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BACKGROUND Antibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized. METHODS Fifty-eight patients with stage IV uveal melanoma received PD-1 or PD-1 ligand (PD-L1) antibodies between 2009 and 2015 at 9 academic centers. Patients who were evaluable for response were eligible for the analysis. Imaging was performed every 12 weeks and at the investigators' discretion. Safety and clinical efficacy outcomes, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively determined. RESULTS Of 56 eligible patients, 48 (86%) had received prior therapy, and 35 (63%) had received treatment with ipilimumab. Three patients had an objective response to ipilimumab, and 8 had stable disease as their best response. Thirty-eight patients (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in 2 patients for an overall response rate of 3.6% (95% confidence interval [CI], 1.8%-22.5%). Stable disease (≥6 months) was observed in 5 patients (9%). The median PFS was 2.6 months (95% CI, 2.4-2.8 months), and the median OS was 7.6 months (95% CI, 0.7-14.6 months). There was no association between prior treatment with ipilimumab or liver-directed therapy and PFS or OS. Treatment was well tolerated, and only 1 patient discontinued treatment because of toxicity. CONCLUSIONS PD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population. Cancer 2016;122:3344–3353. © 2016 American Cancer Society.

The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

Introduction: Immunotherapy using checkpoint inhibitors is providing significant benefit to patients with renal cell carcinoma (RCC), both in overall survival and tolerability of treatment. Given the recent approval of the first checkpoint inhibitor in RCC, this review discusses the background and clinical data for checkpoint inhibition in RCC.Areas covered: This review introduces and discusses the basic biologic mechanisms of checkpoint inhibitor function and focuses on the current evidence in clinical trials for the use of immunotherapy in RCC.Expert commentary: Immunotherapy has been a mainstay of therapy in RCC, but the recent approval of nivolumab with ORR of 25% and durable responses has provided a transformative new therapeutic option.

Treatments that successfully modulate anti-cancer immunity have significantly improved outcomes for advanced stage malignancies and sparked intense study of the cellular mechanisms governing therapy response and resistance. These responses are governed by an evolving milieu of cancer and immune cell subpopulations that can be a rich source of biomarkers and biological insight, but it is only recently that research tools have developed to comprehensively characterize this level of cellular complexity. Mass cytometry is particularly well suited to tracking cells in complex tissues because >35 measurements can be made on each of hundreds of thousands of cells per sample, allowing all cells detected in a sample to be characterized for cell type, signalling activity, and functional outcome. This review focuses on mass cytometry as an example of systems level characterization of cancer and immune cells in human tissues, including blood, bone marrow, lymph nodes, and primary tumours. This review also discusses the state of the art in single cell tumour immunology, including tissue collection, technical and biological quality controls, computational analysis, and integration of different experimental and clinical data types. Ex vivo analysis of human tumour cells complements both in vivo monitoring, which generally measures far fewer features or lacks single cell resolution, and laboratory models, which incur cell type losses, signalling alterations, and genomic changes during establishment. Mass cytometry is on the leading edge of a new generation of cytomic tools that work with small tissue samples, such as a fine needle aspirates or blood draws, to monitor changes in rare or unexpected cell subsets during cancer therapy. This approach holds great promise for dissecting cellular microenvironments, monitoring how treatments affect tissues, revealing cellular biomarkers and effector mechanisms, and creating new treatments that productively engage the immune system to fight cancer and other diseases.

Introduction: Melanoma is the 6th most common cancer in the United States and advanced disease has traditionally been associated with a poor prognosis. Historical therapies had suboptimal activity, including cytotoxic agents and cytokine therapies. However, since 2011, novel targeted therapies and immune checkpoint inhibitors have greatly improved outcomes in this challenging disease.Areas covered: This article reviews the evolving landscape of advanced melanoma therapeutics, focusing on recent immune therapy advances. We will review clinical data from the last 1-2 years with anti-CTLA-4, anti-PD-1/PDL-1, oncolytic viruses and novel combination approaches. We will discuss landmark clinical trials that led to the integration of these agents into clinical management paradigms. We will also briefly cover the search to identify accurate biomarkers of response to these therapies. Finally, we discuss future directions of clinical research with combination immune therapy strategies.Expert opinion: Immune...

Immune-checkpoint blockade therapy with antibodies targeting CTLA-4 and PD-1 has revolutionized melanoma treatment by eliciting responses that can be remarkably durable and is now advancing to other malignancies. However, not all patients respond to immune-checkpoint inhibitors. Extensive preclinical evidence suggests that combining immune-checkpoint inhibitors with other anti-cancer treatments can greatly improve the therapeutic benefit. The first clinical success of the combinatorial approach to cancer immunotherapy was demonstrated using a dual-checkpoint blockade with CTLA-4 and PD-1 inhibitors, which resulted in accelerated FDA approval of this therapeutic regimen. In this review, we discuss the combinations of current and emerging immunotherapeutic agents in clinical and preclinical development and summarize the insights into potential mechanisms of synergistic anti-tumor activity gained from animal studies. These promising combinatorial partners for the immune-checkpoint blockade include therapeutics targeting additional inhibitory receptors of T cells, such as TIM-3, LAG-3, TIGIT, and BTLA, and agonists of T cell costimulatory receptors 4-1BB, OX40, and GITR, as well as agents that promote cancer cell recognition by the immune system, such as tumor vaccines, IDO inhibitors, and agonists of the CD40 receptor of APCs. We also review the therapeutic potential of regimens combining the immune-checkpoint blockade with therapeutic interventions that have been shown to enhance immunogenicity of cancer cells, including oncolytic viruses, RT, epigenetic therapy, and senescence-inducing therapy.

Antibodies aimed at blocking the interaction between programmed cell death-1 (PD-1) and its ligands have shown impressive efficacy in a variety of malignancies and are generally well tolerated. Research has focused intensely on T cells and their interaction with cells within melanoma tumors, while relatively little is understood about the systems immunology of the cells in the blood during checkpoint inhibitor therapy. Longitudinal cytomic analysis using mass cytometry can characterize all the cells in a small sample of blood and has the potential to reveal key shifts in the cellular milieu occurring during treatment. We report a case of advanced melanoma in which mass cytometry detected abnormal myeloid cells resulting from myelodysplastic syndrome (MDS) in the blood following treatment with an anti–PD-1 agent. Myeloid blasts comprised

Introduction: Melanoma is the most aggressive of the cutaneous malignancies. Treatment options for advanced melanoma have greatly expanded through the development of immune checkpoint inhibitors and small molecule targeting agents. The most recently approved therapy, talimogene laherparepvec (Imlygic™, OncoVEXGM-CSF, T-VEC), is a genetically modified herpes simplex virus type 1 that has demonstrated clinical activity in advanced melanoma. This first in class oncolytic virus immunotherapy represents a step forward for the promising class of oncolytic virus therapies.Areas covered: The article reviews melanoma treatment with a focus on the novel oncolytic virus therapy and the preclinical and clinical evidence for treatment of advanced melanoma with T-VEC. The focus for clinical evidence will be on a phase III study of T-VEC in patients with stage IIIB, IIIC or IV melanoma, as well as the phase I and II studies. We also explore the future use of T-VEC in combination with other immunotherapy agents. ...

