Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.
Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People's Republic of China.
Signal Transduct Target Ther. 2024 Sep 2;9(1):227. doi: 10.1038/s41392-024-01939-5.
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.
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积极的反应。然而，仍缺乏探索聚合酶 ε/聚合酶 δ 突变患者中疗效的前瞻性试验。一项 II 期临床试验旨在评估 toripalimab（一种针对人 PD-1 的人源化 IgG4K 单克隆抗体）在未选择聚合酶 ε/聚合酶 δ 突变但无微卫星不稳定高的晚期实体瘤患者中的疗效。共纳入 15 例患者，其中 14 例评估了治疗疗效。总缓解率为 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 个月（95%CI 13.5-未达到）和 2.5 个月（95%CI 1.4-未达到）。对于外切酶结构域突变患者，客观缓解率为 66.7%（2/3），疾病控制率为 66.7%（2/3）。对于非外切酶结构域突变患者，缓解率分别为 9.1%（1/11）和 54.5%（6/11）。值得注意的是，PBRM1 基因突变患者对 toripalimab 的反应率高达 75.0%（3/4）。本研究表明，外切酶结构域突变或非外切酶结构域突变均不能完全预测免疫治疗的疗效，迫切需要进一步研究以阐明聚合酶 ε/聚合酶 δ 突变变异体中潜在的免疫致敏差异。
