Melanoma expression analysis with Big Data technologies

Melanoma is a highly immunogenic tumor. Therefore, in recent years physicians have incorporated drugs that alter the immune system into their therapeutic arsenal against this disease, revolutionizing in the treatment of patients in an advanced stage of the disease. This has led us to explore and deepen our knowledge of the immunology surrounding melanoma, in order to optimize its approach. At present, immunotherapy for metastatic melanoma is based on stimulating an individual’s own immune system through the use of specific monoclonal antibodies. The use of immunotherapy has meant that many of patients with melanoma have survived and therefore it constitutes a present and future treatment in this field. At the same time, drugs have been developed targeting specific mutations, specifically BRAF, resulting in large responses in tumor regression (set up in this clinical study to 18 months), as well as a higher percentage of long-term survivors. The analysis of the gene expression changes and their correlation with clinical changes can be developed using the tools provided by those companies which currently provide gene expression platforms. The gene expression platform used in this clinical study is NanoString, which provides nCounter. However, nCounter has some limitations as the type of analysis is restricted to a predefined set, and the introduction of clinical features is a complex task. This paper presents an approach to collect the clinical information using a structured database and a Web user interface to introduce this information, including the results of the gene expression measurements, to go a step further than the nCounter tool. As part of this work, we present an initial analysis of changes in the gene expression of a set of patients before and after targeted therapy. This analysis has been carried out using Big Data technologies (Apache Spark) with the final goal being to scale up to large numbers of patients, even though this initial study has a limited number of enrolled patients (12 in the first analysis). This is not a Big Data problem, but the underlaying study aims at targeting 20 patients per year just in Málaga, and this could be extended to be used to analyze the 3.600 patients diagnosed with melanoma per year.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. This work was funded in part by Grants TIN2014-58304-R (Ministerio de Ciencia e Innovación) and P11-TIC-7529 and P12-TIC-1519 (Plan Andaluz de Investigación, Desarrollo e Innovación). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

A Phase II Trial of the CD40 Agonistic Antibody Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Confirmed Disease Progression on Anti-PD-1 Therapy

CD40 agonistic antibody; Metastatic melanoma; Anti-PD-1 therapyAnticuerpo agonista CD40; Melanoma metastásico; Terapia anti-PD-1Anticòs agonista CD40; Melanoma metastàtic; Teràpia anti-PD-1Purpose: Disease progression during or after anti-PD-1-based treatment is common in advanced melanoma. Sotigalimab is a CD40 agonist antibody with a unique epitope specificity and Fc receptor binding profile optimized for activation of CD40-expressing antigen-presenting cells. Preclinical data indicated that CD40 agonists combined with anti-PD1 could overcome resistance to anti-PD-1. Patients and Methods: We conducted a multicenter, open-label, phase II trial to evaluate the combination of sotigalimab 0.3 mg/kg and nivolumab 360 mg every 3 weeks in patients with advanced melanoma following confirmed disease progression on a PD-1 inhibitor. The primary objective was to determine the objective response rate (ORR). Results: Thirty-eight subjects were enrolled and evaluable for safety. Thirty-three were evaluable for activity. Five confirmed partial responses (PR) were observed for an ORR of 15%. Two PRs are ongoing at 45.9+ and 26+ months, whereas the other three responders relapsed at 41.1, 18.7, and 18.4 months. The median duration of response was at least 26 months. Two additional patients had stable disease for >6 months. Thirty-four patients (89%) experienced at least one adverse event (AE), and 13% experienced a grade 3 AE related to sotigalimab. The most common AEs were pyrexia, chills, nausea, fatigue, pruritus, elevated liver function, rash, vomiting, headache, arthralgia, asthenia, myalgia, and diarrhea. There were no treatment-related SAEs, deaths, or discontinuation of sotigalimab due to AEs. Conclusions: Sotigalimab plus nivolumab had a favorable safety profile consistent with the toxicity profiles of each agent. The combination resulted in durable and prolonged responses in a subset of patients with anti-PD-1-resistant melanoma, warranting further evaluation in this setting.The study was funded by Apexigen. Drug support was provided by Apexigen and Bristol Myers Squibb. We acknowledge research funding in part from the Yale Calabresi Immuno-oncology Training Program (K12CA215110; to S.A. Weiss) and the Yale SPORE in Skin Cancer (P50 CA121974; to H.M. Kluger)

SEOM-GEM clinical guidelines for cutaneous melanoma (2023)

