Shroff: Multiple Targets in Cholangiocarcinoma Make Biomarker Testing Essential

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 May 2021 abstract at the American Society of Clinical Oncology (ASCO) meeting as offering a “unique covalent binding mode,” increased potency, and a binding site that may work in “second-site” IDH1 mutations. Shroff said the investigational therapy appears to work in a pathway that would allow it to target IDH2 mutations as well. “That’s important here, because thus far we do not have something in the clinic available for IDH2 mutations.”

Results seen in HER2. Shroff spent time discussing the MyPathway study, which is examining currently approved therapies in non-indicated tumors. Results published in September 2021 showed that this approach has yielded results in HER2+ advanced biliary tract cancer, when the well-known therapies pertuzumab and trastuzumab were used to treat 39 patients. After a median follow-up of 8.1 months, 9 of the 39 patients achieved a partial response of 23%. “Clearly, HER2 is targetable,” Shroff said, noting that some patients stayed on therapy for much longer than the median follow-up.

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. Results for 20 patients with CCA or gallbladder cancer, published at the 2021 ASCO Gastrointestinal Cancers Symposium, showed an overall response rate of 47% for the 17 evaluable patients. Based on these results, the HERIZON-1 study is proceeding, which will include about 100 patients with HER2-amplified biliary tract cancer, 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 CRESTONE study, studying patients without prior Pan-ERBB, HER2, or HER3 targeted therapy. CRESTONE also has 2 exploratory cohorts for patients with prior targeted therapy and those with specific types of NRG1 fusions.

Finally, there’s zenocutuzumab, which is being studied in multiple tumor types, including cholangiocarcinoma, through its NRG1 development program. A CCA patient showed a 32% reduction in target lesions, which was considered a partial response, Shroff said.

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 ACCRU 1702 study.

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 BI 907828 is being evaluated in in a first-in-human study multiple advanced tumor types. “It seems to exert its impact in 2 different ways, through direct targeting of the MDM2-p53, as well as through some immunomodulation of the tumor microenvironment,” she said.

“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.”