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Updated: Jun 14, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta
Ying Jin1,2, Run-Jie Huang1,2, Wen-Long Guan1,2
1Department 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.
Abstract:
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.
Insights
Immune checkpoint inhibitors show promise for patients with polymerase epsilon/delta mutations. This Phase II trial found toripalimab yielded a 21.4% response rate, with higher efficacy in exonuclease domain mutations and PBRM1 mutations.
Area of Science:
- Oncology
- Immunotherapy
- Genetics
Background:
- Patients with polymerase epsilon (POLE) or polymerase delta (POLD) mutations have shown responses to immune checkpoint inhibitors.
- Prospective trials evaluating immunotherapy efficacy in this patient group are limited.
- Microsatellite instability-high (MSI-H) status is a known predictor of immunotherapy response, and this study excluded such patients.
Purpose of the Study:
- To evaluate the efficacy of toripalimab, an anti-PD-1 antibody, in patients with advanced solid tumors harboring POLE/POLD mutations.
- To assess treatment response in patients without MSI-high status.
- To explore the correlation between specific mutation types (exonuclease domain vs. non-exonuclease domain, PBRM1) and treatment outcomes.
Main Methods:
- A Phase II clinical trial enrolled 15 patients with advanced solid tumors and POLE/POLD mutations.
- Patients were treated with toripalimab, a humanized IgG4K monoclonal antibody targeting PD-1.
- Treatment efficacy was assessed in 14 patients, with subgroup analyses based on mutation location and PBRM1 status.
Main Results:
- The overall response rate (ORR) was 21.4%, and the disease control rate (DCR) was 57.1%.
- Median overall survival (mOS) was 17.9 months, and median progression-free survival (mPFS) was 2.5 months.
- Patients with exonuclease domain mutations had a higher ORR (66.7%) compared to non-exonuclease domain mutations (9.1%). Patients with PBRM1 mutations showed a 75.0% response rate.
Conclusions:
- Toripalimab demonstrated activity in advanced solid tumors with POLE/POLD mutations, even in the absence of MSI-high status.
- Exonuclease domain mutations and PBRM1 mutations may be associated with better responses, but do not fully predict immunotherapy efficacy.
- Further research is needed to understand the nuances of immune sensitization across different POLE/POLD mutation variants.