Melanoma; Staging; Targeted therapyMelanoma; Estadificación; Terapia dirigidaMelanoma; Estadificació; Teràpia dirigidaCutaneous melanoma incidence is rising. Early diagnosis and treatment administration are key for increasing the chances of survival. For patients with locoregional advanced melanoma that can be treated with complete resection, adjuvant—and more recently neoadjuvant—with targeted therapy—BRAF and MEK inhibitors—and immunotherapy—anti-PD-1-based therapies—offer opportunities to reduce the risk of relapse and distant metastases. For patients with advanced disease not amenable to radical treatment, these treatments offer an unprecedented increase in overall survival. A group of medical oncologists from the Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines, based on a thorough review of the best evidence available. The following guidelines try to cover all the aspects from the diagnosis—clinical, pathological, and molecular—staging, risk stratification, adjuvant therapy, advanced disease therapy, and survivor follow-up, including special situations, such as brain metastases, refractory disease, and treatment sequencing. We aim help clinicians in the decision-making process

On the Use of Explainable Artificial Intelligence for the Differential Diagnosis of Pigmented Skin Lesions

En los últimos años, la Inteligencia Artificial Explicable (XAI) ha atraído la atención en la analítica de datos, ya que muestra un gran potencial en la interpretación de los resultados de complejos modelos de aprendizaje automático en la aplicación de problemas médicos. Se trata de que el resultado de las aplicaciones basadas en el aprendizaje automático deben ser comprendidos por los usuarios finales, especialmente en el contexto de los datos médicos, donde las decisiones deben tomarse cuidadosamente. decisiones. Como tal, se han realizado muchos esfuerzos para explicar el resultado de un modelo complejo de aprendizaje profundo en procesos de reconocimiento y clasificación de y clasificación de imágenes, como en el caso del cáncer de melanoma. Este representa un primer intento (hasta donde sabemos) de investigar experimental y técnicamente la explicabilidad de los métodos modernos de XAI modernos de XAI: explicaciones de modelos de diagnóstico interpretables locales (LIME) y Shapley Additive exPlanations (SHAP), en términos de reproducibilidad de resultados y el tiempo de ejecución en un conjunto de datos de clasificación de imágenes de melanoma. Este artículo muestra que los métodos XAI proporcionan ventajas en la interpretación de los resultados del modelo en la clasificación de imágenes de melanoma. interpretación de los resultados del modelo en la clasificación de imágenes de melanoma. Concretamente, LIME se comporta mejor que el explicador de gradiente SHAP en términos de reproducibilidad y tiempo de ejecución.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Treatment of Metastatic Melanoma at First Diagnosis: Review of the Literature

Metastatic melanoma (MM) is a pathological entity with a very poor prognosis that, until a few decades ago, had a low response rate to systemic treatments. Fortunately, in the last few years, new therapies for metastatic melanoma have emerged. Currently, targeted therapy and immunotherapy are the mainstays of the therapeutic arsenal available for patients with unresectable or metastatic melanoma. However, both clinical evolution and drug efficacy in melanoma patients are very different depending on the stage at which it is diagnosed. In fact, the aggressiveness of melanoma is different depending on whether it debuts directly as metastatic disease or if what occurs is a relapse after a first diagnosis at an early stage, although the biological determinants are largely unknown. Another key aspect in the clinical management of metastatic melanoma at first diagnosis strives in the different prognosis of melanoma of unknown primary (MUP) compared to melanoma of known primary (MPK). Understanding the mechanisms behind this, and the repercussion of implementing targeted and immune therapies in this specific form is crucial for designing diagnosis and treatment decision algorithms that optimize the current strategies. In this review article, we recapitulate the information available thus far regarding the epidemiology and response to immunotherapy treatments or targeted therapy in patients diagnosed with metastatic melanoma as a first diagnosis, with especial emphasis on the emerging specific information of the subpopulation formed by MUP patients

Gut Microbiota and Therapy in Metastatic Melanoma: Focus on MAPK Pathway Inhibition.