Background Precision oncology increasingly utilizes molecular profiling of tumors to determine treatment decisions with targeted therapeutics. The molecular profiling data is valuable in the treatment of individual patients as well as for multiple secondary uses. Objective To automatically parse, categorize, and aggregate clinical molecular profile data generated during cancer care as well as use this data to address multiple secondary use cases. Methods A system to parse, categorize and aggregate molecular profile data was created. A naÿve Bayesian classifier categorized results according to clinical groups. The accuracy of these systems were validated against a published expertly-curated subset of molecular profiling data. Results Following one year of operation, 819 samples have been accurately parsed and categorized to generate a data repository of 10,620 genetic variants. The database has been used for operational, clinical trial, and discovery science research. Conclusions A real-time database of molecular profiling data is a pragmatic solution to several knowledge management problems in the practice and science of precision oncology.

Treatment options for melanoma patients, both young and old, were extremely limited until recently. Elderly patients faced a particular challenge due to less aggressive surgical management, poor tolerance of available therapies, aggressive biologic behaviors, and rapid tumor progression. Over the past several years, however, a number of remarkably active immune and targeted agents have been developed. These agents are generally well tolerated and present numerous effective therapeutic options for elderly patients with advanced melanoma. In this manuscript, we discuss the distinct clinical and genetic aspects of melanoma in elderly patients. Furthermore, we review treatment options for older patients with local and regional melanoma and disseminated disease.

Anti-PD-1 therapy yields objective clinical responses in 30–40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of ‘PD-1 signalling', ‘allograft rejection' and ‘T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4+ and CD8+ tumour infiltrate. MHC-II+ tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection., Immunotherapy is used to treat melanoma, however patient responses vary widely highlighting the need for factors that can predict therapeutic success. Here, the authors show that MHC-II molecules expressed by tumour cells are positively correlated with a good response to therapy and overall patient survival.

Introduction: Immune checkpoint inhibitors (ICI) drive anti-tumor activity however, they also produce immune related adverse effects (irAEs) that mimic autoimmune disease. Different auto-immune diseases are seen across age groups such as inflammatory bowel disease in younger patients and rheumatoid arthritis in older patients. Thus, we assessed whether the types, patterns, and severity of irAEs differed by age. Methods: We reviewed electronic medical records of patients treated with ICI for melanoma. We assessed patient demographics, presence, type and severity of toxicity along with hospitalization and associated length of stay from management of irAEs. Logistic regression was used to assess risk of 1) irAEs, 2) severe irAEs, and 3) hospitalization from irAEs; Poisson regression was used to analyze length of stay (LOS) data. We extracted all cases of myocarditis, colitis, and pneumonitis from ICI from Vigibase through December 2018. Results: 455 patients from one center received anti-PD-1 for melanoma; 226 developed any irAE (49.7%), 59 developed a severe irAE (13.0%) and 54 patients required hospitalization (11.9%). Younger age was not associated with overall rate of irAEs but correlated with increased severe toxicity rate when controlling for gender, baseline performance status, season, and combination ICI (OR 0.97, 95% CI 0.95-0.99), as well as need for hospitalization (OR 0.97, 95% CI 0.95-0.99). Despite the increased severe toxicity and hospitalization for younger patients, older patients, when hospitalized, had increased LOS, (p&lt0.0001). Three patients experienced a fatal irAE (average age 68.0) compared to 63.0 for the rest of the cohort. This relationship was validated in Vigibase where patients with fatal myocarditis where older than those with non-fatal myocarditis (70.9 vs. 60.7 years, p=0.03) although there was no age difference between fatal vs. non-fatal pneumonitis cases. Toxicity types by age were also examined. Colitis and hepatitis were more common in younger patients (16% and 11% for age &lt45, vs. 7% and 2% for age &gt75) and tended to require frequent hospitalizations. In contrast, dermatitis and arthritis were more common in older patients (20% and 6% for age &gt75 compared to 12% and 1% in age Conclusion: A novel and somewhat paradoxical relationship between age and irAEs was seen where younger patients tended to have more severe irAEs, while older patients tender to have longer hospitalizations for irAE management and increased fatality from irAEs. This may be explained by the distinct phenotypes of irAEs that occur with specific age groups. Citation Format: Kaustav P. Shah, Haocan Song, Fei Ye, Joe-Elie Salem, Justin Balko, Douglas B. Johnson. Impact of age on toxicity in patients treated with anti-PD-1 therapy for melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4238.

Purpose:Antibodies blocking programmed death-1 receptor (anti-PD-1) produce durable responses in patients with metastatic melanoma, although >50% of patients ultimately experience disease progression. We aimed to identify prognostic factors and outcomes to subsequent therapies in patients with metastatic melanoma that progressed on anti-PD-1. Materials and methods:We evaluated 383 patients who received anti-PD-1 (alone or in combination with ipilimumab [ipi]) for advanced melanoma between 2009 and 2019. Patient and disease characteristics at baseline and progression, factors correlating with survival after progression (SaP), subsequent therapies, objective response rate (ORR), overall survival (OS), and progression free survival (PFS) were assessed. Results:Of 383 patients, 247 experienced progression. At progression, most patients were stage IV M1c (49.0%), symptomatic from their disease (66.8%), and had progression at both new and existing lesions (39.3%). The median SaP was 206 days. There was no difference in SaP based on primary tumor subtype (cutaneous vs. non-cutaneous), receipt of prior therapy, prior ipi, or therapy type (anti-PD-1 vs. combination). However, significantly improved SaP correlated with clinical features at progression, including normal LDH (p2-5cm, >5-8cm, and >8cm respectively; p Conclusions:We identified multiple clinical factors that correlated with SaP in patients with melanoma progressing on anti-PD-1. Further, we identified improved outcomes for subsequent BRAFi/MEKi or ipi + nivolumab vs. ipi alone. Finally, we identified a subgroup of patients with long-term SaP, potentially explaining the gap between PFS and OS demonstrated in many anti-PD-1 trials. Citation Format: James R. Patrinely, Laura X. Wang, Elizabeth J. Davis, Douglas B. Johnson. Outcomes after progression of disease with anti-PD-1/PDL1 therapy for advanced melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3154.

International audience; Background: In addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI.Patients methods: We performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC025 (lower end of the IC 95% credibility interval) >0 is deemed significant.Results: We identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 [11.6-18.4], IC025 = 3.34), sarcoidosis (n = 94; ROR = 9.6 [7.9-11.9]; IC025 = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 [5.2-9.2]; IC025 = 2.24), myositis (n = 465; ROR = 4.9 [4.5-5.4]; IC025 = 2.12), arthritis (n = 606; ROR = 1.4 [1.3-1.5]; IC025 = 0.34) and scleroderma (n = 17; ROR = 2.0 [1.2-3.2]; IC025 = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6-2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1-4.4, p < .05). Median time to onset occurred early for myositis (31 days [19.2-57.8]) and was the most delayed for scleroderma (395 days [323.8-457.2], p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to [0-6.7%] for other RMS-irAE (p < .0001).Conclusions: Clinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.

