Targeted Therapies for Pancreatic Cancer

Abstract

In locally advanced and metastatic pancreatic cancers, germline sequencing, somatic mutation and fusion testing, and testing for microsatellite instability or mismatch repair are recommended to identify patients who are candidates for targeted therapies or immune checkpoint inhibitors, either as current standard therapy or on a biomarker-driven clinical trial. Biomarkers that impact current standard treatments include germline BRCA1/2 mutation, microsatellite instability or mismatch repair deficiency, BRAF V600E mutation, NTRK1/2/3 fusion, and RET fusion. However, each of these aberrations forms a small minority of patients with pancreatic cancer. The most common driver mutation in pancreatic cancer is an oncogenic KRAS mutation, found in over 90% of patients, and though this is not currently targetable with standard therapy, multiple efforts to effectively target KRAS are underway. In particular, about 1% of patients have pancreatic cancers harboring KRAS G12C mutations, for which KRAS G12C-specific small molecule inhibitors are in clinical trials with promising early data. KRAS wild-type pancreatic cancers, while comprising a minority of pancreatic cancer patients, are more likely to arise among younger patients and are enriched for other potentially targetable driver mutations, including BRAF mutations and activating deletions, BRAF or RAF1 fusions, and additional aberrations, including gene fusions involving NRG1, FGFR1/2/3, NTRK1/2/3, or RET. Emerging potential biomarkers with novel targeted therapies in development include claudin 18.2 expression and MTAP deletion.