Fibroblast inhibition by tocilizumab enabled gemcitabine/nab‐paclitaxel rechallenge for pancreatic cancer

Abstract

AbstractInterleukin‐6 (IL‐6)/signal transducer and activator of transcription 3 (STAT3) pathway inhibition may overcome chemoresistance of metastatic pancreatic cancer (MPC). We sought to determine the safety and recommended dose of tocilizumab (TCZ), an IL‐6 receptor monoclonal antibody, and biological correlates of tumor shrinkage in patients with gemcitabine (GEM)/nanoparticle albumin‐bound paclitaxel (nab‐PTX)‐refractory MPC. This phase 1 study enrolled 10 patients with MPC who had progressed after GEM/nab‐PTX. Patients initially received TCZ 8 mg/kg on Day 1 and nab‐PTX 100 mg/m2 + GEM 750 mg/m2 on Days 2, 9, and 16. Before and at the end of Cycle 1, biopsy of liver metastases was performed 3–5 h after levofloxacin (LVFX) administration to measure LVFX infiltration into tumor tissue. No dose‐limited toxicities occurred, and the recommended dosage of TCZ was determined to be 8 mg/kg. Treatment‐emergent adverse events occurred in 80% of patients, of which decreased neutrophil count was the most common. Tumor reduction during Cycle 1 was observed in four patients, who were defined as responders. In paired‐biopsy samples, responder‐related biological activities were an increase of cleaved PARP expression of tumor nuclei (p = 0.01), a decrease of proliferative cancer‐associated fibroblasts (CAFs) (p = 0.08), and an increase of LVFX infiltration in the tumor (p = 0.04). A decrease of phosphorylated STAT3 expression (p = 0.02) favored an increase in LVFX infiltration. In conclusion, TCZ + GEM/nab‐PTX‐rechallenge had a manageable safety profile and showed preliminary activity via inhibition of CAF and improved intratumoral drug infiltration in MPC.