携带聚合酶ε/聚合酶δ突变的患者对免疫检查点抑制剂表现出阳性反应。然而，仍然缺乏探索对聚合酶ε/聚合酶δ突变患者的疗效的前瞻性试验。启动了一项 II 期临床试验，以评估特瑞普利单抗（一种针对人 PD-1 的人源化 IgG4K 单克隆抗体）对具有未选择的聚合酶 ε/聚合酶 δ 突变但不存在微卫星不稳定性高的晚期实体瘤患者的疗效。共有 15 名患者入组，其中 14 名患者接受了治疗效果评估。总体缓解率为 21.4%，疾病控制率为 57.1%。中位总生存期和中位无进展生存期分别为 17.9（95% CI 13.5 - 未达到）个月和 2.5（95% CI 1.4 - 未达到）个月。对于核酸外切酶结构域突变的患者，客观缓解率为66.7%（2/3），疾病控制率为66.7%（2/3）。对于那些具有非核酸外切酶结构域突变的人，发生率分别为 9.1% (1/11) 和 54.5% (6/11)。值得注意的是，PBRM1 基因突变的患者对特瑞普利单抗的反应率高达 75.0% (3/4)。这项研究表明，核酸外切酶结构域突变和非核酸外切酶结构域突变都不能完全预测免疫治疗的疗效，因此需要进行更多研究来阐明聚合酶 epsilon/聚合酶 delta 突变变体中潜在的免疫敏化差异。© 2024。作者（ s）。

Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors. Yet, prospective trials exploring the efficacy in those with polymerase epsilon/polymerase delta mutations are still lacking. A phase II clinical trial was initiated to evaluate the efficacy of toripalimab, a humanized IgG4K monoclonal antibody to human PD-1, in patients with advanced solid tumors with unselected polymerase epsilon/polymerase delta mutations but without microsatellite instability-high. A total of 15 patients were enrolled, 14 of whom were assessed for treatment efficacy. There was a 21.4% overall response rate, with a disease control rate of 57.1%. The median overall survival and median progression-free survival were 17.9 (95% CI 13.5-not reach) months and 2.5 (95% CI 1.4-not reach) months, respectively. For patients with exonuclease domain mutations, the objective response rate was 66.7% (2/3), with a disease control rate of 66.7% (2/3). For those with non-exonuclease domain mutations, the rates were 9.1% (1/11) and 54.5% (6/11), respectively. Notably, patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0% (3/4). This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy, urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants.© 2024. The Author(s).