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Melanoma patient remains a challenging for the radiologist, due to the difficulty related to the management of a patient more often in an advanced stage of the disease. It is necessary to determine a stratification of risk, optimizing the means, with diagnostic tools that should be optimized in relation to the type of patient, and improving knowledge. Staging and risk assessment procedures are determined by disease presentation at diagnosis. Melanoma staging is a critical tool to assist clinical decision-making and prognostic assessment. It is used for clinical trial design, eligibility, stratification, and analysis. The current standard for regional lymph nodes staging is represented by the sentinel lymph node excision biopsy procedure. For staging of distant metastases, PET-CT has the highest sensitivity and diagnostic odds ratio. Similar trend is observed during melanoma surveillance. The advent of immunotherapy, which has improved patient outcome, however, has determined new issues for radiologists, partly due to atypical response patterns, partly due to adverse reactions that must be identified as soon as possible for the correct management of the patient. The main objectives of the new ir-criteria are to standardize the assessment between different trials. However, these ir-criteria do not take into account all cases of atypical response patterns, as hyperprogression or dissociated responses. None of these criteria has actually been uniformly adopted in routine. The immune-related adverse events (irAEs) can involve various organs from head to toe. It is crucial for radiologists to know the imaging appearances of this condition, to exclude recurrent or progressive disease and for pneumonitis, since it could be potentially life-threatening toxicity, resulting in pneumonitis-related deaths in early phase trials, to allow a proper patient management.

INTRODUCTION The development of new targeted therapies has considerably changed the therapeutic paradigm of melanoma, significantly increasing overall survival (OS) and progression-free survival (PFS). However, skin-related adverse sequelae might occur and impact on patients' quality of life. AREAS COVERED In this article we will cover the most important dermatological toxicities related to BRAF and MEK-inhibitors, along with updated management strategies. EXPERT OPINION BRAF inhibitors have represented a revolution in the treatment of melanoma. They have improved the outcome of the disease and therefore represent an important option in the management and care of patients with advanced melanoma. Skin toxicity (especially the onset of squamous skin carcinomas) has been considered a major cutaneous side effect and, although the addition of MEK inhibitors in combination has significantly reduced the incidence of skin sequelae, serious skin adverse events might develop anyway and impact significantly on patients'quality of life and on national health system budget. The introduction of BRAF and MEK inhibitors as a new effective adjuvant treatment option for stage III and ulcerated melanoma has proved a significant impact on the risk of recurrence, and may have interesting developments in the near future as a further therapeutic tool.

This dataset contains data of patient characteristics and IL6 in a cohort of patients with advanced cutaneous squamous cell carcinoma treated with cemiplimab.

Melanoma displays a rising incidence, and the mortality associated with metastatic form remains high. Monoclonal antibodies that block programmed death (PD-1) and PD Ligand 1 (PD-L1) network have revolutionized the history of metastatic disease. PD-L1 is expressed on several immune cells and can be also expressed on human neutrophils (PMNs). The role of peripheral blood PMNs as predictive biomarkers in anti-PD-1 therapy of melanoma is largely unknown. In this study, we aimed to determine activation status and PD-L1 expression on human neutrophils as possible novel biomarkers in stage IV melanoma patients (MPs). We found that PMNs from MPs displayed an activated phenotype and increased PD-L1 levels compared to healthy controls (HCs). Patients with lower PD-L1

Background: A better understanding of prognostic factors and biomarkers that predict response to treatment is required in order to further improve survival rates in patients with melanoma. Predictive Biomarkers: The most important histopathological factors prognostic of worse outcomes in melanoma are sentinel lymph node involvement, increased tumor thickness, ulceration and higher mitotic rate. Poorer survival may also be related to several clinical factors, including male gender, older age, axial location of the melanoma, elevated serum levels of lactate dehydrogenase and S100B. Predictive Biomarkers: Several biomarkers have been investigated as being predictive of response to melanoma therapies. For anti-Programmed Death-1(PD-1)/Programmed Death-Ligand 1 (PD-L1) checkpoint inhibitors, PD-L1 tumor expression was initially proposed to have a predictive role in response to anti-PD-1/PD-L1 treatment. However, patients without PD-L1 expression also have a survival benefit with anti-PD-1/PD-L1 therapy, meaning it cannot be used alone to select patients for treatment, in order to affirm that it could be considered a correlative, but not a predictive marker. A range of other factors have shown an association with treatment outcomes and offer potential as predictive biomarkers for immunotherapy, including immune infiltration, chemokine signatures, and tumor mutational load. However, none of these have been clinically validated as a factor for patient selection. For combined targeted therapy (BRAF and MEK inhibition), lactate dehydrogenase level and tumor burden seem to have a role in patient outcomes. Conclusions: With increasing knowledge, the understanding of melanoma stage-specific prognostic features should further improve. Moreover, ongoing trials should provide increasing evidence on the best use of biomarkers to help select the most appropriate patients for tailored treatment with immunotherapies and targeted therapies.

