Therapeutics: Focal adhesion kinase (FAK); programmed cell death 1 (PD-1; PDCD1; CD279)

Patient sample and mouse studies suggest combining a FAK inhibitor, anti-PD-1 mAb and Gemzar gemcitabine could help treat pancreatic ductal adenocarcinoma (PDAC). In PDAC patients, levels of FAK protein and FAK phosphorylation were higher in tumor samples than in normal pancreatic tissue for 45 and 47 of 56 patients, respectively, and high tumor levels of phosphorylated FAK were associated with poor prognosis, high levels of fibrosis and low numbers of tumor-infiltrating CD8+ T cells. In a genetic mouse model of PDAC, the FAK inhibitor VS-4718 decreased tumor growth and fibrosis, tumor infiltration by Tregs and myeloid-derived suppressor cells, and increased survival compared with vehicle. Also in the model, the combination of VS-4718, an anti-PD-1 mAb and Gemzar decreased tumor growth and increased tumor CD8+ T cell infiltration and survival compared with any of the agents alone. Next steps include a Phase I study of the combination of the FAK inhibitor defactinib, the anti-PD-1 mAb Keytruda pembrolizumab and Gemzar in pancreatic cancer, sponsored by the Washington University School of Medicine.

Eli Lilly and Co. markets Gemzar, a DNA synthesis inhibitor, for breast, ovarian and pancreatic cancers and non-small cell lung cancer (NSCLC), and has the compound in Phase III testing for biliary and cervical cancers and Phase II testing for bladder cancer...