Ying Jin ORCID: orcid.org/0000-0001-7105-3052,Run-Jie Huang,Wen-Long Guan,Zhi-Qiang Wang,Zong-Jiong Mai,Yu-Hong Li,Jian Xiao,Xing Zhang,Qi Zhao ORCID: orcid.org/0000-0002-8683-6145,Shi-Fu Chen,Ming Liu,Yan-Xia Shi,Feng Wang ORCID: orcid.org/0000-0001-7668-9674 &…Rui-Hua Xu ORCID: orcid.org/0000-0001-9771-8534

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.

https://doi.org/10.1038/s41392-024-01939-5

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