Immune-related (IR)-pneumonitis is a rare and potentially fatal toxicity of anti-PD(L)1 immunotherapy. Expert guidelines for the diagnosis and management of IR-pneumonitis include multidisciplinary input from medical oncology, pulmonary medicine, infectious disease, and radiology specialists. Severe acute respiratory syndrome coronavirus 2 is a recently recognized respiratory virus that is responsible for causing the COVID-19 global pandemic. Symptoms and imaging findings from IR-pneumonitis and COVID-19 pneumonia can be similar, and early COVID-19 viral testing may yield false negative results, complicating the diagnosis and management of both entities. Herein, we present a set of multidisciplinary consensus recommendations for the diagnosis and management of IR-pneumonitis in the setting of COVID-19 including: (1) isolation procedures, (2) recommended imaging and interpretation, (3) adaptations to invasive testing, (4) adaptations to the management of IR-pneumonitis, (5) immunosuppression for steroid-refractory IR-pneumonitis, and (6) management of suspected concurrent IR-pneumonitis and COVID-19 infection. There is an emerging need for the adaptation of expert guidelines for IR-pneumonitis in the setting of the global COVID-19 pandemic. We propose a multidisciplinary consensus on this topic, in this position paper.

10020 Background: Programmed cell death receptor-1 (PD-1) monotherapy is the standard first line therapy for advanced cutaneous melanoma, with efficacy, toxicity, and their correlations well established. Yet these remain poorly characterized for non-Caucasians and for certain rarer melanoma subtypes. Methods: Clinical data from melanoma patients treated with anti-PD-1 monotherapy between 2009 and 2018 was collected retrospectively from three independent institutions from the US and China. Tumor response, survival outcome, and organ/system-specific immune-related adverse effects (irAEs) were directly compared between different subgroups. Results: Among 626 patients, 411 were Caucasian, 214 non-Caucasian; 369 had cutaneous melanoma, and 257 other subtypes. Both ethnicity and melanoma subtype were independently associated with benefit and irAEs. In multivariate analyses, Caucasians had significantly higher objective response rate (ORR) (OR 2.0, 95% CI 1.1-3.5), but this did not translate into a survival advantage (PFS, HR 0.8, 95% CI 0.6-1.1; OS, HR 1.0, 95% CI 0.7-1.4); melanoma of unknown primary shared similar response and survival profile with cutaneous, while acral (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.6, 95% CI 1.1-2.2; OS, HR 1.3, 95% CI 0.8-1.9), mucosal (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.4, 95% CI 1.0-2.0; OS, HR 1.7, 95% CI 1.1-2.6) and ocular (ORR, OR 0.1, 95% CI 0-0.6; PFS, HR 2.3, 95% CI 1.4-3.6; OS, HR 2.2, 95% CI 1.3-3.6) melanomas had inferior outcomes. Non-Caucasian cutaneous patients had a significantly worse ORR than Caucasians with cutaneous melanoma (P < .01). Distinct irAE patterns were observed, exemplified by lower incidence of most irAEs (although more frequent pneumonitis) in Caucasians, and higher and lower liver irAE incidence in ocular and mucosal melanomas, respectively. Endocrine, musculoskeletal and skin irAEs were associated with improved PFS and OS across ethnicities and nearly all melanoma subtypes, whereas heterogeneity existed for other irAE types. Conclusions: Ethnicity and melanoma subtype are associated with distinct response patterns, survival outcomes, and irAE profiles in the setting of anti-PD-1 monotherapy. More research is needed to elucidate the molecular and immunologic determinants of these variable outcomes.

10010 Background: Several predictors of response to checkpoint inhibitors show potential, but use pathological assays and/or molecular characterization, which limits their clinical utility outside of the academic setting. We aimed to develop a streamlined approach by leveraging information immediately available through standard care. Here, we present a computational method that integrates deep learning on histology specimens with clinicodemographic variables to predict treatment outcomes in advanced melanoma. Methods: We used hematoxylin and eosin (H&E) sections from 72 patients ( n= 153 slides) from New York University (NYU) to build a Segmentation Classifier that distinguishes tumor, lymphocyte, and connective tissue. Using pre-treatment H&E slides from 121 NYU patients ( n =302 slides), we trained a Response Classifier to predict response by selectively analyzing tumor regions. We then developed a logistic regression classifier that combines neural network output with clinicodemographic variables. The classifiers were tested on an independent cohort of 32 patients from Vanderbilt University ( n =42 slides). Area under the curve (AUC) was calculated as a measure of prediction accuracy. Results: The Segmentation Classifier distinguished tumor, lymphocyte, and connective tissue with AUCs 0.886-0.984. For the Response Classifier, optimal learning conditions were identified through training on NYU patients and testing on Vanderbilt patients (AUCs 0.685 and 0.728, respectively). The fully trained Response Classifier performed with AUC 0.711 on Vanderbilt patients. The logistic regression model performed with enhanced prediction accuracy with AUC 0.803 on NYU patients and AUC 0.793 on Vanderbilt patients. Conclusions: Histology slides and patients’ clinicodemographic characteristics are readily available through routine standard of care and have the potential to predict immunotherapy response. Our approach is time-efficient, reproducible, and requires minimal resource allocation, thus overcoming multiple common barriers to generalizability for contemporary biomarkers.

e15158 Background: Anti-PD-1 agents produce durable responses in many cancers. However, the long-term impact of PD-1 blockade in terms of chronic toxicities, medical comorbidities, and HRQoL are not well-defined. Methods: We assessed 217 patients (pts) who received anti-PD-1 for melanoma, renal cell carcinoma or non-small cell lung carcinoma, with survival of > 2 years after treatment. Pt and tumor characteristics, immune related adverse events (irAEs), cardiometabolic parameters, body composition measurements (BCM), and HRQoL outcomes were tracked. Results: Median overall survival (OS) was not reached; 33 (15.2%) died during follow-up primarily from progressive cancer (n = 28). Acute irAEs developed during treatment in 65% of pts, 45.2% were grade 1/2, 35.5% required steroids, and most commonly presented with dermatitis (18.4%), thyroiditis (12.9%), or arthritis (9.7%). At last follow up, most pts were ECOG 0 (38%) or 1 (41%). There was no difference in blood pressure, glucose, or weight from baseline to 2 years after treatment initiation. BCM showed increased adiposity (140.1 vs. 144 cm2/m2, p = 0.05), skeletal muscle mass (47.05 vs. 47.72 cm2/m2, p = 0.03), and skeletal muscle gauge (1653.9 vs. 1671 AU, p = 0.04). The most common chronic irAEs at last follow-up included hypothyroidism (10.6%), arthritis (3.2%), adrenal insufficiency (3.2%), neuropathy (2.8%), pneumonitis (1.8%), and type 1 diabetes (0.8%). No pts died from chronic irAEs although one pt had fatal CNS radiation necrosis (with unknown contribution of ICI). Chronic irAEs were more common in pts treated with ipilimumab/nivolumab (49%) vs. those with monotherapy (26%). New comorbidities included type 2 diabetes (6.5%) and hypertension (6.0%). HRQoL at 2 years compared favorably to cancer and general populations, although younger age (p < 0.01) and need for subsequent therapy (p = 0.03) were associated with worse HRQoL using Functional Assessment of Cancer-General questionnaire (FACT-G). Acute irAEs were associated with worse National Comprehensive Cancer Network distress scores (p = 0.019). Conclusions: Durable responses to anti-PD-1 therapy and favorable HRQoL outcomes are encouraging in this long-term survivor population. Chronic irAEs may be more common than previously thought although no clear chronic adverse cardiometabolic effects were observed.

