Abstract CT189: Yttrium-90 radioembolization in combination with tremelimumab and durvalumab for treating patients with locally advanced, unresectable or oligo-metastatic intrahepatic cholangiocarcinoma who are not candidates for curative therapy

Abstract BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a rare but aggressive cancer with limited curative options outside of surgical resection. Trans-arterial radioembolization (TARE) with yttrium-90 is a promising treatment with retrospective data showing an overall survival (OS) of up to 30 months. The single arm prospective MISHPEC trial combined TARE with gemcitabine and cisplatin showed an overall response rate (ORR) of 39% at 3 months along with a median OS of 22 months. PDL1 inhibitor (Durvalumab) has shown modest benefit in addition to chemotherapy in unresectable cholangiocarcinoma with three-year OS of 15% based on the TOPAZ-1 trial. ICC is a biologically cold tumor; preclinical data indicates that Yttrium-90 TARE can alter tumor microenvironment making it conducive to effector T cell recruitment and function leading to enhanced efficacy of immunotherapy. This provides the biological rationale of combining yittrium-90 TARE with systemic immunotherapy involving dual PDL1 and CTLA-4 inhibitors. Here in, we present our ongoing clinical trial investigating the safety and efficacy of yttrium-90 TARE combined with Durvalumab and Tremelimumab in patients with ICC (NCT06058663). METHODS: In this phase 1 study, yittrium-90 TARE will be combined with Durvalumab and Tremelimumab in 16 patients with unresectable or oligometastatic ICC. Eligible patients with histologically confirmed measurable disease must not have received any prior local therapies and any immunotherapy with ECOG PS of 0 or 1, adequate liver (Child Class A, ALBI 1 or 2) and renal function. Patients should also have a favorable mapping angiography based on an angiosomal analysis. Ablative radioembolization would be performed at least a dose of greater than 205 Gy MIRD to >75% of tumor. Study treatment with Tremelimumab (x 1 dose of 300mg total) + Durvalumab 1500mg monthly will continue until unacceptable toxicities, or disease progression for up to 24 months. Durvalumab and Tremelimumab will be infused in two alternate schedules after yittrium-90 TARE. In cohort 1 (3 patients) immunotherapy will be delivered within 24 hours of TARE. In cohort 2 (3 patients) immunotherapy will be delivered 2 weeks after TARE. Subsequent patients will be enrolled in either cohort 1 or 2 based on the safety signal from the first 6 patients. Primary goal of the study is to determine safety of this combination. Secondary goals include ORR per RECIST 1.1, progression-free survival, overall survival, infield and out of field response rate and downstaging to resection. Correlative studies include ctDNA at baseline along with evolution through treatment, pre and post treatment biopsies to look at tumor microenvironment and post treatment dose volume histograms. Three patients have been accrued in the study thus far. Citation Format: Umair Majeed, Jason Starr, Conor O'Donnell, Robert Jones, Jacqueline Boni, Josh Cameron, Oudom Kour, Mitesh Borad, Hani Babiker, Kabir Mody, Beau Toskich. Yttrium-90 radioembolization in combination with tremelimumab and durvalumab for treating patients with locally advanced, unresectable or oligo-metastatic intrahepatic cholangiocarcinoma who are not candidates for curative therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT189.