英国弗农山癌症中心Paul Nathan团队研究了Tebentafusp治疗转移性葡萄膜黑色素瘤的总体生存效益。这一研究成果发表在2021年9月22日出版的《新英格兰医学杂志》上。

葡萄膜黑色素瘤是一种不同于皮肤黑色素瘤的疾病，转移性葡萄膜黑色素瘤患者的肿瘤突变负荷低，1年总生存率约为50%。缺乏相关数据表明系统治疗对总体生存期有益。Tebentafusp是一种双特异性蛋白质，由亲和增强的T细胞受体与抗CD3效应体融合而成，可将T细胞靶向糖蛋白100阳性细胞。

在这项开放标签的3期临床试验中，研究组招募先前未经治疗的HLA-A*02:01-阳性转移性葡萄膜黑色素瘤患者，将其按2：1随机分组，分别接受tebentafusp或研究者选择的单药派姆单抗、伊匹单抗或达卡巴嗪治疗（对照组），根据乳酸脱氢酶水平分层。主要终点是总生存率。

研究组共招募到378名患者，其中tebentafusp组252名，对照组126名。在意向治疗人群中，tebentafusp组的1年总生存率为73%，显著高于对照组的59%。Tebentafusp组6个月时的无进展生存率为31%，显著高于对照组的19%。Tebentafusp组最常见的治疗相关不良事件是细胞因子介导的事件（由于T细胞激活），以及皮肤相关事件（由于糖蛋白100-阳性黑素细胞），包括皮疹（83%）、发热（76%）和瘙痒（69%）。这些不良事件的发生率和严重程度在前三次或四次给药后有所下降，很少导致试验治疗的中断（2%）。无治疗相关死亡报告。

研究结果表明，在先前未经治疗的转移性葡萄膜黑色素瘤患者中，使用tebentafusp治疗与对照治疗相比，总生存期更长。

附：英文原文

Title: Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

Author: Paul Nathan, M.D., Ph.D.,, Jessica C. Hassel, M.D.,, Piotr Rutkowski, M.D., Ph.D.,, Jean-Francois Baurain, M.D., Ph.D.,, Marcus O. Butler, M.D.,, Max Schlaak, M.D.,, Ryan J. Sullivan, M.D.,, Sebastian Ochsenreither, M.D.,, Reinhard Dummer, M.D.,, John M. Kirkwood, M.D.,, Anthony M. Joshua, M.D., Ph.D.,, Joseph J. Sacco, M.D., Ph.D.,, Alexander N. Shoushtari, M.D.,, Marlana Orloff, M.D.,, Josep M. Piulats, M.D., Ph.D.,, Mohammed Milhem, M.D.,, April K.S. Salama, M.D.,, Brendan Curti, M.D.,, Lev Demidov, M.D.,, Lauris Gastaud, M.D.,, Cornelia Mauch, M.D., Ph.D.,, Melinda Yushak, M.D., M.P.H.,, Richard D. Carvajal, M.D.,, Omid Hamid, M.D.,, Shaad E. Abdullah, M.D.,, Chris Holland, M.S.,, Howard Goodall, M.D.,, and Sophie Piperno-Neumann, M.D.

Issue&Volume: 2021-09-22

Abstract:

Background

Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100–positive cells.

Methods

Download a PDF of the Research Summary.

In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01–positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator’s choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival.

Results

A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P=0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100–positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported.

Conclusions

Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma.

DOI: 10.1056/NEJMoa2103485

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2103485