A phase II clinical trial of toripalimab in advanced solid tumors with POLE/POLD1 mutation.

802 Background: Prior studies indicated that polymerase epsilon/polymerase delta (POLE/POLD1) exonuclease domain mutations (POL-EDMs) was associated with the efficacy of immune checkpoint inhibitor (ICI). However, there remains controversy about whether patients with POLE/POLD1 non-exonuclease domain mutations (POLE-non-EDMs), which occupied the majority of POLE/POLD1 mutations, could benefit from ICI. Currently, few prospective clinical trials have evaluated the predictive value of POLE/POLD1 mutation in ICI. Methods: We initiated a phase II clinical trial for non-microsatellite instability-high (non-MSI-H) patients with POLE/POLD1 mutant advanced solid tumors to investigate the treatment efficacy of toripalimab, an anti-PD-1 antibody. Eligible patients received one dose of 240mg toripalimab every three weeks for up to two years until disease progression or intolerable toxicity occurred. The primary endpoint was overall response rate, and secondary endpoints included disease control rate, overall survival, progression-free survival, and safety. Treatment responses were assessed using the RECIST v1.1 after each six-week treatment cycle. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. This study is registered on ClinicalTrials.gov, NCT03810339. Results: A total of 15 patients were enrolled to receive treatment, of whom 14 underwent response assessment. The overall response rate was 21.4%, and the disease control rate was 57.1%. The median overall survival and median progression-free survival were 2.5 months and 28.2 months, respectively. The overall response rate of the patients with POL-EDMs and POL-non-EDMs were 66.7% and 7.1%, while the disease control rates were 66.7% and 54.5%, respectively. Grade three or four treatment-related adverse events occurred in 20% of patients. Conclusions: This study showed that patients with POL-EDMs had a good response to ICI therapy, and those with POL-non-EDMs could clinically benefit from anti-PD-1 antibody monotherapy, urging the need for more investigations on immunotherapy combined with chemotherapy in patients with POL-non-EDMs. Clinical trial information: NCT03810339 .