Notably, ctDNA may offer valuable insights into the efficacy of T cell-engaging bispecific molecules, such as tebentafusp. The review provides a comprehensive overview of the evolving landscape of melanoma biomarkers, their role in personalizing treatment, and future research directions, including neoadjuvant immune checkpoint inhibition.

Although the bispecific tebentafusp is FDA-approved, immunotherapy has largely failed, likely given the poorly immunogenic nature of UM...In particular, the CPT1 inhibitor, etomoxir, induced propidium iodide uptake, caspase 3 cleavage and the release of HMGB1 and IL-1β, indicating that the observed cleavage of gasdermins led to pyroptosis...Together, these data show that metabolic inhibitors can induce pyroptosis in UM cell lines, potentially offering an approach to enhance inflammation-mediated immune targeting in metastatic UM patients. Implications: Induction of pyroptosis by metabolic inhibition may alter the tumor immune microenvironment and improve the efficacy of immunotherapy in uveal melanoma.

Both treatment sequences are clinically feasible. A clinical benefit was noted in the sequential combination of ICIs followed by tebentafusp. This observation is limited by the retrospective nature of the study and merits further investigation in prospective clinical trials.

P3, N=540, Recruiting, Immunocore Ltd | Trial completion date: Sep 2027 --> Jul 2028 | Trial primary completion date: Dec 2026 --> Mar 2028 | Phase classification: P2/3 --> P3

P3, N=290, Recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Not yet recruiting --> Recruiting

We also explore molecular and histological features of secondary resistance. Our case highlights that PD-1-resistant melanomas should be screened for GNAQ/11 mutations, as tebentafusp may be a treatment option in this extremely rare disease.

P2, N=19, Not yet recruiting, Thomas Jefferson University | Trial completion date: Dec 2028 --> Apr 2029 | Initiation date: Sep 2024 --> Jan 2025 | Trial primary completion date: Jun 2025 --> Oct 2025

Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells...Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape.

P1/2, N=109, Not yet recruiting, Thomas Jefferson University

P2, N=30, Not yet recruiting, University of Miami

New drugs undergoing clinical trials are mostly targeted drugs designed to inhibit the protein products of mutant genes or immunotherapeutic agents designed to stimulate the immune response against specific antigens. In addition to these approaches, potential therapeutic targets of epigenetic regulation of UM development are considered in the review.

Tebentafusp, a bispecific T cell engager (TCE) approved for metastatic UM, showed potential in clinical trials, but the objective response rate remains modest...Quantification of predictive power suggested a limited predictive power for single pre-treatment biomarkers, which was improved by early on-treatment biomarkers and combination of predictive biomarkers. Ultimately, this QSP model could facilitate biomarker-guided patient selection, improving clinical trial efficiency and UM treatment outcomes.

Tebentafusp frequently induced cutaneous reactions. Pathogenesis is likely due to binding of tebentafusp to stimulated melanocytes in the skin followed by infiltration and activation of lymphocytes. Development of treatment induced skin reactions may be associated with survival benefit.

Continued clinical trials will provide additional insights into the impact of tebentafusp on treatment-resistant metastatic cutaneous melanoma. Furthermore, we are exploring the potential of T cell engagers directed against the cancer testis antigen PRAME, which could have widespread utility in the treatment of cutaneous melanoma as well as other PRAME-expressing malignancies.

Customizing uveal melanoma surveillance to match metastatic risks could transform current practices, ensuring more precise protocols, reducing unnecessary examinations, and directing health care resources to those in greatest need.

P1/2, N=0, Withdrawn, Immunocore Ltd | N=113 --> 0 | Completed --> Withdrawn

Treatment options are limited to Tebentafusp in patients with HLA-A*02:01 mutation with immunotherapy and chemotherapy yielding poor results...In a recent phase I trial of a PRMT5 inhibitor, PRT811, clinical activity was described in cases of CAUM. 676 CAUM and 9666 CASM patients underwent hybrid capture based CGP to evaluate genomic alterations (GA)... Although MTAP loss is less frequent in CAUM than in CASM, the recent evidence that this genomic alteration predicts responsiveness to PRMT5 inhibition is noteworthy. This highlights the importance of further investigating this biomarker for patients with this rare and clinically aggressive type of cancer.

When adjusted for baseline prognostic features, patients with rash within the first week of tebentafusp treatment had the same overall survival compared to patients without a rash in the phase 3 randomized trial IMCgp100-202 (HR 0.84; 95% CI 0.53-1.32). In summary, skin rash is an off-tumour, on-target effect of tebentafusp against gp100+ melanocytes, in line with the mechanism of action.

