Tebentafusp 100micrograms/0.5ml solution for infusion vials

Background: Metastatic uveal melanoma (mUM) is an aggressive malignancy with a dismal prognosis, posing a severe threat to patients' survival and quality of life. In recent years, tebentafusp, a novel immunotherapeutic agent, has demonstrated promising potential in the management of mUM. However, inconsistencies and controversies persist in the findings of related research. This meta-analysis seeks to synthesize existing studies to more comprehensively and accurately assess the efficacy (with a primary focus on overall survival [OS]) and safety of tebentafusp in treating this disease. Methods: Systematic searches were conducted across databases including PubMed, Embase, and the Cochrane Library. Literature screening was performed rigorously in line with predefined inclusion and exclusion criteria, while the quality of included studies was assessed using the Minors scale. To ensure accuracy, data extraction was carried out independently by two researchers. Results: This meta-analysis included 18 studies meeting predefined criteria, encompassing patients with mUM treated with tebentafusp. These comprised 3 randomized controlled trials (RCTs) and 15 single-arm studies, with sample sizes ranging from 10 to 252 participants, and most patients being HLA-A*02:01 positive. The pooled complete response (CR) rate across 3 studies was 0.01 (1%, 95%CI: -0.01 to 0.01, p=0.18). For 15 studies, the pooled partial response (PR) rate was 0.07 (7%, 95%CI: 0.06 to 0.09, p<0.00001), and the pooled stable disease (SD) rate was 0.34 (34%, 95%CI: 0.26 to 0.41, p<0.00001), though significant heterogeneity was observed for SD (I²=84%).Across 15 studies, ORR ranged from 4.7% to 21.7%, with a pooled rate of 0.07 (7%, 95%CI: 0.06 to 0.09, p<0.0001) and low heterogeneity (I²=34%).For 16 studies, the pooled DCR was 0.46 (46%, 95%CI: 0.40 to 0.53, p<0.0001) with significant heterogeneity (I²=77%).The pooled 1-year overall survival (OS) rate across 9 studies was 0.69 (69%, 95%CI: 0.66-0.72, p<0.0001); the 2-year OS across 3 studies was 0.42 (42%, 95%CI: 0.38-0.46, p<0.0001); and the 3-year OS across 2 studies was 0.26 (26%, 95%CI:0.21-0.30, p<0.0001). Pooled median progression-free survival (PFS) across 10 studies was 2.74 months(95%CI: 2.58-2.90), and median OS across 4 studies was 19.78 months(95% CI:17.79-21.77). The pooled incidence of grade ≥3 treatment-related adverse events (TRAE) across 7 studies was 0.40 (40%, 95%CI:0.16-0.63, p=0.001) with high heterogeneity (I²=98%).The pooled incidence of cytokine release syndrome (CRS) across 8 studies was 0.86 (86%, 95%CI: 0.83-0.89, p<0.0001) with moderate heterogeneity (I²=54%). Subgroup analysis showed patients with no previous treatment received had higher PR (0.11 vs. 0.06 in previously treated patients), ORR (0.11 vs. 0.07 in previously treated patients), 1-year OS (0.72 vs. 0.63 in previously treated patients), and 2-year OS (0.45 vs. 0.39 in previously treated patients). Conclusions: Tebentafusp exhibits significant clinical efficacy in mUM, with its greatest value reflected in improving long-term survival (1-year, 2-year, and 3-year OS) - a finding consistent with its FDA approval basis. While ORR and DCR provide supplementary evidence of therapeutic benefit, radiological response rates (e.g., CR, PR) are limited in fully capturing its clinical value. Safety concerns include high CRS incidence (mostly low-grade and manageable) and variable grade ≥3 TRAE rates. No previous treatment received patients may derive greater benefits. Limitations (heterogeneity, HLA-A*02:01 restriction, limited long-term data) highlight the need for more high-quality studies to validate long-term efficacy/safety, expand applicability to broader populations, and explore combination therapies. Additionally, circulating tumor DNA (ctDNA) may serve as a more sensitive efficacy biomarker than radiological responses, warranting further investigation. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251084090.

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ABSTRACT Metastatic uveal melanoma (mUM) is a rare disease associated with poor prognosis and limited therapeutic options. Recent studies showed that detecting ctDNA is feasible and can aid treatment decisions for patients with mUM. We systematically searched PubMed, EMBASE, and Cochrane databases for eligible studies published up to May 2025 that included patients with mUM and reported data on the association between ctDNA and survival outcomes (OS and PFS). Statistical analyses were performed using Review Manager 5.4 software. Of the initial 450 records, seven studies met eligibility, including 518 patients with mUM. At baseline, ctDNA positivity was associated with significantly worse PFS (HR 2.34; 95% CI 1.56–3.51; p &lt; 0.01; I 2 = 0%) and OS (HR 3.32; 95% CI 2.09–5.29; p &lt; 0.01; I 2 = 48%). In patients treated with tebentafusp, ctDNA clearance was associated with superior OS (HR 0.19; 95% CI 0.07–0.49; p &lt; 0.01; I 2 = 46%) and any decrease in ctDNA was associated with better OS (HR 0.42; 95% CI 0.22–0.80; p &lt; 0.01; I 2 = 0%). This meta‐analysis underscores ctDNA as a potential predictor of worse survival in patients with mUM, highlighting its potential to refine risk stratification and guide treatment strategies. Trial Registration: International Prospective Register of Systematic Reviews (PROSPERO): CRD42025638076

Abstract licence: CC BY-NC-ND

BACKGROUND: Uveal melanoma, a rare and aggressive intraocular malignancy, poses significant challenges due to its high metastatic potential. Tebentafusp, an innovative immunotherapy targeting melanoma-associated antigens, has shown promise in early clinical trials for metastatic uveal melanoma. METHODS: This systematic review adhered to PRISMA guidelines, analyzing four studies encompassing 475 patients until January 18, 2024. Meta-analysis techniques, utilizing RevMan software version 5.4, were employed to calculate hazard ratios (HR) or risk ratios (RR) with their respective 95% confidence intervals for each outcome. RESULTS: The 1-year overall survival rate, pooled from the included studies, was 68% with moderate heterogeneity (I2=56%, p=0.1). Cytokine release syndrome was observed in 83% of patients across three studies, with high heterogeneity (I2=79%, p<0.01). CONCLUSION: Our findings underscore modest responses and manageable adverse effects such as cytokine release syndrome and fatigue, highlighting the necessity for careful monitoring and proactive management in the clinical application of Tebentafusp for metastatic uveal melanoma.

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Metastatic disease from uveal melanoma occurs in almost 50% of patients suffering from this ocular tumour, with median survival from development of symptoms being around 1 year. In contrast to cutaneous melanoma, kinase inhibitors and immune checkpoint inhibitors are usually ineffective in patients with metastatic uveal melanoma. Tebentafusp is a novel form of immunotherapy based on the immune-mobilising monoclonal T cell receptor against cancer (ImmTAC) platform, which comprises a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment. The T cell receptor domain of tebentafusp targets cells present a human leukocyte antigen-A*02:01 complexed with a peptide derived from the melanoma-associated antigen gp100, which is expressed strongly by melanoma cells, weakly by normal melanocytes and minimally by other tissues. The anti-CD3 domain recruits CD3+ T cells (and, indirectly, other immune cells), redirecting these to the melanoma cells. The most common adverse events with tebentafusp are manageable and usually transient. Early survival data in patients with metastatic uveal melanoma are promising when considered alongside historical data. Based on these encouraging results, a randomised study comparing tebentafusp to investigator's choice of therapy in metastatic uveal melanoma is ongoing.

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