Several studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients.We conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI.One thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21-92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6-46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events [irAEs] (p 0.0001), G3/G4 irAEs (p 0.0001) and irAEs leading to discontinuation (LTD) (p 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5-14.9 for overweight, and 16.6 (95%CI: 10.3-26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 [95%CI: 6.4-22.3], p 0.0001) and LTD irAEs (OR = 8.8 [95%CI: 4.3-18.2], p 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients.Considering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'.

BackgroundImmune checkpoint inhibitors (ICIs) are approved by the U.S. Food&Drug Administration in over 17 tumor types. Older adult patients make up about a quarter of all cancer patients but are historically understudied in cancer clinical trials. ICIs are associated with immune-related adverse events (irAEs), which may be particularly morbid for older adult patients with underlying comorbidities and impaired functional status. In this study, we provide insight into the real-world safety and efficacy of ICIs among older adult patients (≥80 years) with cancer.MethodsThis is a multicenter, international retrospective study of tumor-agnostic older adult patients with cancer treated with single-agent ICIs between 2010–2019 from 18 academic centers in the U.S. and Europe. A cohort of 928 patients aged ≥80 years during treatment with ICI was assembled and analyzed to evaluate clinical outcomes and irAE patterns in older adult patients treated with single-agent ICIs.ResultsMedian age at ICI initiation was 83.0 years (range 75.8–97.0). Most patients (86.9%) were treated with anti-PD-1 therapy. Among the full cohort, the three most common tumors were non-small cell lung cancer (NSCLC, 37.2%,n=345), melanoma (35.5%,n=329), and genitourinary (GU) tumors (16.5%,n=153). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median progression-free survival (PFS) was 6.7 months (95%CI, 5.2–8.6) for patients with NSCLC, 11.1 months (95%CI, 8.9–16.0) for patients with melanoma, and 6.0 months (95% CI, 5.0–10.7) for patients with GU malignancy. Median overall survival (OS) was 10.9 months (95%CI, 8.6–13.1) for patients with NSCLC, 30.0 months (95%CI, 23.6–46.4) for patients with melanoma, and 15.0 months (95%CI 9.1–25.4) for GU patients (Figure 1A-C). Within histology-specific cohorts (NSCLC, melanoma and GU), clinical outcomes were similar across age subgroups (90). Among all patients (N=928), 41.3% experienced ≥1 irAE(s), including 12.2% reported to be grade (G)3–4. No irAE-related deaths occurred. The median time to irAE onset was 9.8 weeks; 57% occurred within the first 3 months after ICI initiation. ICI was discontinued due to irAEs in 16.1% patients. There was no significant difference in the rate of irAEs among patients age ConclusionsICIs are effective and generally well-tolerated among older patients with cancer. However, ICI discontinuation due to irAE is more frequent with increasing age.

BackgroundNivolumab is an anti-PD-1 antibody approved for treating metastatic melanoma (MM), for which still limited evidence is available on the correlation between drug exposure and patient outcomes.MethodsIn this observational retrospective study, we assessed whether nivolumab concentration is associated with treatment response in 88 patients with MM and if the patient’s genetic profile plays a role in this association.ResultsWe observed a statistically significant correlation between nivolumab serum concentration and clinical outcomes, measured as overall and progression-free survival. Moreover, patients who achieved a clinical or partial response tended to have higher levels of nivolumab than those who reached stable disease or had disease progression. However, the difference was not statistically significant. In particular, patients who reached a clinical response had a significantly higher concentration of nivolumab and presented a distinct genetic signature, with more marked activation of ICOS and other genes involved in effector T-cells mediated proinflammatory pathways.ConclusionsIn conclusion, these preliminary results show that in patients with MM, nivolumab concentration correlates with clinical outcomes and is associated with an increased expression of ICOS and other genes involved in the activation of T effectors cells.

