In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2–10%), the 1 year overall survival rate was 62% (95% CI: 53–70%) with a median overall survival of 16.8 months (95% CI: 12.9–21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.

在先前接受过治疗的转移性葡萄膜黑色素瘤患者中，历史 1 年总生存率为 37%，中位总生存期为 7.8 个月。我们在 127 名治疗难治性转移性葡萄膜黑色素瘤 (NCT02570308) 患者中对 tebentafusp（一种可溶性 T 细胞受体双特异性 (gp100×CD3)）进行了多中心、单臂、开放标签 2 期研究。主要终点是基于 RECIST（实体瘤反应评估标准）v1.1 的客观反应率估计。次要目标包括安全性、总生存期、无进展生存期和疾病控制率。所有患者都至少出现一种与治疗相关的不良事件，其中最常见的是皮疹 (87%)、发热 (80%) 和瘙痒 (67%)。毒性的严重程度大多为轻度至中度，但在最初的三个剂量后，毒性的发生率和强度大大降低。尽管总体缓解率较低，仅为 5%（95% CI：2-10%），但 1 年总体生存率为 62%（95% CI：53-70%），中位总体生存期为 16.8 个月（95% CI：12.9–21.3），表明其益处超出了传统的基于射线照相的反应标准。在一项探索性分析中，早期治疗中循环肿瘤 DNA 的减少与总生存期密切相关，即使在影像学进展的患者中也是如此。我们的研究结果表明，tebentafusp 在先前接受过治疗的转移性葡萄膜黑色素瘤患者中具有良好的临床活性和可接受的安全性，