10026 Background: Clinical trials of immunotherapy exclude patients (pts) with pre-existing AD. While retrospective data exist regarding the efficacy and safety of single agent ipi and anti-PD1 antibodies (PD1) in pts with AD, no data are available regarding the safety and efficacy of combination therapy in pts with AD, which has a higher toxicity risk. Methods: Pts with melanoma and pre-existing AD treated with combination ipi/PD1 were retrospectively identified from 10 international centres. Data regarding AD, treatment, toxicity and outcomes were examined. Results: Fifty-five pts were included, 46 were treated with ipi/nivolumab and 9 with ipi/pembrolizumab. 40 had an ipi dose of 3mg/kg while 15 had a lower dose regimen. 9 pts received prior PD1 therapy; 3 suffered moderate immune-related adverse events (irAE) with no flares of AD on single agent PD1. Pre-existing AD included inflammatory bowel disease (IBD), thyroiditis, rheumatoid arthritis (RA), multiple sclerosis and psoriasis. 10 pts had active symptoms of AD and 13 were immunosuppressed at commencement of ipi/PD1. Eighteen pts (33%) experienced a flare of their AD including 4/7 with RA, 3/6 with psoriasis, 5/9 with IBD, 3/18 with thyroiditis, 1/1 with Sjogren’s syndrome, 1/1 with polymyalgia, 1/1 with Behcet’s syndrome. Median time to flare was 19 days (range 4 – 167). 13 pts were managed with steroids, 5 required additional immunosuppressants. 7 pts were hospitalised for management of flare (5 with IBD, 2 with RA). 2 pts required intensive care and vasopressors for severe IBD flare, quiescent prior to ipi/PD1. One for diarrhoea and shock and one for duodenal perforation. 8 pts ceased treatment due to flare (3 with IBD, 2 with RA, 1 with Behcet’s, 1 with Sjogren’s). Thirty-seven pts (67%), experienced an irAE unrelated to their AD, 38% G3 or G4. The most frequent irAEs were colitis (n = 16), hepatitis (n = 12), endocrinopathies (n = 12), with 13 pts experiencing an irAE in ≥ 2 organs. 9 pts experienced both AD flare and an irAE. 20 pts (36%) ceased immunotherapy due to irAEs. ORR was 55% (54% in PD1 naive pts), at a median follow up of 14 months, 77% of responses ongoing. ORR in pts who had a flare of their AD was 44% and in pts on immunosuppression was 46%. Median PFS was shorter in pts who had a flare of AD compared with those who did not (2.6 vs 9 months; P-value 0.047). Conclusions: Combination ipi/PD1 shows efficacy comparable to clinical trial populations in pts with pre-existing AD and advanced melanoma. Whilst there was a substantial risk of flare of AD, no increased frequency of irAE’s was observed.

The discovery of immune checkpoint inhibitors (ICI), which include anti-programmed-cell-death-protein-1 (PD-1), its ligand (PD-L1) and anti-cytotoxic T cell lymphocyte-associated protein-4 (CTLA-4), has since transformed the field of oncology with indications continuing to increase. For example, anti-PD1 and anti-CTLA-4 ICIs which includes nivolumab, pembrolizumab and ipilimumab, are FDA/EMA approved for a variety of cancers such as melanoma and non-small cell lung carcinoma (NSCLC) [1]. Considered the Achilles' heel of ICIs, however, are immune-related adverse events (irAEs) (10–60% high grade) that represent an inflammatory response that can affect multiple organ systems which can be fatal (0.3–1.3%) [2]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Moey has nothing to disclose. Conflict of interest: I declare no conflict of interest Conflict of interest: Dr. Goldschmidt has nothing to disclose. Conflict of interest: Dr. Johnson reports grants and other from BMS, other from Array Biopharma, other from Jansen, other from Novartis, other from Merck, grants from Incyte, outside the submitted work. Conflict of interest: Dr. Lebrun-Vignes has nothing to disclose. Conflict of interest: Dr. Moslehi reports personal fees from BMS, personal fees from Pfizer, personal fees from Audentes, personal fees from Nektar, during the conduct of the study; In addition, Dr. Moslehi has a patent Method for treating checkpoint inhibitors induced adverse events pending. Conflict of interest: Dr. Cadranel reports grants and personal fees from AZ, personal fees from Roche, personal fees from BMS, personal fees from MSD, outside the submitted work. Conflict of interest: Dr. SALEM reports personal fees from BMS, outside the submitted work; In addition, Dr. SALEM has a patent Method for treating checkpoint inhibitors induced adverse events pending.

Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity.The expression of 65 cytokines was profiled longitudinally in 98 patients with melanoma treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high-dose steroids.Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline (PRE) and early during treatment (EDT). The expression of these 11 cytokines was integrated into a single toxicity score, the CYTOX (cytokine toxicity) score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The AUC for the CYTOX score in the validation cohort was 0.68 at PRE [95% confidence interval (CI), 0.51-0.84;The CYTOX score is predictive of severe immune-related toxicity in patients with melanoma treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes proinflammatory cytokines such as IL1a, IL2, and IFNα2, may help in the early management of severe, potentially life-threatening immune-related toxicity.

Background Anti-programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) immunotherapy is now routinely used to treat several cancers. Clinical trials have excluded several populations, including patients with solid organ transplant, HIV infection and hepatitis B/C infection. We examined the safety outcomes of these populations treated with anti-PD-1/PD-L1 treatment in a multicentre retrospective study. Methods Patients from 16 centres with advanced cancer and solid organ transplant, HIV infection or hepatitis B/C infection were included. Demographic, tumour, treatment, toxicity and outcome data were recorded. Results Forty-six patients were included for analysis, with a median age of 60 years, and the majority of patients diagnosed with melanoma (72%). Among six patients with solid organ transplants, two graft rejections occurred, with one resulting in death, whereas two patients achieved partial responses. There were four responses in 12 patients with HIV infection. In 14 patients with hepatitis B, there were three responses, and similarly, there were three responses in 14 patients with hepatitis C. There was no unexpected toxicity in any viral infection group or an increase in viral load. Conclusion Patients with HIV or hepatitis B/C infections treated with anti-PD-1/PD-L1 immunotherapy may respond to treatment without increased toxicity. Given the risk of graft rejection in solid organ transplant patients and also the potential for response, the role of anti-PD-1/PD-L1 immunotherapy needs to be carefully considered.

