
Shroff: Multiple Targets in Cholangiocarcinoma Make Biomarker Testing Essential
Rachna Shroff, MD, associate dean of clinical and translational research and associate professor of medicine at the University of Arizona, offered a review of early-stage research in her talk, “The Hottest Targeted Therapies on the Horizon for Cholangiocarcinoma.”
The abundance of treatment targets in cholangiocarcinoma (CCA) means that biomarker testing at diagnosis is “essential,” and that next-generation sequencing is needed to clarify a treatment strategy, according to a speaker at last week’s Cholangiocarcinoma Foundation (CCF) 2022 annual meeting in Salt Lake City.
Rachna Shroff, MD, MS, associate dean of clinical and translational research and associate professor of medicine at the University of Arizona, offered a review of early-stage research in her February 24 talk, “The Hottest Targeted Therapies on the Horizon for Cholangiocarcinoma.”
Targeting IDH1 and IDH2. Shroff discussed a phase 1 dosing trial for Loxo Oncology’s LY3410738, a first-in-class covalent inhibitor of mutant IDH1, found in 20% to 30% of intrahepatic CCA diagnoses. Described in a
Results seen in HER2. Shroff spent time discussing the
Such a finding “sparks interest and makes us thing that there are potentially ways to target this important pathway in biliary cancers.” Zanidatamab, a bispecific antibody targeting HER2, has also shown promise in a phase 1 study, she said.
NRG1 fusions. While rare, Shroff said, neuregulin-1 fusions are “incredibly important to find,” because of their behavior. “NRG1 is the predominant ligand in HER3 and, to a lesser extent, HER4,” she said. “This pathway is involved with downstream activation of the HER pathways when you think through tumor proliferation and cellular dysregulation.”
She explained how seribantumab, an anti-HER3 monoclonal antibody, inhibits the downstream pathway by inactivating NRG1 and limiting HER2 and HER3 dimerization; these actions in turn impact P13K/AKT and MAP kinase pathways. In addition to the dual activity of the drug, Shroff said, so far seribantumab seems to be well-tolerated. It will be further evaluated in a pivotal cohort of the
Finally, there’s
DDR pathway. DNA damage repair (DDR) studies could be particularly beneficial the 25% to 35% of Asians who have alterations driving biliary tract cancer, which include the well-known BRCA1/2 genes. “There’s a large component of our patients who may have some potential sensitivity to PARP inhibitors,” Shroff said, explaining that olaparib (Lynparza), is being studied in the
MDM2 and p53. Shroff concluded by mentioning a study with an experimental treatment that will target the MDM2 oncoprotein, which plays a role in p53 activity. The dual agent
“There are many potential targets in biliary tract cancers,” Shroff said. “Upfront biomarker testing—I’m sure we've heard this 100 times already today—is essential. These rare alterations are crucial to find, because now we have trials for these patients. And we may soon have drugs available for these patients. Comprehensive testing, looking for fusions, looking for alterations, mutations, amplifications is going to be very important here.”
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