Advanced/Metastatic Cholangiocarcinoma Treatment Landscape - Episode 2
Expert insight on the current role of biomarker testing and targeted therapy in cholangiocarcinoma management.
Anthony B. El-Khoueiry, MD: In cholangiocarcinoma over time, these various sites can be broken down by site of origin—intrahepatic, extrahepatic, gall bladder, Klatskin, hilar cholangiocarcinoma—and they can harbor different molecular alterations. We’re making significant progress in targeting some of these alterations. We have some drugs approved for these specific alterations. This disease is being broken down into specific molecular subtypes. The alterations vary by site of origin. Intrahepatic cholangiocarcinoma tends to have FGFR2 alterations and IDH1 and IDH2 mutations vs gallbladder and extrahepatic cholangiocarcinoma, which tend to have HER2[human epidermal growth factor receptor 2] alterations,EGFR alterations, and some RAS and RAF alterations. These aren’t exclusive, but they’re more frequent in extrahepatic and gall bladder compared with intrahepatic. Other alterations can be picked up in cholangiocarcinoma, including BRCA and other DNA-repair alterations, as well as ARC, ROS, and MET, but I’d like to focus on FGFR,IDH,HER2, andRAF. For all these there are emerging therapies, and we may come back to this later today. ForIDH and FGFR, we have approved agents.
Because cholangiocarcinoma is broken down into molecular subtypes, and because we have therapies approved for specific molecular subtypes—and many others in clinical trials—it’s become critical that we do molecular profiling on these tumors. The preferred test is a next-generation sequencing test that would be quite comprehensive, to pick up FGFR, IDH, HER2, RAF, RAS, and DNA-repair alterations. I would highlight these specifically. I would favor these patients being tested with first-line treatment if possible, before or along with starting first-line therapy, because a large proportion of these patients may make it into the second and third lines. Currently, we have FGFR-targeted therapies andIDH-targeted therapies approved for second and third lines. We have data on emerging HER2-targeted therapies that have some activity. Knowing that these alterations up front could help develop a treatment strategy for these patients.
This is a disease that remains quite rare, and there are clinical trials that are testing some of these targeted therapies in first line. If we have this information before the patient starts first-line therapy, they may end up being referred for a specific clinical trial to examine whether targeting FGFRor IDH along with chemotherapy may be superior to chemotherapy alone, for example. I wouldn’t want to miss those opportunities. At times, tissue may be insufficient or inadequate, and doing liquid biopsies with circulating tumor DNA is certainly reasonable. It’s happening in other tumor types. There’s a reasonable level of concordance between what we see in liquid biopsies and what we see in the tumor. Keeping that option in mind is also important.
Transcript edited for clarity.