Importance Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data. Objective To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects. Design, Setting, and Participants We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti–programmed death-1/ligand-1 (PD-1/PD-L1) and anti–cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally. Exposures Anti–CTLA-4 (ipilimumab or tremelimumab), anti–PD-1 (nivolumab, pembrolizumab), or anti–PD-L1 (atezolizumab, avelumab, durvalumab). Main Outcomes and Measures Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects. Results Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti–CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti–PD-1/PD-L1–related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti–PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti–PD-1), 0.38% (anti–PD-L1), 1.08% (anti–CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4). Conclusions and Relevance In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

Introduction Actuellement, les inhibiteurs de check-points immunitaires (ICI) sont recommandes pour le traitement de plus de 16 types de cancers differents et le nombre de patients eligibles ne cesse d’augmenter notamment avec l’approbation recente dans le cancer du sein. La gestion des toxicites immunitaires induites par ces anticorps monoclonaux anti-cytotoxic-T-lymphocyte-associated protein-4 (CTLA4) ou anti-programme cell death 1/programme cell death ligand 1 (PD1/PDL1) devient cruciale. En effet, en restaurant l’immunite cellulaire T antitumorale, les ICI peuvent induire des effets indesirables dont la frequence, le tropisme et la severite dependent notamment des schemas therapeutiques utilises. Une etude recente des toxicites cardiovasculaires immuno-induites a montre un risque de mortalite majeur lie aux myocardites. Cependant, les effets indesirables rhumatologiques sont a ce jour peu decrits. Objectifs Identifier et caracteriser les toxicites rhumatologiques induites par les ICI a l’aide de la base internationale de pharmacovigilance de l’OMS. Materiels et methodes A l’aide de la base de pharmacovigilance de l’OMS, nous avons compare par une analyse de disproportionnalite bayesienne la declaration des effets indesirables rhumatologiques chez les patients exposes aux ICI a la declaration de ces effets dans la base de donnees complete a partir de 2008 (date de la premiere declaration d’evenement indesirable sous ICI). Toutes les pathologies systemiques rhumatologiques (a l’exception de la vascularite) ont ete incluses selon la definition des termes Medical Dictionary for Regulatory Activities (MedDRA). Les molecules suivantes ont ete prises en compte : pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, tremelimumab, cemiplimab et ipilimumab. L’association entre effet indesirable et medicament est calculee par l’information component (IC) ou le reporting odds ratio (ROR). La borne inferieure de l’intervalle de confiance a 95 % de l’IC : IC0,25 est significatif si positif. Resultats Nous avons identifie 54 416 effets indesirables rapportes sous ICI (14 988 450 effets indesirables rapportes dans la base depuis 2008). Comparativement a l’ensemble de la base, une association significative entre ICI et effets indesirables rhumatologiques a ete mise en evidence pour 6 pathologies : les arthrites (n = 606/121 811, ROR 1,4 [1,3–1,5] ; IC0,25 0,45), les myosites (n = 465/26 722, ROR 4,9 [4,5–5,4] ; IC0,25 2,12), la sarcoidose (n= 94/2772, ROR 9,6 [7,9–11,9] ; IC0,25 2,85), la pseudopolyarthrite rhizomelique (n= 76/1504, ROR 14,6 [11,6–18,4] ; IC0,25 3,34), le syndrome de Gougerot-Sjogren (n = 49/2000, ROR 6,9 [5,2–9,2] ; IC0,25 2,24) et le sclerodermie (n =17/2385 vs 17, ROR 2,0 [1,2–3,2] ; IC0,25 0,17). Les patients atteints de myosite etaient plus souvent des hommes (70,4 % ; p Conclusion Parmi les toxicites rhumatologiques, les myosites sont les plus precoces et les plus graves. Le phenotype des toxicites rhumatologiques differe des pathologies auto-immunes spontanees et leur type varie selon l’ICI (PD1 ou CTLA-4), ce qui suggere des mecanismes physiopathologiques distincts. Une meilleure connaissance de ces effets indesirables est necessaire pour si possible les prevenir et ameliorer leur prise en charge therapeutique.

Immune checkpoint inhibitors have dramatically transformed melanoma treatment options. However, intrinsic and acquired resistance remain fundamental limitations to extending the benefits to all patients. Understanding molecular and clinical features that correlate with response to treatment (biomarkers) may unravel therapeutic resistance, assist in treatment decision-making, and facilitate drug development. An intensive effort to characterize these biomarkers is underway. Herein, we highlight promising molecular biomarkers involving the tumor microenvironment, host immune response, and microbiome. We particularly focus on anti-programmed death-1 (PD-1) therapy but will also briefly cover anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) and novel combination therapies.

Resistance to current therapies still impacts a significant number of melanoma patients and can be regulated by epigenetic alterations. Analysis of global cytosine methylation in a cohort of primary melanomas revealed a pattern of early demethylation associated with overexpression of oncogenic transcripts. Loss of methylation and associated overexpression of the CSF 1 receptor (CSF1R) was seen in a majority of tumors and was driven by an alternative, endogenous viral promoter in a subset of samples. CSF1R was particularly elevated in melanomas with BRAF and other MAPK activating mutations. Furthermore, rebound ERK activation after BRAF inhibition was associated with RUNX1-mediated further upregulation of CSF-1R and its ligand IL-34. Importantly, increased CSF-1R and IL-34 overexpression were detected in an independent cohort of resistant melanomas. Inhibition of CSF-1R kinase or decreased CSF-1R expression by RNAi reduced 3-D growth and invasiveness of melanoma cells. Coinhibition of CSF-1R and BRAF resulted in synergistic efficacy in vivo. To our knowledge, our data unveil a previously unknown role for the autocrine-regulated CSF-1R in BRAF V600E resistance and provide a preclinical rationale for targeting this pathway in melanoma.

Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) are a promising class of immunotherapeutics that activate innate immunity to increase tumour immunogenicity. However, the efficacy of CDNs is limited by drug delivery barriers, including poor cellular targeting, rapid clearance and inefficient transport to the cytosol where STING is localized. Here, we describe STING-activating nanoparticles (STING-NPs)—rationally designed polymersomes for enhanced cytosolic delivery of the endogenous CDN ligand for STING, 2′3′ cyclic guanosine monophosphate–adenosine monophosphate (cGAMP). STING-NPs increase the biological potency of cGAMP, enhance STING signalling in the tumour microenvironment and sentinel lymph node, and convert immunosuppressive tumours to immunogenic, tumoricidal microenvironments. This leads to enhanced therapeutic efficacy of cGAMP, inhibition of tumour growth, increased rates of long-term survival, improved response to immune checkpoint blockade and induction of immunological memory that protects against tumour rechallenge. We validate STING-NPs in freshly isolated human melanoma tissue, highlighting their potential to improve clinical outcomes of immunotherapy. Rationally designed polymer vesicles increase cytosolic delivery of cGAMP, activating the STING pathway and increasing the immunogenicity of the tumour microenvironment in in vivo murine models of melanoma and in human metastatic melanoma tissues.

