BACKGROUND: Immune checkpoint inhibitors (ICIs) such as PD(L)1 and CTLA4 antibodies as well as targeted therapies such as BRAF and MEK inhibitors have significantly improved the systemic treatment of skin cancer in adjuvant and advanced therapy settings. All these drugs differ in their spectrum of side effects.
METHODS: The aim of this article is to provide an overview of the spectrum of side effects of dermato-oncological therapies and their management, taking into account the current literature.
RESULTS: The most important side effects of ICIs, the CCR4 inhibitor mogamulizumab, the ImmTAC tebentafusp, the BRAF and MEK inhibitors and the multityrosine kinase inhibitor imatinib are considered.
CONCLUSIONS: Side effects can manifest themselves in all organ systems. Chronic side effects and long-term harm are possible, especially with ICIs, and require close therapy monitoring and patient education. Knowledge of the side effects and the temporal, sometimes delayed course of their occurrence are essential for diagnosis and prompt initiation of therapy.
UNASSIGNED: HINTERGRUND: Immuncheckpointblocker (ICB) wie PD-(L)1- und CTLA-4-Antikörper sowie zielgerichtete Therapeutika wie BRAF(v-raf murine sarcoma viral oncogene homolog B1)- und MEK(Mitogen-aktivierte Proteinkinase-Kinase)-Inhibitoren haben die systemische Therapie von Hauttumoren in adjuvanter und lokal fortgeschrittener Therapiesituation maßgeblich verbessert. All diese Substanzen unterscheiden sich in ihrem Nebenwirkungsspektrum.
METHODS: Ziel dieses Beitrags ist es, eine Übersicht über das gesamte Spektrum der Nebenwirkungen dermatoonkologischer Therapien und ihres Managements unter Berücksichtigung der aktuellen Literatur zu geben.
UNASSIGNED: Es werden die wichtigsten Nebenwirkungen unter ICB, dem CCR4-Inhibitor Mogamulizumab, dem ImmTAC („immune mobilising monoclonal T‑cell receptors against cancer“) Tebentafusp, den BRAF-und MEK-Inhibitoren und dem Multityrosinkinaseinhibitor Imatinib betrachtet.
UNASSIGNED: Nebenwirkungen können sich in allen Organsystemen manifestieren. Chronische Nebenwirkungen und Langzeitschäden sind v. a. unter ICB möglich und bedürfen einer engmaschigen Therapieüberwachung und Patientenedukation. Die Kenntnis der Nebenwirkungen und der zeitliche, teils verzögerte Verlauf des Auftretens sind für die Diagnosestellung und die zeitnahe Therapieeinleitung unerlässlich.

BACKGROUND: Uveal melanoma is a rare cancer, in which metastases occur in approximately one half of cases. In metastatic disease, the prognosis is unfavorable and the median of survival does not exceed 6 months. Effective treatment options were very limited up to date. Tebentafusp is a bispecific fusion protein, which as the first drug proved efficacy in uveal melanoma.
METHODS: The patient was referred for suspected uveal melanoma of the left eye. She was treated for Hodgkin\'s disease in the past. Primarily, the tumor was treated by radiosurgery with radiotherapy of a small lesion of the vertebral body. However, later the patient had to undergo bulbus enucleation with confirmation of a large tumor category pT4b. PET/CT revealed metastases of the bones and the liver; simultaneously, haplotype A*02: 01 was confirmed. The patient underwent radiotherapy of the sternum and later, after confirmation of payment from the health insurance company, she started treatment with tebentafusp. The first three doses were administered during admission to the hospital, with a need to treat cytokine release syndrome by corticosteroids. Later, the administration was performed in an out-patient regimen, without complications, except for a transient elevation of transaminases. The first CT restaging confirmed stable disease; however, the second restaging confirmed a new osteolytic lesion in the processus of Th11. Because of progression, the treatment with tebentafusp was withdrawn after 6 months. Unfortunately, the lesion could not be treated by radiotherapy. Two months later, the patient was urgently admitted to the hospital because of right-sided hemiplegia; MRI revealed bleeding metastatic lesion in the brain stem.
CONCLUSIONS: In this case report, we present the case of the first patient treated with this drug in the Czech Republic.

