A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta(POLE/POLD1)mutation

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.