Immune checkpoint inhibitors (CPI) have proven remarkably effective in treating many types of malignancies but have been associated with significant risk for immune-related adverse events (irAEs) (1). Among these, new onset of insulin-dependent diabetes mellitus (DM) occurs in 0.2–1.0% of patients (2,3) and is being seen more frequently as CPI become more widely used. However, the incidence, clinical course, and pathogenesis of CPI-associated DM (CPI-DM) are not well understood. To better understand the characteristics of CPI-DM, we analyzed VigiBase (4), the World Health Organization’s database of individual case safety reports, and detected 283 cases of new-onset DM from 2014 to April 2018 following treatment with CPI using the following preferred terms according to MedDRA (Medical Dictionary for Regulatory Activities): diabetic ketoacidosis (DKA), diabetic ketosis, type 1 diabetes mellitus, or fulminant type 1 diabetes mellitus; any one of these was sufficient to define CPI-DM. We noted a marked increase in reporting of CPI-DM over this time period, with over 50% of cases reported in 2017 (Table 1). Overall, half of the patients with DM presented in DKA (50.2%); 5.6% of all cases were also on steroids at diagnosis of DM, and 6.4% were on noninsulin diabetes medications in addition to insulin. …

Purpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1. Experimental Design: We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies. Results: Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy. Placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti-PD1 as compared with the same tumors in young mice (8 weeks). These data suggest that this increased response in aged patients occurs even in the absence of a more complex mutational landscape. Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8+:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice. Conclusions: While there are obvious limitations to our study, including our inability to conduct a meta-analysis due to a lack of available data, and our inability to control for mutational burden, there is a remarkable consistency in these data from over 500 patients across 8 different institutes worldwide. These results stress the importance of considering age as a factor for immunotherapy response. Clin Cancer Res; 24(21); 5347–56. ©2018 AACR. See related commentary by Pawelec, p. 5193

Background Glembatumumab vedotin is an antibody-drug conjugate that produced preliminary clinical activity against advanced melanoma in a phase 1 dose-escalation trial. The objective of the current study was to investigate further the antitumor activity of glembatumumab vedotin at the recommended phase 2 dose in heavily pretreated patients with melanoma. Methods This single-arm, phase 2 study enrolled patients with stage IV melanoma who were refractory to checkpoint inhibition and to B-raf proto-oncogene, serine/threonine kinase (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibition (in the presence of a BRAF valine mutation at codon 600). Patients received 1.9 mg/kg glembatumumab vedotin intravenously every 3 weeks until they developed disease progression or intolerance. The primary endpoint was objective response rate (ORR), which was determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), safety, and clinical efficacy versus tumor glycoprotein NMB (gpNMB) expression. Tumor expression of gpNMB was assessed using immunohistochemistry. Results In total, 62 patients received treatment. The ORR was 11% and the median response duration was 6.0 months (95% confidence interval [CI], 4.1 months to not reached). The median PFS was 4.4 months (95% CI, 2.6-5.5 months), and the median OS was 9.0 months (95% CI, 6.1-11.7 months). For patients who developed rash during the first cycle versus those who did not, the ORR was 21% versus 7%, respectively, and there was an overall improvement in PFS (hazard ratio, 0.43; P = .013) and OS (hazard ratio, 0.43; P = .017). The most frequent adverse events were alopecia, neuropathy, rash, fatigue, and neutropenia. With one exception, all evaluable tumors were positive for gpNMB, and 46 of 59 tumors (76%) had 100% gpNMB-positive epithelial cells. Conclusions Glembatumumab vedotin had modest activity and an acceptable safety profile in patients with advanced melanoma who were refractory to checkpoint inhibitors and MEK/BRAF inhibition. Treatment-related rash may be associated with response.

Immune checkpoint inhibitors have demonstrated efficacy across many cancer types in numerous clinical trials. However, because patients with preexisting autoimmune disease were excluded from these seminal trials, there are serious gaps in knowledge regarding the efficacy-and in particular the safety-of these transformative agents in patients with autoimmune disease. The safety of immune checkpoint inhibitors in this population has been an important concern, since these agents unleash immune activation, a potentially dangerous situation for patients with already heightened and aberrant immune function. Several retrospective studies have begun to address this question, finding that autoimmunity is often exacerbated by immune checkpoint inhibitor therapy, but is generally manageable with standard treatment algorithms and close multidisciplinary monitoring. Further, the activity of these agents appears to be comparable to that seen in unselected patients. Here we detail the experience with immune checkpoint inhibitors in patients with autoimmune disease.

Melanoma is the most aggressive of the skin cancers, with historically high rates of morbidity and mortality due to its resistance to traditional cytotoxic therapies. Recently, however, breakthroughs in new therapies have dramatically changed clinical outcomes of this disease. These advances emerged from an improved understanding of tumor oncogenesis and the interacting tumor microenvironment. Small molecules that target the oncogenic mitogen-activated protein kinase (MAPK) pathway, specifically the tyrosine kinase BRAF and its downstream signaling partner MEK, have demonstrated an improved overall survival and progression-free survival for BRAF-mutant melanoma. Additionally, manipulation of tumor immune surveillance by inhibitors of the immune suppressive programmed cell death 1 receptor (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathways have recently demonstrated durable responses in various cancers by promoting an anti-tumor immune response. Application of these targeted and immune-modulatory therapies has shown promising outcomes in melanoma. Combinations of these therapies may hold promise to enhance responses further. In this review, we will discuss the current targeted therapies and immunotherapies, and review the results of combination studies and speculate on future treatment paradigms.

Purpose: PD-1/L1 axis–directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti–PD-1 response. Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti–PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti–PD-1 treatment outcomes. Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti–PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival. Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250–60. ©2018 AACR.

Immunotherapies targeting programmed cell death protein 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1), dramatically improve the survival of melanoma patients. However, only ∼40% of treated patients demonstrate a clinical response to single-agent anti-PD-1 therapy. An intact tumor response to type-II interferon (i.e. IFN-γ) correlates with response to anti-PD-1, and patients with de novo or acquired resistance may harbor loss-of-function alterations in the JAK/STAT pathway, which lies downstream of the interferon gamma receptor (IFNGR1/2). In this study, we dissected the specific roles of individual JAK/STAT pathway members on the IFN-γ response, and identified JAK1 as the primary mediator of JAK/STAT signaling associated with IFN-γ-induced expression of antigen-presenting molecules MHC-I and MHC-II, as well as PD-L1 and the cytostatic response to IFN-γ. In contrast to the crucial role of JAK1, JAK2 was largely dispensable in mediating most IFN-γ effects. In a mouse melanoma model, inhibition of JAK1/2 in combination with anti-PD-L1 therapy partially blocked anti-tumor immunologic responses, while selective JAK2 inhibition appeared to augment therapy. Amplification of JAK/STAT signaling in tumor cells through genetic inhibition of the negative regulator PTPN2 potentiated IFN-γ response in vitro and in vivo, and may be a target to enhance immunotherapy efficacy.

Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57-81%), including nineteen patients (32%) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF1 mutations (fourteen out of seventeen cases) in these tumours. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P = 0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.