Gut microbiome (GM) and its either pro-tumorigenic or anti-tumorigenic role is intriguing and constitutes an evolving landscape in translational oncology. It has been suggested that these microorganisms may be involved in carcinogenesis, cancer treatment response and resistance, as well as predisposition to adverse effects. In melanoma patients, one of the most immunogenic cancers, immune checkpoint inhibitors (ICI) and MAPK-targeted therapy-BRAF/MEK inhibitors-have revolutionized prognosis, and the study of the microbiome as a modulating factor is thus appealing. Although BRAF/MEK inhibitors constitute one of the main backbones of treatment in melanoma, little is known about their impact on GM and how this might correlate with immune re-induction. On the contrary, ICI and their relationship to GM has become an interesting field of research due to the already-known impact of immunotherapy in modulating the immune system. Immune reprogramming in the tumor microenvironment has been established as one of the main targets of microbiome, since it can induce immunosuppressive phenotypes, promote inflammatory responses or conduct anti-tumor responses. As a result, ongoing clinical trials are evaluating the role of fecal microbiota transplant (FMT), as well as the impact of using dietary supplements, antibiotics and probiotics in the prediction of response to therapy. In this review, we provide an overview of GM's link to cancer, its relationship with the immune system and how this may impact response to treatments in melanoma patients. We also discuss insights about novel therapeutic approaches including FMT, changes in diet and use of probiotics, prebiotics and symbiotics. Finally, we hypothesize on the possible pathways through which GM may impact anti-tumor efficacy in melanoma patients treated with targeted therapy, an appealing subject of which little is known

Genes Involved in Immune Reinduction May Constitute Biomarkers of Response for Metastatic Melanoma Patients Treated with Targeted Therapy

Targeted therapy in metastatic melanoma often achieves a major tumour regression response and significant long-term survival via the release of antigens that reinduce immunocompetence. The biomarkers thus activated may guide the prediction of response, but this association and its mechanism have yet to be established. Blood samples were collected from nineteen consecutive patients with metastatic melanoma before, during, and after treatment with targeted therapy. Differential gene expression analysis was performed, which identified the genes involved in the treatment, both in the first evaluation of response and during progression. Although clinical characteristics of the patients were poorer than those obtained in pivotal studies, radiological responses were similar to those reported previously (objective response rate: 73.7%). In the first tumour assessment, the expression of some genes increased (CXCL-10, SERPING1, PDL1, and PDL2), while that of others decreased (ARG1, IL18R1, IL18RAP, IL1R1, ILR2, FLT3, SLC11A1, CD163, and S100A12). The analysis of gene expression in blood shows that some are activated and others inhibited by targeted therapy. This response pattern may provide biomarkers of the immune reinduction response, which could be used to study potential combination treatments. Nevertheless, further studies are needed to validate these results

Access to melanoma drugs in Spain: a cross-sectional survey

BackgroundThe development of highly active drugs has improved the survival of melanoma patients, but elevated drug prices place a significant burden on health care systems. In Spain, the public health care system is transferred to the 17 autonomous communities (AACC). The objective of this study is to describe the situation of drug access for melanoma patients in Spain and how this decentralized system is affecting equity.MethodsFrom July to September 2023, a cross-sectional survey was sent to members of the Spanish Multidisciplinary Melanoma Group (GEM Group). The questionnaire consulted about the real access to new drugs in each hospital. The responses were collected anonymously and analyzed according to several variables, including the AACC.ResultsThe survey was answered by 50 physicians in 15 AACC. No major differences on access between AACC were observed for indications that are reimbursed by the Spanish Health Care System (adjuvant immunotherapy for stage IIIC-IIID and resected stage IV melanoma). Important differences in drug access were observed among AACC and among centers within the same AACC, for most of the EMA indications that are not reimbursed (adjuvant immunotherapy for stages IIB-IIC-IIIA-IIIB) or that are not fully reimbursed (ipilimumab plus nivolumab in advanced stage). Homogeneously, access to adjuvant targeted drugs, TIL therapy and T-VEC, is extremely low or non-existing in all AACC.ConclusionsFor most indications that reimbursement is restricted out of the EMA indication, a great diversity on access was found throughout the different hospitals in Spain, including heterogeneity intra-AACC

Efficacy and safety of cosibelimab, an anti-PD-L1 antibody, in metastatic cutaneous squamous cell carcinoma

BACKGROUND: Programmed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab. METHODS: In this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety. RESULTS: Objective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (≥15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported. CONCLUSIONS: Cosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile. TRIAL REGISTRATION NUMBER: NCT03212404

Dabrafenib plus trametinib for compassionate use in metastatic melanoma: A STROBE-compliant retrospective observational postauthorization study

The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5-68.9%) and 36.4% (95% CI, 27.8-45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1-47.5%) and 21.6% (95% CI, 14.5-28.7%), respectively. Fifty-seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%).Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients' prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen-activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain