Dr Bekaii-Saab on the Expanding Targeted Therapy Paradigm for Biliary Tract Cancers

“[Approximately] 30% to 40% of [biliary tract] cancers combined seem to have a target that we can match with a proper therapy.”

Tanios S. Bekaii-Saab, MD, the leader of the Gastrointestinal Cancer Program at the Mayo Clinic Comprehensive Cancer Center; as well as medical director of the Cancer Clinical Research Office and vice chair and section chief for Medical Oncology in the Department of Internal Medicine at Mayo Clinic, discussed current and emerging therapeutic targets for the treatment of patients with biliary tract cancers.

Approximately 30% to 40% of all biliary tract cancers harbor actionable molecular alterations that are amenable to targeted therapy, Bekaii-Saab began. Among patients with intrahepatic cholangiocarcinomas, FGFR2 fusions are present in approximately 5% to 7%, he said. Two FGFR inhibitors, pemigatinib (Pemazyre) and futibatinib (Lytgobi), have received regulatory approval for the treatment of patients with this disease subset, both demonstrating overall response rates (ORRs) of approximately 40%, and a subset of patients experiencing durable clinical benefit, he explained. Ongoing development of second- and third-generation FGFR inhibitors aims to improve therapeutic efficacy, although these agents may be associated with increased toxicity profiles, he cautioned. The clinical utility and optimal sequencing of these newer inhibitors remain areas of active investigation, he summarized.

In gallbladder carcinoma and extrahepatic cholangiocarcinoma, HER2 amplification represents a key oncogenic driver, particularly outside the United States, where up to 30% of gallbladder tumors may exhibit HER2 overexpression, Bekaii-Saab continued. Several HER2-targeted therapies have demonstrated clinical efficacy in this setting, he reported. These include the combination of tucatinib (Tukysa) and trastuzumab (Herceptin), the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu), and the bispecific antibody zanidatamab-hrii (Ziihera). Notably, zanidatamab is FDA approved specifically for patients with HER2 immunohistochemistry 3+ gallbladder or extrahepatic cholangiocarcinoma.

Additional actionable alterations include the KRAS G12C mutation, for which the KRAS G12C inhibitor adagrasib (Krazati) has been incorporated into National Comprehensive Cancer Network guidelines, according to Bekaii-Saab. BRAF V600E mutations, found in approximately 5% to 10% of biliary tract cancers, are responsive to combined BRAF/MEK inhibition using agents like dabrafenib (Tafinlar) plus trametinib (Mekinist), he noted. IDH1 mutations, present in approximately 20% of intrahepatic cholangiocarcinomas, can be targeted with ivosidenib (Tibsovo), which has demonstrated progression-free survival benefit and a modest overall survival advantage, although ORRs have been limited, he stated.

Furthermore, an expanding list of rare oncogenic fusions is being identified and matched with corresponding targeted therapies, contributing to the growing paradigm of precision oncology in biliary tract cancers, Bekaii-Saab emphasized. Overall, despite the relative rarity of biliary tract malignancies, approximately 30% to 40% of patients may benefit from biomarker-driven therapies beyond conventional chemotherapy and immunotherapy, many of which elicit ORRs in the 30% to 40% range, with the notable exception of ivosidenib, he concluded.