Summary Background Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy. Methods This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study. Findings The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694 [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio [HR] 0·77 [95% CI 0·66–0·90] for progression-free survival and 0·74 [0·58–0·95] for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 [0·57–0·91] for progression-free survival and 0·60 [0·45–0·79] for overall survival) and immunotherapy (HR 0·75 [0·56–1·00] and 0·64 [0·47–0·86]). No associations were observed with chemotherapy (HR 0·87 [0·65–1·17, p interaction =0·61] for progression-free survival and 1·03 [0·80–1·34, p interaction =0·01] for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 [0·40–0·70]), but no associations observed in women (HR 0·85 [0·61–1·18, p interaction =0·03]). Interpretation Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations. Funding ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.

Immune checkpoint inhibitors, particularly those targeting PD-1/PD-L1, produce durable responses in a subset of patients across cancer types. Although often well-tolerated, these agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Treatment of these toxicities primarily consists of immune suppression with corticosteroids and other agents. This review will briefly discuss the mechanisms of immune-related adverse events (irAEs), overview the clinical and pathologic features of major toxicities caused by PD-1/PD-L1 blockade, and review their management.

Background Combination IPI+PD1 immunotherapy has a high initial response rate, but patients can subsequently progress. The best management of this acquired resistance is unknown. We sought to explore the efficacy and safety of rechallenge IPI+PD1 in this setting. Methods Retrospective data from four melanoma centres were reviewed. Demographics, disease characteristics, initial and rechallenge treatment efficacy and toxicity were examined. Results 15 patients (pt) were identified: 60% male, median age 51y, 40% BRAF mutant. 14 pt received IPI+PD1 as 1st line of treatment, 1 received prior BRAFi+MEKi. 9 pt received ipilimumab (I) 3mg/Kg and nivolumab (N) 1mg/kg (I3N1), 5 received I 1mg/kg and pembrolizumab (P) 2mg/kg, 1 patient I 100mg q12w/P200mg q3w, with a median 4 cycles of I. 1 pt had CR, 10 had PR, and 4 prolonged SD (>6 months) to initial treatment. 7 pt (47%) developed significant irAE (4 hepatitis, 2 colitis, 1 pneumonitis), of which 6 (85%) ceased IPI + PD1 and only 1 pt continued PD1 alone. Median time to progression (TTP1) was 11 months (range 5-31 months). After progression, 5 (33%) had no intervening systemic therapy prior to rechallenge IPI+PD1 (of which 3 progressed on while receiving maintenance PD1), 5 had BRAFi/MEKi (33%), 2 (13%) had anti-PD1 monotherapy, 2 (13%) had investigational immunotherapy agents on a trial, and 1 pt had DTIC. At rechallenge, 13 pt received I3N1, 1pt I1N3 and 1 pt I3q12w + N1q2w, with a median 2 cycles of I. Only 1 pt had PR, 1 had SD, while 13 (87%) had PD, with mPFS2 only 2.7 mo (95% CI 2- NA). OS from rechallenge was 7.5 mo (95% CI 6.7- NA). All 7 pt with prior treatment-limiting irAE had the same irAE recur, except for 1 pt who died one week after re-exposure of PD, and 1 pt with prior pneumonitis who remained on 10mg prednisone without recurrence. Conclusions Rechallenge with IPI + PD1 appears to have little efficacy in those with acquired resistance and prior toxicity often recurs. An expanded multi-institutional analysis is under way. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure A. Hepner: Advisory / Consultancy: Novartis; Travel / Accommodation / Expenses: Roche. M.S. Carlino: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: AMGEN; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche. D.B. Johnson: Advisory / Consultancy: Array Biopharma; Advisory / Consultancy: BMS; Advisory / Consultancy: Incyte; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Incyte; Travel / Accommodation / Expenses: Genentech. O.A. Michielin: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MSD. G.V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Mass-Array; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche. A.M. Menzies: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Pierre Fabre. All other authors have declared no conflicts of interest.

// Katherine E. Hutchinson 1 , Douglas B. Johnson 2 , Adam S. Johnson 3 , Violeta Sanchez 2 , Maria Kuba 3 , Pengcheng Lu 4 , Xi Chen 4 , Mark C. Kelley 5 , Qingguo Wang 6 , Zhongming Zhao 1, 6 , Mark Kris 7 , Michael F. Berger 8, 9 , Jeffrey A. Sosman 2 , William Pao 2, 10 1 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA 2 Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA 3 Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA 4 Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA 5 Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA 6 Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA 7 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA 8 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA 9 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA 10 Currently an employee of Roche Pharma Research and Early Development, Basel, Switzerland Correspondence to: Katherine E. Hutchinson, e-mail: katie.hutchinson@vanderbilt.edu Keywords: melanoma, ERBB, DUSP4, trametinib, afatinib Received: April 09, 2015 Accepted: June 01, 2015 Published: June 13, 2015 ABSTRACT Melanomas are characterized by activating “driver” mutations in BRAF, NRAS, KIT, GNAQ, and GNA11. Resultant mitogen-activated protein kinase (MAPK) pathway signaling makes some melanomas susceptible to BRAF (BRAF V600 mutations), MEK1/2 (BRAF V600, L597, fusions; NRAS mutations), or other kinase inhibitors (KIT), respectively. Among driver-negative (“pan-negative”) patients, an unexplained heterogeneity of response to MEK1/2 inhibitors has been observed. Analysis of 16 pan-negative melanoma cell lines revealed that 8 (50%; termed Class I) are sensitive to the MEK1/2 inhibitor, trametinib, similar to BRAF V600E melanomas. A second set (termed Class II) display reduced trametinib sensitivity, paradoxical activation of MEK1/2 and basal activation of ERBBs 1, 2, and 3 (4 lines, 25%). In 3 of these lines, PI3K/AKT and MAPK pathway signaling is abrogated using the ERBB inhibitor, afatinib, and proliferation is even further reduced upon the addition of trametinib. A potential mechanism of ERBB activation in Class II melanomas is minimal expression of the ERK1/2 phosphatase, DUSP4, as ectopic restoration of DUSP4 attenuated ERBB signaling through potential modulation of the ERBB ligand, amphiregulin (AREG). Consistent with these data, immunohistochemical analysis of patient melanomas revealed a trend towards lower overall DUSP4 expression in pan-negative versus BRAF- and NRAS-mutant tumors. This study is the first to demonstrate that differential ERBB activity in pan-negative melanoma may modulate sensitivity to clinically-available MEK1/2 inhibitors and provides rationale for the use of ERBB inhibitors, potentially in combination with MEK1/2 inhibitors, in subsets of this disease.

