Targeted Therapies on the Horizon for CCA

On day 3 of the 2022 Cholangiocarcinoma Foundation annual meeting, Rachna T. Shroff, MD, MS, Chief, Section of GI Medical Oncology, University of Arizona Cancer Center, Tucson, reviewed promising clinical data regarding novel targeted therapies currently under clinical investigation for the treatment of cholangiocarcinoma (CCA). She highlighted several areas that are “really exciting…potentially targetable, actionable, and in the works in terms of becoming available to our patients.”

• The next-generation IDH1 inhibitor LY3410738 exhibited greater potency and more durable efficacy than ivosidenib in in vitro studies. Based on encouraging preclinical data, the LOXO-IDU-20002 phase 1 study (NCT04521686) is evaluating LY3410738 in patients with advanced solid tumors harboring IDH1/2 mutations, with the primary outcomes of safety and determination of the recommended phase 2 dose.
• In terms of NTRK fusions, Dr Shroff noted that “it’s very, very rare in cholangiocarcinoma patients.” In initial data presented in NTRK-positive solid tumors, the NTRK inhibitor larotrectinib showed very high activity,¹ including in “a patient with cholangiocarcinoma who had a very impressive and deep response,” she said.
• The HER2-directed bispecific antibody zanidatamab showed a disease control rate of 65% in preliminary results from a phase 1 study in heavily pretreated patients with biliary tract cancers (BTCs).² Based on these data, the ongoing HERIZON-BTC-01 study (NCT04466891) is evaluating zanidatamab in 100 patients with HER2-amplified BTC; confirmed objective response rate is the primary study end point.
• NRG1 gene fusions are also rare alterations in BTCs, occurring in about 6% of CCAs, “but an incredibly important one to find, because we have ways of targeting these now,” Dr Shroff said. The anti-HER3 monoclonal antibody seribantumab is well-characterized in solid tumors. The CRESTONE phase 2 tumor-agnostic basket trial (NCT04383210) is evaluating seribantumab in 75 adult patients with NRG1 fusion–positive locally advanced or metastatic solid tumors.
• Dr Shroff pointed out that the DNA damage repair (DDR) pathway is “incredibly relevant in BTC.” Defective DDR genes, including ATM, BAP1, MSH2, BRCA1/2, and PLB2, occur in about 34% of patients with BTC. In addition, patients with IDH1 mutations may also exhibit DDR phenotype. Taken together, Dr Shroff noted that “a large component of our patients may have potential sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. As we know, PARP inhibitors are FDA approved in pancreatic and ovarian cancers with BRCA mutations and are being explored in a number of other tumors with a DDR phenotype.” The phase 2 ACCRU-ICRN-1702 study (NCT04042831) is evaluating olaparib in patients with advanced/metastatic BTC expressing aberrant DNA repair gene mutations.
• MDM2 amplification in BTCs is rare but may be relevant. The highly potent MDM2-p53 antagonist BI 907828 has shown antitumor efficacy in an animal xenograft model and is in early clinical testing (NCT03449381).

Dr Shroff concluded: “There are many potential targets in biliary tract cancers; these rare alterations are crucial to find because we now have trials and we may soon have drugs available for these patients. So, comprehensive testing looking for fusions, looking for alterations, mutations, amplifications is going to be very important here.”

References

1. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion–positive cancers in adults and children. N Engl J Med. 2018;378:731-739.
2. Meric-Bernstam F, Hanna DL, EL-Khoueiry AB, et al. Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): results from a phase I study [abstract]. J Clin Oncol. 2021;39(suppl_3):299.