Toripalimab, an immune checkpoint inhibitor, has demonstrated promising anti-tumor activity in a Phase II clinical trial involving patients with advanced solid tumors harboring mutations in polymerase epsilon (POLE) or POLD1. The study, which enrolled 15 patients with various cancer types including colorectal adenocarcinoma, renal medullary carcinoma, and endometrial cancer, showed an overall response rate (ORR) of 21.4% (95% CI: 4.7-50.8%) and a disease control rate (DCR) of 57.1% (95% CI: 28.9-82.3%).
The trial included patients with locally advanced or metastatic disease who had progressed on prior treatments and had confirmed germline or somatic POLE/POLD1 mutations. The median age of the patients was 50 years (range 24-72), and most had stage IV disease.
Anti-Tumor Activity
The observed objective responses included one complete response and two partial responses. Notably, patients with POLE exonuclease domain mutations (EDMs) exhibited a higher ORR of 66.7% and a DCR of 66.7%, compared to 9.1% and 54.5% respectively for those with non-EDM mutations. According to the study, three patients with POLE-EDMs were likely oncogenic or functional mutation/hypermutation, two of them (66.7%) achieved an objective response.
The median overall survival (OS) was 17.9 months (95% CI: 13.5-NR), and the median progression-free survival (PFS) was 2.5 months (95% CI: 1.4-NR).
Treatment-Related Adverse Events
Treatment-related adverse events (TRAEs) were reported in 60% of patients, with 20% experiencing grade 3 or higher events. One patient (6.7%) experienced a grade 5 adverse event (hepatic hemorrhage and hepatic failure) deemed related to treatment. Common TRAEs included elevated transaminase (33.3%), anemia (20.0%), and hypothyroidism (20.0%).
POLE/POLD1 Mutations and Co-Mutations
Further analysis revealed that co-mutation of PBRM1 with POLE/POLD1 was associated with a significantly higher tumor mutational burden (TMB) and increased expression of immunotherapy response signatures. Specifically, three out of four patients harboring PBRM1 gene mutation responded to immunotherapy (Fisher’s Exact Test P = 0.024).
ctDNA Monitoring
Monitoring circulating tumor DNA (ctDNA) dynamics, specifically POLE variant allele frequency (VAF), showed potential as a tool for tracking treatment response and disease progression in patients with somatic POLE mutations. In two responders, POL VAF was detected at an extremely low level before treatment (0.63% and 0.52%), and it remained undetectable throughout the clinical response. For patient SYSUCC06, the POL VAF remained at an almost undetectable level before the second dose of treatment, but then dramatically increased from 4.1% to 25.3% when the volume of the tumor increased.
These findings suggest that toripalimab may offer a valuable treatment option for patients with advanced solid tumors harboring specific POLE/POLD1 mutations, particularly those with exonuclease domain mutations or co-occurring PBRM1 mutations. The study also highlights the potential of ctDNA monitoring to inform treatment decisions and assess disease dynamics.
