358 Trial in progress: A pilot study of combined immune checkpoint inhibition in combination with ablative therapies in subjects with hepatocellular carcinoma (HCC)

BackgroundLocoregional therapies for hepatocellular carcinoma, such as transcatheter arterial chemoembolization (TACE) or ablation, can induce a peripheral anti-tumor immune response. This may be amplified by immune checkpoint inhibitors (ICI). Early and higher anti-CTLA4 dosing could potentially lead to better priming and a stronger immune response. Recent data has suggested that early (Day 1 only), increased doses of anti-CTLA4 therapy, was associated with encouraging clinical activity and a tolerable safety profile. This study will evaluate dual immune checkpoint, CTLA4 (tremelimumab, day 1-only dosing) and PD-L1 (durvalumab) blockade in combination with TACE in patients with advanced HCC. Intensive peripheral immune-monitoring and longitudinal on-treatment tumor biopsies will focus on the role of the innate immune system, particularly Natural Killer cells, in anti-tumor responses.MethodsPatients with HCC (Childs Pugh A/B7; Barcelona Clinic Liver Cancer Stage B/C; ECOG 0/1; sorafenib-naïve or experienced) are being enrolled in a pilot study (Study Number UCDCRC/19/01) of tremelimumab at 2 dose levels (DL1 and DL2) in combination with durvalumab and TACE until disease progression (per irRECIST). DL1: tremelimumab (75 mg q28 days for 4 doses) and durvalumab (1500 mg q28 days). DL2: tremelimumab (300 mg in a single dose on day 1) and durvalumab (1500 mg q28 days). Subtotal TACE will be performed during study week 6 with the dose-limiting toxicity (DLT) evaluation period encompassing the first 8 weeks of the study. Primary endpoint is 6-month progression-free survival with secondary efficacy endpoints being safety, tolerability and overall survival. Exploratory objectives will evaluate changes in immune parameters in the tumor and peripheral blood of patients undergoing anti-CTLA4 therapy pre- and post-RFA or TACE. A major focus will be on the role of the innate immune system, particularly Natural Killer cells, in anti-tumor responses. Patients will be enrolled and treated at St Vincent’s University Hospital in Dublin, Ireland. This study is currently open and actively recruiting.ResultsN/AConclusionsN/ATrial RegistrationEudraCT Number 2019-002767-98Ethics ApprovalSt Vincent’s University Hospital Research Ethics Committee Study Number UCDCRC/19/01.ReferencesDuffy AG, Ulahannan SV, Makorova-Rusher O, Rahma O, Wedemeyer H, Pratt D, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 2017;66(3):545–51.Lencioni R, Petruzzi P, Crocetti L. Chemoembolization of hepatocellular carcinoma. Semin Intervent Radiol 2013;30(1):3–11.Slovak R, Ludwig JM, Gettinger SN, Herbst RS, Kim HS. Immuno-thermal ablations – boosting the anticancer immune response.Mehta A, Oklu R, Sheth RA. Thermal Ablative Therapies and Immune Checkpoint Modulation: Can Locoregional Approaches Effect a Systemic Response?Gastroenterol Res Pract2016; 2016:9251375.Ng J, Dai T. Radiation therapy and the abscopal effect: a concept comes of age. Ann Transl Med 2016;4(6):118.O’Brien MA, Power DG, Clover AJ, Bird B, Soden DM, Forde PF. Local tumour ablative therapies: opportunities for maximising immune engagement and activation. Biochim Biophys Acta2014; 1846(2):510–23.Kelley RK, Sangro B, Harris WP, Ikeda M, Okusaka T, Kang Y-K, et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC). Journal of Clinical Oncology 2020;38(15_suppl):4508-.Mariniello A, Novello S, Scagliotti GV, Ramalingam SS. Double immune checkpoint blockade in advanced NSCLC. Crit Rev Oncol Hematol 2020;152:102980.