Background. Ipilimumab improves overall survival (OS) in advanced melanoma. Acral melanoma is an uncommon clinical subtype of this disease associated with poor prognosis. The clinical activity of ipilimumab has not been well-defined in advanced acral melanoma. Methods. We retrospectively reviewed the demographics, treatment history, and clinical outcomes for all patients with acral melanoma treated with ipilimumab from two academic centers between February 2006 and June 2013. Using Cox proportional hazards models, we assessed for factors that correlated with OS. Results. A total of 35 patients with acral melanoma received ipilimumab. Melanomas arose on volar surfaces (n = 28) and subungual sites (n = 7); stage M1c disease was present in 54%, and 45% had elevated serum lactate dehydrogenase (LDH). Best response by RECIST 1.1 criteria was complete response in 1 patient, partial response in 3, and stable disease (SD) in 4 for an objective response rate (ORR) of 11.4% and a clinical benefit rate (ORR + SD) at 24 weeks of 22.9%. Median progression-free survival was 2.5 months (95% confidence interval [CI]: 2.3–2.7 months); median OS was 16.7 months (95% CI: 10.9–22.5 months). Normal LDH and absolute lymphocyte count ≥1,000 at 7 weeks predicted longer OS. Immune-related adverse events (irAEs) were noted in 16 patients including 7 with grade 3/4 irAEs (20%). Conclusion. Ipilimumab is clinically active in acral melanoma with similar ORR and OS compared with unselected melanoma populations. Ipilimumab remains a viable therapeutic option for patients with advanced acral melanoma. Implications for Practice: Ipilimumab is a commonly used immune therapy that improves survival in metastatic melanoma. The clinical activity of ipilimumab in certain rare melanoma subtypes, such as uveal or mucosal melanomas, is suboptimal. Acral melanoma is another unusual subtype of this disease that arises on the palms, soles, and nailbeds. In this study of 35 patients with acral melanoma from 2 centers, ipilimumab was found to have activity that appears equivalent to unselected melanoma (response rate of 11.4%, median overall survival of 16.7 months). Ipilimumab remains a viable treatment option for this melanoma subpopulation.

Ipilimumab, a novel immune checkpoint inhibitor, is associated with long-term survival in approximately 20% of patients with advanced melanoma and is also being evaluated in the adjuvant setting. With this growing cohort of survivors, long-term health outcomes, chronic toxicities, and functional outcomes among survivors treated with ipilimumab need to be defined. Using retrospective medical record abstraction, we evaluated disease status, chronic immune- and non–immune-related health events, pharmacologic management of symptoms, and functional status in patients with melanoma, with overall survival ≥2 years following ipilimumab treatment at Vanderbilt University. Ninety patients received ipilimumab for metastatic disease or as adjuvant therapy between January 2006 and September 2012, and 33 patients survived ≥2 years, with a median overall survival of 60.1 months. Of these, 24 patients were alive at the last follow-up (73%), with 14 patients free of disease (42%). Gastrointestinal and dermatologic adverse events were frequent but largely transient. By contrast, patients with hypophysitis universally required ongoing corticosteroids, although largely remained asymptomatic with appropriate hormone replacement. Surviving patients generally had excellent performance status (ECOG 0–1 in 23 of 24). Chronic neurologic toxicities caused substantial morbidity and mortality in 2 patients who received whole-brain radiotherapy >5 years before analysis, and in one patient with chronic, painful peripheral neuropathy. No previously undescribed cardiac, pulmonary, gastrointestinal, hematologic, or neoplastic safety signals were identified. In conclusion, ipilimumab was associated with largely excellent functional outcomes among long-term survivors. Chronic endocrine dysfunction and occasional neurologic toxicity (primarily associated with whole-brain radiation) were observed in a small number of patients. Cancer Immunol Res; 3(5); 464–9. ©2015 AACR.

INTRODUCTION: Aberrant Mitogen Activated Protein Kinase (MAPK) pathway signaling is a hallmark of melanoma. Mitogen/Extracellular signal-regulated Kinase (MEK) 1/2 are integral components of MAPK signaling. Several MEK inhibitors have demonstrated activity as single agents and in combination with other therapies. Trametinib was the first MEK inhibitor approved for use in treatment of advanced BRAF(V600) mutant melanoma as a single agent and in combination with BRAF inhibitor, dabrafenib. AREAS COVERED: In this article, we discuss the underlying biology of MEK inhibition and its rationale in melanoma treatment with special emphasis on the clinical development of trametinib, from initial phase I studies to randomized phase II and III studies, both as monotherapy and in combination with other therapeutics. Furthermore, we briefly comment on trametinib for NRAS mutant and other non–BRAF mutant subsets of melanoma. EXPERT OPINION: Trametinib is a novel oral MEK inhibitor with clinical activity in BRAF(V600) mutant metastatic melanoma alone and in combination with dabrafenib. Trametinib is currently being explored in other genetic subsets as well, particularly those with NRAS mutations or atypical BRAF alterations. Furthermore, to maximize efficacy and overcome acquired resistance, studies evaluating the combination of trametinib with other targeted agents and immunotherapy are underway.

Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies have become a mainstay in advanced melanoma treatment. We sought to evaluate whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune therapy in melanoma. We identified 229 patients with melanoma treated with immune therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1 (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune therapy for patients with or without NRAS mutations. Of the 229 patients with melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild type. The NRAS-mutant cohort had superior or a trend to superior outcomes compared with the other cohorts in terms of response to first-line immune therapy (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P = 0.07), clinical benefit (response + stable disease lasting ≥24 weeks; 50% vs. 31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P = 0.09). Benefit from anti–PD-1/PD-L1 was particularly marked in the NRAS cohort (clinical benefit rate 73% vs. 35%). In an independent group of patient samples, NRAS-mutant melanoma had higher PD-L1 expression (although not statistically significant) compared with other genotypes (8/12 vs. 9/20 samples with ≥1% expression; 6/12 vs. 6/20 samples with ≥5% expression), suggesting a potential mechanism for the clinical results. This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes. If confirmed by prospective studies, this may be explained in part by high rates of PD-L1 expression. Cancer Immunol Res; 3(3); 288–95. ©2015 AACR.

Therapies such as BRAF inhibitors have become standard treatment for melanoma patients whose tumors harbor activating BRAFV600 mutations. However, analogous therapies for inhibiting NRAS mutant signaling have not yet been well established. In this study, we performed an integrative analysis of DNA methylation, gene expression, and microRNA expression data to identify potential regulatory pathways associated with the most common driver mutations in NRAS (Q61K/L/R) through comparison of NRASQ61-mutated melanomas with pan-negative melanomas. Surprisingly, we found dominant hypomethylation (98.03%) in NRASQ61-mutated melanomas. We identified 1,150 and 49 differentially expressed genes and microRNAs, respectively. Integrated functional analyses of alterations in all three data types revealed important signaling pathways associated with NRASQ61 mutations, such as the MAPK pathway, as well as other novel cellular processes, such as axon guidance. Further analysis of the relationship between DNA methylation and gene expression changes revealed 9 hypermethylated and down-regulated genes and 112 hypomethylated and up-regulated genes in NRASQ61 melanomas. Finally, we identified 52 downstream regulatory cascades of three hypomethylated and up-regulated genes (PDGFD, ZEB1, and THRB). Collectively, our observation of predominant gene hypomethylation in NRASQ61 melanomas and the identification of NRASQ61-linked pathways will be useful for the development of targeted therapies against melanomas harboring NRASQ61 mutations.