Toripalimab combined with albumin-paclitaxel plus gemcitabine as first-line treatment for locally advanced or metastatic pancreatic ductal adenocarcinoma: an open-label, phase Ib/II study and investigation of potential biomarkers

Abstract

Abstract Advanced pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Immunotherapy alone offers limited efficacy, but its combination with chemotherapy could offer synergist anti-tumor effects. This phase Ib/II study evaluated the safety and efficacy of combining toripalimab with the albumin-paclitaxel plus gemcitabine (AG) regimen as first-line treatment for locally advanced or metastatic PDAC. The primary endpoints were safety and overall survival (OS). The secondary outcomes were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Immune-related biomarkers including programmed death-ligand 1 (PD-L1) expression, genetic status, cytokine levels, and immune microenvironment were investigated. Among the 72 patients enrolled, the median OS was 8.8 months, and the 12-month OS rate was 33.3%. No serious treatment-related adverse events, grade 4 immune-related adverse events, or treatment-related deaths were reported. The combination therapy led to a median PFS of 5.3 months, ORR of 33.3%, and DCR of 90.3%. Non-liver metastasis status predicted a better PFS, and the number of lesion sites and baseline CA199 level were independently associated with OS. One patient (1.4%) with mismatch repair deficiency achieved pathologic complete response and prolonged OS > 19 months. Higher PD-L1 expression was associated with a better ORR than lower expression (56.3% vs 25%), and a higher CD3 + cell density, decreased CD68 + cell infiltration, and lower baseline serum interleukin-8 level were associated with better treatment response. Overall, AG plus toripalimab exhibited a certain level of safety and probable clinical efficacy for locally advanced or metastatic PDAC, especially in some potentially advantaged subgroups.