Simple Summary Immune checkpoint inhibitors have improved the prognosis for patients with advanced melanoma. Despite the recent success of immunotherapy, many patients still do not benefit from these treatments, and their real-life application may yield different outcomes compared to the advantage presented in clinical trials. There is therefore a need to select patients who can really benefit from these treatments. We have focused our study on a real-life retrospective analysis of metastatic melanoma patients treated with immunotherapy at a single institution—the Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” of Napoli, Italy. With the help of AI and machine learning we validated an algorithm based on clinical variables of patients—namely, the Clinical Categorization Algorithm (CLICAL)—that defines five predictable cohorts of benefit to immunotherapy with 95% accuracy. It can be a useful tool for the stratification of metastatic melanoma patients who may or may not improve from immunotherapy treatment. Abstract The real-life application of immune checkpoint inhibitors (ICIs) may yield different outcomes compared to the benefit presented in clinical trials. For this reason, there is a need to define the group of patients that may benefit from treatment. We retrospectively investigated 578 metastatic melanoma patients treated with ICIs at the Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” of Napoli, Italy (INT-NA). To compare patients’ clinical variables (i.e., age, lactate dehydrogenase (LDH), neutrophil–lymphocyte ratio (NLR), eosinophil, BRAF status, previous treatment) and their predictive and prognostic power in a comprehensive, non-hierarchical manner, a clinical categorization algorithm (CLICAL) was defined and validated by the application of a machine learning algorithm—survival random forest (SRF-CLICAL). The comprehensive analysis of the clinical parameters by log risk-based algorithms resulted in predictive signatures that could identify groups of patients with great benefit or not, regardless of the ICI received. From a real-life retrospective analysis of metastatic melanoma patients, we generated and validated an algorithm based on machine learning that could assist with the clinical decision of whether or not to apply ICI therapy by defining five signatures of predictability with 95% accuracy.

Background Fatigue was reported as the most common any-grade adverse event (18.3%), and the most common grade 3 or higher immune-related adverse event (irAE) (0.89%) in patients receiving PD-1/PD-L1 checkpoint inhibitors in clinical trial. Methods The aim of this retrospective multicenter study was to evaluate the correlations between “early ir-fatigue”, “delayed ir-fatigue”, and clinical outcomes in cancer patients receiving PD-1/PD-L1 inhibitors in clinical practice. Results 517 patients were evaluated. After the 12-weeks landmark selection, 386 (74.7%) patients were eligible for the clinical outcomes analysis. 40.4% were NSCLC, 42.2% were melanoma, 15.3% renal cell carcinoma and 2.1% other malignancies. 76 patients (19.7%) experienced early ir-fatigue (within 1 month from treatment commencement), while 150 patients (38.9%) experienced delayed ir-fatigue. Early ir-fatigue was significantly related to shortened PFS (HR = 2.29 [95% CI 1.62–3.22], p Conclusions Early ir-fatigue seems to be negative prognostic parameter, but to proper weight its role we must to consider the predominant role of performance status, which was related to early ir-fatigue in the study population.

Introduction: Treatment of extensive-stage SCLC is still a challenge but immunotherapy with checkpoint inhibitors is showing promising results. Nivolumab alone or in combination with ipilimumab has demonstrated a benefit in terms of response and survival in patients with pre-treated extensive-stage disease and has been approved as third-line therapy after failure of chemotherapy. However, data from two phase III trials with nivolumab are negative. In the first trial, nivolumab was administered as a single agent compared to second-line chemotherapy, while in the second it was given alone or in combination with ipilimumab as maintenance treatment after platinum-based chemotherapy.Areas covered: Our review focuses on the role of immunotherapy, and in particular nivolumab, in the treatment of SCLC, describing the results of the main trials and its future perspectives, with reference to clinical trials with other checkpoint inhibitors.Expert opinion: The future of nivolumab in the treatment of SCLC needs to be clarified with further clinical trials, in which improved patient selection and a more specific setting and/or timepoint of the disease may be identified.

