Melanoma is a highly aggressive skin tumor nicknamed “black cancer of the skin” because it originates from the pigment‐forming cells (melanocytes). The tumors are prone to invasive growth and early lymphogenic and hematogenic metastasis. Known risk factors are UV radiation, light skin type, the presence of multiple atypical nevi, and a positive family history. Decisive for the course of the disease are a guideline‐based diagnosis and therapy. In addition to complete excision of the primary tumor with an adequate safety margin, various systemic therapies are available. These are in particular BRAF‐targeted therapy and PD‐1‐based immune checkpoint therapy. This mini‐review does not claim to be exhaustive, but is intended to focus primarily on those aspects of the disease that are currently in clinical and scientific focus, and on which there are new developments to report. In particular, there are new therapeutic regimens for unresectable melanoma and studies of adjuvant treatments, as well as developments in diagnostics.

Melanom

Das Melanom ist ein hoch aggressiver Hauttumor mit dem Beinamen „schwarzer Hautkrebs“, da er von den pigmentbildenden Zellen (Melanozyten) ausgeht. Die Tumoren neigen zu invasivem Wachstum und früher lymphogener und hämatogener Metastasierung. Bekannte Risikofaktoren sind UV‐Strahlung, ein heller Hauttyp, das Vorhandensein multipler atypischer Nävi sowie eine positive Familienanamnese. Entscheidend für den Krankheitsverlauf sind eine leitliniengerechte Diagnostik und Therapie. Neben der vollständigen Exzision des Primärtumors mit adäquatem Sicherheitsabstand stehen verschiedene Systemtherapien zur Verfügung. Dies sind insbesondere die gegen BRAF zielgerichtete Therapie sowie die PD‐1‐basierte Immuncheckpoint‐Therapie. Das vorliegende Mini‐Review erhebt keinen Anspruch auf Vollständigkeit, sondern soll vorrangig diejenigen Aspekte der Erkrankung berücksichtigen, die derzeit im klinischen und wissenschaftlichen Fokus stehen und zu denen es neue Entwicklungen zu berichten gibt. Insbesondere gibt es neue Therapieschemata bei inoperablen Melanomen und Studien zu adjuvanten Behandlungen, aber auch Entwicklungen zur Diagnostik.

Simple Summary Melanoma represents only 1% of human skin cancers, but in several cases can lead to the death of the patient. Nowadays, there are different systemic therapies used for the treatment of human melanoma. Although these substantially improve patients’ lifespan, they are still associated with resistance. Extracellular vesicles (EVs), tiny vesicles released by tumor cells involved in intercellular communication, play an important role in melanoma pathogenesis and progression. They are crucially involved in several mechanisms of cancer drug resistance in several types of cancer, and there is a strong indication that EVs released by melanoma cells might play a role in the development of resistance, modulating the response towards anti-cancer drugs. Understanding their role will help improve the outcome of melanoma treatment. Abstract Extracellular vesicles (EVs) are involved in the pathogenesis of neoplastic diseases. Their role in mediating drug resistance has been widely described in several types of cancers, including melanoma. EVs can mediate drug resistance through several different mechanisms, such as drug-sequestration, transfer of pro-survival proteins and RNA, induction of cancer stem cell-like features and interaction with cells of the tumor microenvironment and immune-system. Melanoma is a highly immunogenic tumor originating from the malignant transformation of melanocytes. Several therapeutic strategies currently used in the treatment of melanoma and the combination of BRAF and MEK-inhibitors, as well as immune check-point inhibitors (ICI), have consistently improved the overall survival time of melanoma patients. However, the development of resistance is one of the biggest problems leading to a poor clinical outcome, and EVs can contribute to this. EVs isolated from melanoma cells can contain “sequestered” chemotherapeutic drugs in order to eliminate them, or bioactive molecules (such as miRNA or proteins) that have been proven to play a crucial role in the transmission of resistance to sensitive neoplastic cells. This leads to the hypothesis that EVs could be considered as resistance-mediators in sensitive melanoma cells. These findings are a pivotal starting point for further investigations to better understand EVs’ role in drug resistance mechanisms and how to target them. The purpose of this review is to summarize knowledge about EVs in order to develop a deeper understanding of their underlying mechanisms. This could lead to the development of new therapeutic strategies able to bypass EV-mediated drug-resistance in melanoma, such as by the use of combination therapy, including EV release inhibitors.

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Extracellular Vesicles in Cancer Drug Resistance: Implications on Melanoma Therapy

Nearly half of advanced melanoma patients do not achieve a clinical response with anti-programmed cell death 1 protein (PD1) therapy (i.e. primary resistance) or initially achieve a clinical response but eventually progress during or following further treatment (i.e. secondary resistance). A consensus definition for tumor resistance to anti-PD1 monotherapy was published by Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce (SITC) in 2020. A systematic literature review (SLR) of clinical trials and observational studies was conducted to characterize the proportions of advanced melanoma patients who have progressed on anti-PD1 therapies. The SLR included 55 unique studies and the SITC definition of primary resistance was applied to 37 studies that specified disease progression by best overall response. Median and range of patients with primary resistance in studies that specified first-line and second-line or higher anti-PD1 monotherapy was 35.50% (21.19–39.13%; n = 4 studies) and 41.54% (30.00–56.41%, n = 3 studies); median and range of patients with primary resistance in studies that specified first-line and second-line or higher combination therapy was 30.23% (15.79–33.33%; n = 6 studies), and 70.00% (61.10–73.33%; n = 3 studies). Primary resistance to anti-PD1 monotherapies and when in combination with ipilimumab are higher in patients receiving second-line or higher therapies, in patients with acral, mucosal, and uveal melanoma, and in patients with active brain metastases. The percentage of patients with primary resistance was generally consistent across clinical trials, with variability in resistance noted for observational studies. Limitations include applying the SITC definitions to combination therapies, where consensus definitions are not yet available. Future studies should highly consider utilizing the SITC definitions to harmonize how resistance is classified and facilitate meaningful context for clinical activity.

Resistance to anti-PD1 therapies in patients with advanced melanoma: systematic literature review and application of the Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce anti-PD1 resistance definitions

CO123 Health-Related Quality of Life (HRQOL) Among Mucopolysaccharidoses (MPS) Patients Receiving Enzyme Replacement Therapy (ERT): A Systematic Literature Review

HTA4 Applicability of Willingness to Pay Thresholds for Oncology Drugs: A Review of Submissions Made to the Canadian Agency for Drugs and Technologies in Health

A. Mynzhassarova

Papers

Resistance to anti-PD1 therapies in patients with advanced melanoma: systematic literature review and application of the Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce anti-PD1 resistance definitions

CO123 Health-Related Quality of Life (HRQOL) Among Mucopolysaccharidoses (MPS) Patients Receiving Enzyme Replacement Therapy (ERT): A Systematic Literature Review

HTA4 Applicability of Willingness to Pay Thresholds for Oncology Drugs: A Review of Submissions Made to the Canadian Agency for Drugs and Technologies in Health