P2; Trial completion date: Jun 2029 --> Sep 2029 | Initiation date: Jun 2024 --> Sep 2024 | Trial primary completion date: Jun 2026 --> Sep 2026

Here we show that SCIB1, a TRP-2 and gp100 directed ImmunoBody® DNA vaccine, generates a strong TRP-2 specific immune response, as demonstrated by the high number of TRP2-specific IFNγ spots produced and the detection of a significant number of pentamer positive T cells in the spleen of vaccinated mice...Time-to-death was significantly prolonged, and this correlated with increased CD4+ and CD8+ T cell infiltration in the tissue microenvironment (TME). However, in addition to PD-L1 and IDO, the GBM TME was found to contain a significant number of immunoregulatory T (Treg) cell-associated transcripts, and the presence of such cells is likely to significantly affect clinical outcome unless also tackled.

In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients...Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively). This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens.

P2, N=130, Recruiting, Scancell Ltd | N=87 --> 130

Notably, tebentafusp, an entirely novel class of anti-cancer drugs, has received official authorization for the treatment of metastatic UM. Further, promising data from targeted therapies independent of MEK-inhibitors, such as the combination of darovasertib and crizotinib, raise hope for additional options in metastatic UM in the future. This narrative review provides a timely and comprehensive overview of the current treatment landscape for metastatic UM.

This study represents the longest follow-up of a Tcell receptor bispecific to date and confirms the durable survival benefits achieved with tebentafusp in previously treated mUM with good tolerability long-term. A role for ctDNA reduction as an early indicator of clinical benefit was again suggested for patients treated with tebentafusp.

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.

Despite tebentafusp has demonstrated promising results in the treatment of uveal melanoma, the number of patients to benefit from this new approach can strongly vary by ethnic and racial issues. New strategies for the systemic treatment of advanced uveal melanoma have to be developed and tested as this disease still represents an unmet medical need.

P2, N=19, Not yet recruiting, Thomas Jefferson University

The evolving landscape includes promising systemic treatments, such as tebentafusp, a novel immune-modulating bispecific fusion protein, and targeted therapies...Although recent progress has improved outcomes, ongoing research aims to address the unique challenges of UM and develop effective therapies, particularly for HLA-A*02:01-negative patients who represent a significant unmet medical need. This review comprehensively discusses the molecular characteristics of UM, risk stratification methods, and the current and future spectrum of regional and systemic therapeutic modalities.

P2; Trial completion date: Nov 2028 --> Jun 2029 | Initiation date: Nov 2023 --> Jun 2024 | Trial primary completion date: Nov 2026 --> Jun 2026

P3, N=290, Not yet recruiting, European Organisation for Research and Treatment of Cancer - EORTC

P1/2, N=113, Completed, Immunocore Ltd | Phase classification: P1b/2 --> P1/2

Detectable ctDNA at baseline did not correlate with progression. Early response to tebentafusp may be incompletely captured by conventional imaging, leading to a need to consider both tumor morphology and metabolism.

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 HLA-A*02:01+ adult patients with mUM.

Tebentafusp-tebn (Kimmtrak), a bispecific HLA-directed CD3 T cell engager, is FDA approved specifically for patients with uveal melanoma and HLA-A*02:01, whereas HLA-A*03 is linked to resistance to checkpoint inhibitors... We successfully validated the TSO500 HT assay to genotype HLA-A, -B, and -C from tumor samples to the field 2-level required for study eligibility. By including tumor-informed HLA allele haplotypes with CGIP results, clinicians and drug developers can get a better insight of a patient's immune phenotype to aid HLA-directed therapy selection in uveal melanoma and enrollment of other tumor types in HLA-restricted clinical trials.

P1b/2, N=113, Completed, Immunocore Ltd | Active, not recruiting --> Completed | N=312 --> 113 | Trial completion date: Nov 2023 --> Jun 2023

This 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).

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. 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.

P2; N=44; Not yet recruiting; Sponsor:Diwakar Davar

P1b/2, N=312, Active, not recruiting, Immunocore Ltd | Trial completion date: Jan 2025 --> Nov 2023 | Trial primary completion date: Jan 2025 --> Jul 2023 | Recruiting --> Active, not recruiting

Metastatic uveal melanoma patients face limited treatment options and poor survival rates. Results from this retrospective analysis indicate that immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1 therapies, were associated with improved survival outcomes. Factors such as extrahepatic-only metastases, better baseline performance status, and female sex contributed to a more than 2-fold reduction in death risk. These findings highlight the potential of immunotherapy in treating metastatic uveal melanoma.

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.