Increased understanding of the interactive mechanisms between tumors and the immune system led to the development of immune checkpoint inhibitors, which have revolutioned the treatment of metastatic melanoma and subsequently many other tumors. In 2014, nivolumab and pembrolizumab, two checkpoint inhibitors binding to PD-1, were approved for the treatment of metastatic melanoma. Since then, a plethora of new molecules have enriched the armamentarium against melanoma.This review summarizes the last updates about treatment with nivolumab and pembrolizumab, data on other PD-1/PDL-1 agents such as spartalizumab and atezolizumab and emerging compounds, new combinations with NKTR-214, anti LAG-3, anti IDO-1 and TVEC, new checkpoint inhibitors (e.g. TIM-3 or TIGIT) and other new molecules for the treatment of metastatic melanoma.Currently, several ongoing clinical trials are investigating novel molecules, or immunotherapy combinations, in order to achieve even better survival outcomes for patients, overcoming resistance mechanisms and improving toxicity profiles. The challenge in the near future will be to select the most appropriate treatments according to the specific characteristics of the patients.

Simple Summary Several studies have explored the role of the inflammatory cells and cytokines involved in the protection or pathogenesis of coronavirus disease 2019. Unfortunately, the results have been controversial, and further studies are needed to better understand not only the roles but also the balance of these parameters, which are crucial data to improve prevention and treatment. As COVID-19 has a well-determined phasic progression and rapidly deteriorates approximately seven days after the onset of symptoms, it is extremely necessary to detect the clinical signs that are predictive of the outcome as early as possible. To this end, in this preliminary study, we evaluated the data relating to the monocyte intracellular TNF-α expression and lymphocyte subpopulations in peripheral blood collected from patients at admission and every day of hospitalization until day 7. Our findings point to a modulation of the different cellular mediators of the immune system, which probably play a key role in the outcome of the coronavirus disease 2019. Abstract In December 2019, a novel coronavirus, “SARS-CoV-2”, was recognized as the cause of coronavirus disease 2019 (COVID-19). Several studies have explored the changes and the role of inflammatory cells and cytokines in the immunopathogenesis of the disease, but until today, the results have been controversial. Based on these premises, we conducted a retrospective assessment of monocyte intracellular TNF-α expression (iTNF-α) and on the frequencies of lymphocyte sub-populations in twenty-five patients with moderate/severe COVID-19. We found lymphopenia in all COVID-19 infected subjects compared to healthy subjects. On initial observation, in patients with favorable outcomes, we detected a high absolute eosinophil count and a high CD4+/CD8+ T lymphocytes ratio, while in the Exitus Group, we observed high neutrophil and CD8+ T lymphocyte counts. During infection, in patients with favorable outcomes, we observed a rise in the lymphocyte count, in the monocyte and in Treg lymphocyte counts, and in the CD4+ and in CD8+ T lymphocytes count but a reduction in the CD4+/CD8+ T lymphocyte ratio. Instead, in the Exitus Group, we observed a reduction in the Treg lymphocyte counts and a decrease in iTNF-α expression. Our preliminary findings point to a modulation of the different cellular mediators of the immune system, which probably play a key role in the outcomes of COVID-19.

Background Immunotherapy dramatically changed the landscape of melanoma treatment. Even if nearly 40% of patients has a long-term benefit from anti-PD-1 agents, nearly 30% relapse in the first year of treatment, showing in some cases very rapid disease progression. Actually, there are no effective biomarkers that could predict patient‘s clinical benefit. Aim of this study is to identify gene profiling biomarkers that could help to select melanoma patients who most likely respond to anti-PD-1 therapy. Methods We defined as fast responder (FR) or fast progressor (FP) patients who got clinical response or clinical progression within eight weeks from first cycle of therapy. We retrospectively collected data from 51 metastatic melanoma patients (25 FR and 26 FP) treated from October 2016 to June 2020 in first-line with anti-PD1 monotherapy (nivolumab or pembrolizumab) at National Cancer Institute of Naples, Italy. Gene expression profiling analysis was performed using NanoString® IO 360 panels on PBMCs collected at baseline from 18 patients (10 FR and 8 FP). Patients with ECOG≥2 were excluded. They were all IV stage (5 M1a, 1 M1b, 12 M1c) of which 15 were B-RAF wild-type (83%) and 3 were B-RAF mutated (17%). Statistical associations between treatment response and gene score variables were estimated through Bonferroni correction for multiple comparisons and Benjamini-Hochberg. Results Patterns of gene expression were assessed for correlation to response. We compared PBMCs Nanostring analysis between FR and FP patients. We found a higher expression of KRas, CD39, IFI16, IL18, FCGR2A, IL1RN, MAP3K8, TLR5, TLR8, MyD88 and NF-kB in FP patients (all with p-value ≤0.005), most of them related to cell proliferation and immunosuppressive mechanism. Instead we found a higher expression of PRF1, PIK3R1, HLA-DPA1, HLA-DRB1, HLA-DOA, CD45RA, LDHB, KIR3DL2, CD2, CD28, CD7, CD27 in FR patients (all with p-value ≤0.01), most of them related to priming and cytolysis. Conclusions Our study suggests that a specific gene signature may discriminate FR or FP patients. These preliminary data provide a rationale for further investigating gene profiling signature as a potential biomarker of response to immunotherapy. Acknowledgements The study was supported by the Institutional Project ‘Ricerca Corrente’ of Istituto Nazionale Tumori IRCCS Fondazione ‘G. Pascale’ of Napoli, Italy. Ethics Approval The study was approved by the internal ethics board of the Istituto Nazionale Tumori IRCCS Fondazione ‘G. Pascale’ of Napoli Italy, approval number of registry 17/17 OSS.

Background Immune checkpoint inhibitors (ICI) have greatly improved the treatment options for patients with metastatic melanoma. Yet, a large percentage of melanoma patients do not respond to ICIs, there is a need for biomarkers that can predict patients‘ clinical benefit thereby identifying the patient population most likely to respond. Here, we apply unbiased discovery proteomics to deeply characterize global tumor proteomes and associate proteins and pathways at baseline with clinical response to anti-PD-1 immunotherapy. Methods Unbiased, data-independent acquisition (DIA) mass spectrometry was used to analyze Formalin Fixed Paraffin Embedded (FFPE) tumor tissue from subjects with stage IIIc-IV melanoma which were resected prior to initiation of first-line anti-PD-1 therapy. The selected samples represent two distinct clinical subgroups; those who received clinical benefit (CR or PR by RECIST criteria or OS >1 year with SD by RECIST criteria, n = 13), and those with no clinical benefit (PD by RECIST criteria or OS Results 8’548 proteins were quantified across all samples, with 7’416 quantified on average per sample. Univariate statistical testing between groups identified 285 proteins that were significantly regulated in subjects who received clinical benefit. Through partial least squares discriminant analysis (PLS-DA) a set of 25 proteins was identified that describe the variance between the two sample groups. Ganglioside GM2 activator (GM2A) and other members of its interaction network such as HEXB, HRNR and CPPED1 were identified to be upregulated in the non-responder group. Conclusions Global profiling of the baseline tumor proteome provides a unique characterization of melanoma tumor biology. A signature of 25 protein markers was identified as a driver of separation between responder and non-responder patients to PD-1 blockade. Among the protein markers, GM2A and its interactors, were previously shown to perturb T cell function, which might explain their enrichment in the non-responder group and provide an attractive target for improving patient response to immunotherapy.

Background: Cutaneous malignant melanoma (CMM) is one of the most aggressive types of skin cancer. Currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice for the treatment of metastatic CMM. Data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility. The aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CMM in several Italian centers which are part of the Clinical National Melanoma Registry (CNMR), and the oncological outcomes obtained. Methods: CNMR collects data of patients with a histologically confirmed diagnosis of primary CMM treated in one of the 38 Italian institutions (hospitals, research institutes, etc.) participating in the network. Melanoma-specific survival and Overall survival were calculated. Kaplan-Meier curves and medians of OS and 95% CI are presented overall and by immunotherapy and target treatments. The Log-rank test compared curves by treatments. Multivariate Cox regression models were used to estimate the hazard ratios adjusting for confounders and other prognostic factors. Results: The median follow-up time was 36 months (range 1.2-185.1). 787 CMM were included in the analysis with completed information about therapies.Global immunotherapy showed a significant improved survival compared with all other therapies (p=0.001). 75% was the highest reduction of death reached by nivolumab/pembrolizumab immunotherapy (anti-PD1 HR=0.25 95% CI 0.14-0.42), globally immunotherapy was significantly associated with improved survival, either for anti-CTL A4 monotherapy or combined with anti-PD1 (HR=0.47;95% CI 0.33-0.66 and HR=0.26; 95% CI 0.15-0.46, respectively). Conclusions: The nivolumab/pembrolizumab and the combination of ipilimumab can be considered the best therapy to improve survival in a real-world-population. The CNMR can complement clinical registries with the intent of improving cancer management and standardizing cancer treatment.

IMPORTANCE: Geriatric (aged ≥80 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population. OBJECTIVE: To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged ≥80 years) with cancer. DESIGN, SETTING, AND PARTICIPANTS: A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021. MAIN OUTCOMES AND MEASURES: Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs. RESULTS: Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti–programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non–small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged

BackgroundMerkel cell carcinoma (MCC) is a rare and aggressive skin cancer with neuroendocrine features, and it is associated with elevated mortality. The pathogenesis is associated with presence of clonally integrated Merkel cell polyomavirus (MCPyV) or ultraviolet light (UV) exposure.1 The MCPyV causes up to 80% of MCC tumors in North America and Europe.2–4 Recently immunotherapy is having good results,5 the phase 2 trial JAVELIN Merkel 200 indicated that treatment with Avelumab (PDL1 inhibitor) in patients with metastatic MCC pre-treated have a meaningful long-term survival outcomes respect chemotherapy. Moreover, ORRs were highest in patients with high TMB that were also MCPyV−, PD-L1+ or had a greater CD8+ T cell density at the invasive margin.6 In this study, we investigated the biological signatures in patients with MCPyV or not.MethodsFrom April 2011 to June 2018, we collected retrospectively 50 FFPE (Formalin-Fixed Paraffin-Embed) from 37 patients with metastatic MCC and 13 tissues from a secondary metastatic site. All patients have appropriately signed informed consent. We performed an immunohistochemistry assays (IHC) for MCPyV and PDL1. In addition, through the NanoString GeoMx DSP (Digital Spatial Profiling), we analysed 11 patients (6 MCPyV+; 5 MCPyV-) with cutaneous metastasis using a 44-plex antibody cocktail. For each slide we selected three different areas: Intratumoral, extratumoral and tumour border, in each area we selected CD4+ and CD8+ cells in 4 different ROIs (Region of Interest). Statistical analysis was performed via Bonferroni correction, P< 0.05 was considered statistically significant for median stratification.ResultsThe DSP analysis showed that the tumour border cells have an overexpression of IDO respect intratumoral area (adj. pConclusionsIn this retrospective study, our preliminary data shown that tumour edge have an important role in the modulations of immune infiltrate and patients with Merkel cell polyomavirus could have a different pathway of immunosuppression compared to patients with non-virus related etiology. Further investigations are needed to get additional information.AcknowledgementsThe study was supported by the Institutional Project ”Ricerca Corrente” of Istituto Nazionale Tumori IRCCS Fondazione ”G. Pascale” of Napoli, Italy.ReferencesKaae J, Hansen AV, Biggar RJ, et al. Merkel cell carcinoma: incidence, mortality, and risk of other cancers. J Natl Cancer Inst 2010 June 2;102(11):793–801.Feng H, Shuda M, Chang Y, et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008 February 22;319(5866):1096–100.Garneski KM, Warcola AH, Feng Q, et al. Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors. J Invest Dermatol 2009 January;129(1):246–8.Goh G, Walradt T, Markarov V, et al. Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget 2016 January 19;7(3):3403–15.Bichakjian CK, Olencki T, Aasi SZ, et al. Merkel cell carcinoma, version 1.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2018 June;16(6):742–774.D’Angelo SP, Bhatia S, Brohl AS, et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial. J Immunother Cancer 2020 May;8(1):e000674.Ethics ApprovalThe study was approved by internal ethics board of the Istituto Nazionale Tumori IRCCS Fondazione ”G. Pascale” of Napoli Italy, approval number of registry 33/17 OSS.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines. MEK inhibitor therapy in combination with a BRAF inhibitor is more effective and less toxic than treatment with a BRAF inhibitor alone, and has become the standard of care for patients with BRAF-mutated melanoma. Trametinib was the first MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors, and is also approved in combination with the BRAF inhibitor dabrafenib. Furthermore, cobimetinib is another MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma in combination with a BRAF inhibitor, vemurafenib. The MEK inhibitor binimetinib in combination with the BRAF inhibitor encorafenib is in clinical development. The addition of an anti-PD-1/PD-L1 agent, such as pembrolizumab, durvalumab or atezolizumab, to combined BRAF and MEK inhibition has shown considerable promise, with several trials ongoing in metastatic melanoma. Binimetinib has also shown efficacy in NRAS-mutated melanoma patients. Future possibilities for MEK inhibitors in advanced melanoma, as well as other solid tumors, include their use in combination with other targeted therapies (e.g. anti-CDK4/6 inhibitors) and/or various immune-modulating antibodies.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region.MethodsThis survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2–positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher’s exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options.ResultsThis is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2–positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients’ planned treatment approach). The results from responders in Campania did not differ significantly from the national ones.ConclusionOur study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.

