New Therapeutic Targets in RAS Wild-type Pancreatic Cancer

The landscape of treatment of advanced PDAC is witnessing significant changes. This is in part due to the advent of molecular profiling, which has highlighted molecularly-distinct subsets of pts, especially those with KRAS wild-type disease. We now know that these pts harbor genomic alterations that not only serve as molecular drivers but also pose as therapeutically relevant markers. In the absence of strong evidence to support the use of targeted therapy in the front-line setting, we continue to offer chemotherapy for treatment-naïve pts. However, an argument can be made for the front-line use of targeted therapy in pts who are not fit for chemotherapy or who are not interested in it. The challenge is ensuring that molecular profiling is done in a timely fashion to prevent significant delays in therapy. In our practice, we offer molecular testing to all pts with a new diagnosis of advanced PDAC. We prefer the utility of targeted therapy in the second line and beyond for pts who have an actionable target, over the use of further chemotherapy, as targeted therapy appears to confer deep and durable responses and longer survival. For pts with MSI-H or MMRd disease, the use of immunotherapy is indicated, although it has to be noted that MSI-H/MMRd PDAC performed worse that other MSI-H/MMRd cancers treated with immunotherapy. Therefore, in the presence of MSI-H/MMRd and an additional actionable target, we prefer treating with targeted therapy and reserving immunotherapy for later lines. Pt preference has to be taken into consideration at all times though.