits. Background: The prevalence of metastatic melanoma is increasing, necessitating the identification of patients who do not benefit from immunotherapy. This study aimed to develop a radiomic biomarker based on the segmentation of all metastases at baseline and the first follow-up CT for the endpoints best overall response (BOR), progression-free survival (PFS), and overall survival (OS), encompassing various immunotherapies. Additionally, this study investigated whether reducing the number of segmented metastases per patient affects predictive capacity. Methods: The total tumour load, excluding cerebral metastases, from 146 baseline and 146 first follow-up CTs of melanoma patients treated with first-line immunotherapy was volumetrically segmented. Twenty-one random forest models were trained and compared for the endpoints BOR; PFS at 6, 9, and 12 months; and OS at 6, 9, and 12 months, using as input either only clinical parameters, whole-tumour-load delta radiomics plus clinical parameters, or delta radiomics from the largest ten metastases plus clinical parameters. Results: The whole-tumour-load delta radiomics model performed best for BOR (AUC 0.81); PFS at 6, 9, and 12 months (AUC 0.82, 0.80, and 0.77); and OS at 6 months (AUC 0.74). The model using delta radiomics from the largest ten metastases performed best for OS at 9 and 12 months (AUC 0.71 and 0.75). Although the radiomic models were numerically superior to the clinical model, statistical significance was not reached. Conclusions: The findings indicate that delta radiomics may offer additional value for predicting BOR, PFS, and OS in metastatic melanoma patients undergoing first-line immunotherapy. Despite its complexity, volumetric whole-tumour-load segmentation could be advantageous. [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: Combined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in numerous cancer indications, with PD-1 inhibitor nivolumab plus CTLA-4 inhibitor ipilimumab in advanced melanoma as first-ever approved therapies for combined ICB. However, gains in efficacy must be balanced against a higher frequency and severity of adverse drug reactions (ADR). Because delays in diagnosis and management might result in symptom worsening and further complications, clinicians shall be well trained to identify ADR promptly and monitor patients adequately. This paper reviews safety data assessed by the European Medicines Agency for the anti-PD-1/CTLA-4 combination and provides a literature overview on published case reports for rare ADR with suspected potential underreporting. Incidences and kinetics of immune-related ADR are described. Recommendations for the evaluation and management of ADR are convened by an interdisciplinary expert panel focusing on rare but clinically important side effects arising from combined ICB. Pooled safety data from 1551 patients with advanced melanoma, treated either with 3mg/kg ipilimumab plus 1mg/kg nivolumab (N=407), or nivolumab alone (N=787), or ipilimumab alone (N=357) demonstrate that immune-related ADR occur more frequently for the combination, with a shorter time-to-onset, and tend to be more severe. The majority of events is reversible after systemic use of glucocorticoids, notably methylprednisolone or equivalents; in certain cases of long-lasting and refractory immune toxicities, non-steroidal immunosuppressants may be used, once ICB is interrupted or terminated. Combined ICB has considerable toxicities, therefore close monitoring and high experience in diagnosis and treatment of ADR is necessary. [ABSTRACT FROM AUTHOR]

PD-1 checkpoint inhibitors are associated with a specific spectrum of immune-related adverse events. This spectrum is different from toxicities known for kinase inhibitors or cytotoxic drugs. Since PD-1 directed therapies show effectivity in an increasing number of malignant diseases, their clinical usage will increase rapidly. Therefore clinicians from different specialities such as medical oncology, internal medicine, family doctors and emergency unit staff should be aware of the adverse effects of PD-1 checkpoint inhibitors to avoid delays in diagnosis and treatment. Based on pooled data from pivotal trials as reported by the European Medicines Agency, the present paper reviews incidences and kinetics of onset and resolution of immune-mediated "adverse events of specific interest" (AEOSI) of both approved PD-1 inhibitors nivolumab and pembrolizumab. In general, the severity of AEOSI is mild to moderate (grade 1-2); the frequency of immune-mediated but also idiopathic grade 3-4 adverse drug reactions is ⩽2% for any event term. Recommendations for the diagnosis, monitoring and management of the relevant dermatological, gastrointestinal, pulmonary, endocrine, renal and hepatic toxicities are convened by an expert panel that consolidated and clarified treatment recommendations after the onset of AEOSI. Although the time of onset is not predictable - the medians range from 1 to 6months - the huge majority of events is reversible, with no impact of the time of onset. By the systemic use of glucocorticoids, notably methylprednisolone or equivalents, most AEOSI are well manageable. Non-steroidal immunosuppressants may be used in certain cases of refractory/recalcitrant, long-lasting immune toxicities. With regard to the outstanding clinical activity of the anti-PD-1 antibodies, therapy restart is the principal therapeutic option after recovery of grade 2 AEOSI, or diminution of higher grade skin or endocrine events to mild severity. Early diagnosis and close clinical monitoring are essential for successful management of immune-related adverse events. [ABSTRACT FROM AUTHOR]

The incidence of melanoma is increasing worldwide, and the prognosis for patients with high-risk or advanced metastatic melanoma remains poor despite advances in the field. Standard treatment for patients with thick (S2.0 mm) primary melanoma with or without regional métastases to lymph nodes is surgery followed by adjuvant therapy or clinical trial enrollment. Adjuvant therapy with interferon-a and cancer vaccines is discussed in detail. Patients who progress to stage IV metastatic melanoma have a median survival of <1 year. Standard treatment with chemotherapy yields low re- sponse rates, of which few are durable. Cytokine therapy with IL-2 achieves durable benefits in a greater fraction, but it is accompanied by severe toxicities that require the patient to be hospitalized for support during treatment. A systematic literature review of treatments for advanced, metastatic disease was conducted to present the success of current treatments and the promise of those still in clinical development that may yield incremental improvements in the treatment of advanced, metastatic melanoma. The Oncologist 2011 ; 16: 5-24 [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]