The treatment of advanced melanoma has changed dramatically in recent years with several new drugs having been approved for the treatment of melanoma since 2011. This review aims to evaluate the role of BRAF-targeted therapy for advanced melanoma in the immunotherapy era. Currently, in patients with BRAF wild-type advanced melanoma, anti-PD-1 (nivolumab or pembrolizumab) is the main treatment. The combination of nivolumab and ipilimumab (anti-CTLA-4) is also an important option for these patients, resulting in a better outcome, but with less favorable toxicity profile. In patients with BRAF mutations, three regimens of BRAF plus MEK inhibitors are now approved (vemurafenib plus cobimetinib, dabrafenib plus trametinib, and encorafenib plus binimetinib), which achieve rapid antitumor responses and a significant survival benefit. In these patients, as well as in BRAF wild-type patients, immunotherapy can be also effective and is regularly used. Immunotherapy and targeted therapy have become the new standards of care, substantially improving survival rates. However, many questions still remain unanswered, such as what is the best first- and second-line treatment and the best treatment sequence. New combinations of drugs, targeted therapy combined with immunotherapy, and sequencing approaches are now underway in many ongoing clinical trials.

Skin toxicity after anti-PD1 treatment in melanoma patients is the most common type of immune related adverse effect (irAE) and has been associated with improved overall response rate and survival. Nonetheless, not many mechanistic biomarkers have been identified so far, that could be associated with low-grade skin toxicity and good response rates. In this study we have addressed this question by analyzing tumor tissue samples from late-stage melanoma patients with first-line anti-PD1 treatment. Samples obtained prior to treatment were submitted for an unbiased deep proteomic analysis using mass spectrometry (LC-MS) and a targeted transcriptomic analysis. Using the unbiased analysis as a discovery platform we were able to define a potential biomarker panel associated not only with improved response but also low-grade skin toxicity. Unbiased quantification of proteins in tumor tissues was done using data-independent acquisition (DIA) LC-MS technology. Proteins from tissue samples were denatured, digested, and analyzed on a mass spectrometer. A deep spectral library was generated, and proteins were quantified using Spectronaut software (Biognosys). In addition, from the same tumor tissue RNA was extracted and subjected to transcriptomic analysis with NanoString nCounter using the PanCancer IO 360 panel. Subsequent data analysis was done using a sPLS-DA using combined factor of skin toxicity and response. Unbiased analysis of 22 baseline tumor tissue samples from late-stage melanoma patients treated in first line with anti-PD1 resulted in identification and quantification of more than 8000 proteins. Progression free survival analysis showed difference between patients with reported low-grade skin toxicity against all others. Therefore, for sPLS-DA both factors, presence/absence of skin toxicity and response status, were used (non-responders with low-grade skin toxicity were not present in this cohort). Complete separation of subjects was achieved with a panel of 21 proteins. This panel was used for hierarchical clustering and was able to fully restore all three groups of patients. Among all proteins identified in the proteomic panel, melanoma-associated antigen C1 (MAGEC1) has been also assessed in the targeted transcriptomic analysis and represents strikingly similar results. MAGEC1 is also found as a strong predictor in the Human Protein Atlas project. Interestingly, MAGE protein family are tumor-specific antigens that can be recognized by autologous cytolytic T lymphocytes and could serve as a novel ICI target or predictive biomarker. In this study we confirm prior observations of a survival benefit related to irAEs after treatment with PD-1 blockade in late-stage melanoma patients. We also demonstrate the power of deep proteomic profiling and transcriptomic analysis in molecular biomarker selection associated to response and irAEs which further benefit patient survival. Citation Format: Jakob Vowinckel, Domenico Mallardo, Kamil Sklodowski, Martin Soste, Mariaelena Capone, Gabriele Madonna, Vito Vanella, Sarah Warren, Kristina Beeler, Paolo A. Ascierto. Response and skin toxicity related protein signature in late stage melanoma patients after anti-PD-1 treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1623.

