Abstract 724: Target identification for antibody-drug-conjugate (ADC) therapy in biliary tract cancers (BTC)

Background: BTCs are an uncommon malignancy with poor prognosis. ADCs have efficacy in several solid tumors with antigen surface expression serving as a potential biomarker in some instances. Herein, we evaluate the protein expression and heterogeneity of ADC target antigens and their prognostic implications in BTC. Methods: Utilizing an IRB-approved, retrospective biospecimen protocol, we constructed tissue microarrays (TMA) from resected, early staged intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma (EHC) and gallbladder cancer (GB). IHC for Nectin-4, TROP2, c-MET, CLDN18.2 was assessed. Positivity defined as ≥10% weakly stained tumor cells and quantified by H-score (intensity × percentage). HER2 IHC scored per standard colon criteria. Clinicopathological factors and outcomes were associated with ADC target expression. Results: N=65 resected cases were selected (median age 72 years (range 36-92); 55% males, anatomical subtype 40% IHC, 43% EHC, 17% GB; 84% moderately differentiated adenocarcinoma. c-MET and TROP2 were expressed in 75% and 83% of cases with differential expression based on anatomic site (c-MET: IHC: 62%, EHC: 89% vs GB: 73%, p=0.049; TROP2: IHC: 65%, EHC: 93% vs GB: 100%, p=0.010, Table). HER2, CLDN18.2, and Nectin-4 were expressed in 7.7%, 46%, and 66% of cases, and did not differ based on anatomic site. Median RFS and OS were 20 (95%CI 10-NR) and 40 (95%CI 27-NR) months respectively and outcomes were not impacted by expression of HER2, Nectin-4, TROP2, c-MET, or CLDN18.2. Conclusion: Modest to high expression of Nectin-4, TROP2, c-MET and CLDN18.2 was identified across BTC anatomic subtypes, suggesting a potential role for ADCs to these antigens in patients with BTC. Preclinical validation is ongoing in BTC patient derived xenografts with trastuzumab deruxtecan (HER2 sensitive and HER2 resistant models), enfortumab vendotin (Nectin-4 positive model), and sacituzumab govitecan and these results will be presented at the meeting. Citation Format: Aruj Dhyani, Zeynep Tarcan, Joanne Chou, Rohit Thummalapalli, Walid Chatila, Sharanya Nag, Ezra Rosen, Sydney Bowker, Wungki Park, Elisa De Stanchina, Sarat Chandarlapaty, David Solit, William Jarnagin, Marinela Capanu, Eileen M O'Reilly, Ghassan K Abou-Alfa, Olca Basturk, James Harding. Target identification for antibody-drug-conjugate (ADC) therapy in biliary tract cancers (BTC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 724.