Novel Therapies for Pancreatic Cancer

Pancreatic adenocarcinoma (PDAC) unfortunately remains a highly fatal disease with a 5-year survival rate of only 11%. If surgical resection is not possible, systemic chemotherapy represents the standard-of-care approach to management. Combination chemotherapy regimens using fluorouracil (fluorouracil, oxaliplatin, leucovorin, and irinotecan; and fluorouracil, leucovorin, and oxaliplatin) or gemcitabine with albumin-bound paclitaxel have the potential to improve overall survival for patients with advanced disease. With the increasing understanding of the molecular drivers of pancreatic cancer, novel therapeutic approaches have made incremental progress for these patients. The molecular landscape of PDAC has been studied extensively. Approximately 90% of PDACs harbor mutations in the KRAS gene, a driver mutation that has long been considered undruggable. However, novel KRAS inhibitors have shown therapeutic promise in early-phase clinical trials, with larger studies ongoing. Less frequently encountered genomic aberrations that have therapeutic potential include NRG, BRAF, NTRK, HER2, BRCA, PALB2, and claudin. Immune checkpoint inhibitors have unfortunately yielded disappointing efficacy for the majority of patients with pancreatic cancer, except for those with tumors exhibiting deficiency in mismatch repair proteins. Alternative approaches to incorporate immunotherapy have shown more promise such as use of immune checkpoint inhibitors for selected patients in the maintenance setting and potential vaccine therapies in the postsurgery adjuvant setting. It is vital to perform molecular profiling in all patients with PDAC to identify potential treatment targets, and to enroll patients in clinical trials whenever possible.