e21543 Background: Despite advances of anti-PD1 treatment in melanoma, still large subset of patients does not respond or relapses due to primary or acquired resistance. One potential way to overcome the mechanisms of resistance is to identify molecular signatures associated with response to treatment. Here, we are presenting the results of an integrated deep transcriptomic and proteomic analysis of melanoma tissue samples coming from patients prior the treatment with anti-PD1. The combination of targeted transcriptomic approach with unbiased proteomic approach allowed for identification of a molecular response signature specific to anti-PD1 therapy. Methods: Unbiased quantification of proteins in tumor tissues was done using data-independent acquisition (DIA) LC-MS technology. Proteins from tissue samples were denatured, digested, and analyzed on a mass spectrometer. A deep spectral library was generated, and proteins were quantified using Spectronaut software (Biognosys). From the same tumor tissue RNA was extracted and subjected to transcriptomic analysis with NanoString nCounter using the PanCancer IO 360 panel. Integration analysis using latent components, a generalized PLS and sparse sGCCA method implemented in R mixOmics package was used for signature discovery. Results: Studied cohort was balanced for gender, BRAF mutations and stage. Treatment included Nivolumab or Pembrolizumab. Only among responding subjects, low grade (≤ 2) skin toxicity was identified at a significant level (p-value < 0.05). In total, 22 samples were measured (nine non-responders and 13 responders). Overall, the analysis of proteome across all samples resulted in 8548 proteins being identified and quantified. The IO 360 panel contained 770 targets. In combined analysis, 10 mRNA targets together with 64 protein targets were highly associated with response to treatment. Two top candidates identified for mRNA and proteins were SIGLEC5 and ACP6 respectively. The panel of 74 features was sufficient to separate all subjects using unsupervised hierarchical clustering into to two main clusters enriched for responders and non-responders (p-value < 0.05). String-DB analysis revealed numerous interactions and associations within identified panel. Functional analysis using GO enrichment showed major involvement of the selected mRNA and proteins in T-cell regulation as well as in neutrophil degranulation and antigen receptor mediated signaling. Conclusions: Combination of both omics assays provides a very comprehensive image of tumor tissue responses to anti-PD1 treatment in late-stage melanoma patients. Identified candidates show striking changes in responder and non-responder groups and should undergo further validation for use in precision medicine.

The median overall survival (OS) and local control (LC) of patients with melanoma brain metastases (MBMs) are poor even with immune checkpoint inhibitors and/or radiotherapy (RT). The aims of the study were to evaluate the association and timing of stereotactic radiotherapy (SRT)/radiosurgery (SRS) performed with the CyberKnife® System and ipilimumab (IPI). A total of 63 MBMs patients were analyzed: 53 received RT+IPI and 10 RT alone. Therefore, the patients were divided into four groups: RT PRE-PI (&gt, 4 weeks before IPI) (18), RT CONC-IPI (4 weeks before/between first and last cycle/within 3 months of last cycle of IPI) (20), RT POST-IPI (&gt, 3 months after IPI) (15), and NO-IPI (10). A total of 127 lesions were treated: 75 with SRS (one fraction) and 24 with SRT (three to five fractions). The median follow-up was 10.6 months. The median OS was 10.6 months for all patients, 10.7 months for RT+IPI, and 3.3 months for NO-IPI (p = 0.96). One-year LC was 50% for all patients, 56% for RT+IPI, and 18% for NO-IPI (p = 0.08). The 1-year intracranial control was 45% for all patients, 44% for RT+IPI, and 51% for NO-IPI (p = 0.73). IPI with SRS/SRT in MBMs treatment could improve LC. However, the impact and timing of the two modalities on patients’ outcomes are still unclear.

Background: It is unknown whether melanoma patients achieving complete response (CR) with targeted therapy can safely discontinue treatment. Methods: All patients treated with BRAF/MEK inhibitors achieving CR and ceasing treatment before progression were identified. Clinical data at treatment initiation, cessation and progression were examined. Results: A total of 12 eligible patients were identified, with median follow-up of 16 months, of whom 6 (50%) recurred at a median of 6.6 months after treatment cessation. One patient lost to follow-up until presentation with symptomatic recurrence was the only relapser to die. At relapse, the remaining five patients had an LDH