Uveal melanoma (UM) is a rare subtype of melanoma, accounting for less than 5% of all melanoma cases. Metastatic UM differs notably from cutaneous melanoma, exhibiting variations in etiology, prognosis, driver mutations, metastatic patterns, and poor responses to immune checkpoint inhibitors (ICI). Beyond local treatment options, such as resection, radiation therapy, and enucleation, and systemic treatments, such as ICIs, the approval of tebentafusp, a bispecific gp100 peptide-HLA-directed CD3 T-cell engager, marks a breakthrough in treating HLA-A*02:01 metastatic UM. Despite the advancements in treatment options, the long-term survival rates remain inadequate. We report a patient with metastatic UM who previously received ICI and progressed on tebentafusp treatment but subsequently exhibited a remarkable response to local treatment targeting liver metastasis. Such observations highlight the significance of exploring sequential therapeutic strategies for advanced UM, offering potential avenues to enhance treatment efficacy and patient prognosis.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Conventional methods of UM treatment are based on chemotherapy and radiotherapy, which have been able to control tumor growth in a limited way. But due to the inadequacy and many side effects of these treatments, many UM patients die during treatment, and approximately 50% of patients develop metastasis. Meanwhile, the 2-year survival rate of these patients from the time of metastasis is 8%. Since immunotherapy has the potential to be the most specific and efficient method in the treatment of tumors, it is considered an attractive and promising research field in the treatment of UM. This review highlights recent advances in UM immunotherapy and provides new immunological approaches on how to overcome the challenges of UM immunotherapy.

BACKGROUND: Tebentafusp demonstrated a superior overall survival (OS) benefit [hazard ratio (HR) 0.51] compared to investigator\'s choice (82% pembrolizumab) in a randomized, phase III trial (IMCgp100-202; N = 378) in untreated metastatic uveal melanoma (mUM). The 1-year OS rates for tebentafusp and pembrolizumab were 73% and 59%, respectively. In the single-arm GEM1402 (N = 52), the 1-year OS rate for nivolumab plus ipilimumab (N+I) in mUM was 52%. Due to limitations in conducting randomized trials in mUM, we compared OS on tebentafusp or pembrolizumab (IMCgp100-202) to N+I (GEM1402) in untreated mUM using propensity scoring methods.
METHODS: Analyses were adjusted using propensity score-based inverse probability of treatment weighting (IPTW), balancing age, sex, baseline lactate dehydrogenase (LDH), baseline alkaline phosphatase, disease location, Eastern Cooperative Oncology Group status, and time from primary diagnosis to metastasis. OS was assessed using IPT-weighted Kaplan-Meier and Cox proportional hazard models. Sensitivity analyses using alternative missing data and weights methods were conducted.
RESULTS: The primary IPTW analysis included 240 of 252 patients randomized to tebentafusp from IMCgp100-202 and 45 of 52 N+I-treated patients from GEM-1402. Key baseline covariates, including LDH, were generally well balanced before weighting. The IPTW-adjusted OS favored tebentafusp, HR 0.52 [95% confidence interval (CI) 0.35-0.78]; 1-year OS was 73% for tebentafusp versus 50% for N+I. Sensitivity analyses showed consistent superior OS for tebentafusp with all IPTW HRs ≤0.61. IPTW analysis of pembrolizumab versus N+I showed no significant difference in OS (HR 0.72; 95% CI 0.50-1.06).
CONCLUSIONS: Tebentafusp was previously shown to provide an OS benefit compared to checkpoint inhibitors or chemotherapy in untreated mUM. Propensity score analysis demonstrated a similar OS benefit for tebentafusp compared with N+I. These data further support tebentafusp as the standard of care in previously untreated human leukocyte antigen (HLA)-A∗02:01+ adult patients with mUM.

Tebentafusp, a bispecific T-cell receptor fusion protein directed against gp100 and CD3, can improve survival in patients with metastatic uveal melanoma and was recently approved for the treatment of HLA-A*02:01-positive uveal melanoma patients. Since tebentafusp often induces cytokine-release syndrome, doses must be escalated and patients monitored as inpatients after the first infusions. The occurrence of tumor lysis syndrome, a potentially life-threatening condition, after administration of a single dose of tebentafusp, is reported here. With adequate therapy, including the application of rasburicase, the patient made a full recovery. It is important to raise awareness of the adverse event profile of this new therapeutic approach among healthcare professionals to promptly recognize and treat side effects.
Tebentafusp is a new treatment for a type of eye cancer called uveal melanoma. It helps the body\'s defense system fight against cancer cells and has shown promise in helping patients live longer. However, not all patients with uveal melanoma can use this treatment. Only those who have a specific gene marker called HLA-A*02:01-positive can benefit from it. Like any new treatment, tebentafusp may have some side effects. One of them is called cytokine-release syndrome, which can cause symptoms like rash, fever and flu-like feelings. Usually, this side effect is not serious and can be treated well. There was a rare but serious case where one patient had a bad reaction after getting only one dose of tebentafusp. This reaction is called tumor lysis syndrome, which happens when cancer cells break down quickly and release harmful substances into the blood. This can be life-threatening. Thankfully, the patient received the right treatment and got better. This information is shared here with doctors and patients, so they know about possible side effects and can use tebentafusp safely.

Tebentafusp is a new T cell receptor bispecific fusion protein and the first approved treatment option for human leucocyte antigen-A*02:01 (HLA-A*02:01) metastatic uveal melanoma, with a proven benefit in overall survival versus the investigator\'s choice. As a first-in-class therapeutic option, this Immune mobilising monoclonal T cell receptor Against Cancer (ImmTAC) is associated with a new adverse event (AE) profile. Based on clinical experience, a national expert group discussed recommendations for tebentafusp treatment, focusing on AE management. Further topics included prerequisites for initiating tebentafusp treatment, appropriate treatment setting, and patient selection criteria. To provide guidance for treating physicians, the resulting recommendations are summarised including a model standard operating procedure for AE management. Patients in good clinical condition and with a low tumour burden are good candidates for tebentafusp treatment, particularly if treated as early as possible after the diagnosis of metastatic disease. The safety profile of tebentafusp is manageable and includes two major pathologies: cytokine release syndrome (CRS) and skin-related events. Postdose monitoring should thus focus on pyrexia and hypotension as the first symptoms of cytokine release. To minimise the risk of hypotension associated with CRS, patients should receive intravenous fluids before starting treatment. The monitoring of liver values is crucial, as patients may experience an increase in transaminases, which can even manifest as tumour lysis syndrome.

Uveal melanoma (UM) is the most common ocular malignancy in adults, associated with the poorest prognosis, with metastatic disease occurring in up to 50% of patients. In contrast to metastatic cutaneous melanoma, the use of immune checkpoint inhibitors is associated with poor outcomes in metastatic uveal melanoma (mUM). Tebentafusp, a bispecific molecule, has recently become the first treatment in decades to improve overall survival for mUM. This review summarises the existing and emerging immuno-oncology approaches for the treatment of mUM, and biomarkers of response and resistance to the same. Finally, we propose future research directions that could maximise treatment benefit to a wider pool of patients with UM.

Uveal melanoma (UM), also known as choroidal melanoma, is the leading adult intraocular tumor worldwide, affecting mainly Caucasian populations. The last decade has seen an improvement in the outcome of these tumors at the localized stage, in favor of conservative treatment of the eye, notably with new radioactive treatment techniques. Despite optimal management, half of the patients will become metastatic, with liver involvement in 90% of cases. The prognosis is pejorative and considers clinical, tumor anatomy, histological and molecular parameters. This review provides a broad overview of the different therapeutic options for the management of localized or metastatic UM disease, with recently updated data. Despite the known limited efficacy of chemotherapy and immune checkpoint inhibitors (ICI), we discuss the first results of combined immunotherapies, the arrival of a new first-in-class immunomodulatory treatment Tebentafusp, in HLA-A*02:01 patients, avenues of research into targeted anti-tyrosine kinase therapies, and the growing use of ctDNA to guide treatment prescription.

BACKGROUND: Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting.
METHODS: This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM.
RESULTS: Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient.
CONCLUSIONS: Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence.