A phase 2, open-label single-arm, multi-center study of trans-arterial tirapazamine embolization (TATE) combined with nivolumab (nivo) in patients with advanced immunotherapy-refractory hepatocellular carcinoma (HCC).

538 Background: Advanced HCC after failure of first line immunotherapy has limited options and is an urgent unmet need. Trans-arterial Tirapazamine embolization (TATE) is a locoregional therapy capable of inducing tumor necrosis and generating anti-tumor T cells. We investigated the efficacy and safety of TATE with Nivolumab (nivo) in salvage setting. Methods: The study was an open-label single-arm, multi-center Phase 2 study (NCT03259867). Advanced HCC patients who progressed on at least one line of dual immunotherapy, ECOG 0-2, Child-Pugh 5-7, BCLC-C, with liver tumor > 2 cm but < 15 cm, total tumor volume up to 50% of the liver, and suitable for embolization, were enrolled. TATE was performed 1 week after first nivo infusion with nivo maintenance 360 mg IV Q3W until progression by Immune Related Response Criteria (irRC) or death. Efficacy was evaluated by overall response rate (ORR) and duration of response (DOR) using mRECIST and RECIST every 9 weeks with chest CT and abdominal MRI. Safety was assessed by CTCAE v.5. After the first 10 patients, we assessed the impact of TATE on T-cell clonal expansion by performing RNA next generation sequencing on pre-/post-TATE peripheral mononuclear blood cells (PMBC) in a correlative translational study. Results: Breakthrough designation application has been submitted. 20 advanced HCC patients with progression on an average of 1.9 lines of systemic therapy including immune checkpoint inhibitors were enrolled with 18 completing 2-month treatment and evaluable for efficacy. 11/18 failed prior TACE, average 2.9 TACEs per patient. Among the 18 evaluable patients, 10 were responders (4 CR, 6 PR) with ORR (CR+PR) 55.6% and DCR (CR+PR+SD) 83.3% by mRECIST, and 16.7% ORR, 77.8% DCR by RECIST, in this immune-refractory population. Median DOR by mRECIST was not reached, longest 404 days. Thirteen remain alive with median OS 595 days by Kaplan Meier estimate. Abscopal effect was documented in patients with extra-hepatic metastatic lesions. The combination was well tolerated with transient elevation of AST/ALT as the main AE. TATE induced significant polyclonal expansion of pre-existing CDR3 clones by 10 folds for > 80 clones and new CDR3 clones with > 100 copies comprising 10-20% of the total CDR3 post-TATE. Further details will be presented at the meeting. Conclusions: TATE plus nivo is promising in the salvage setting of advanced HCC patients who failed at least one line of immunotherapy. Further investigation is warranted to confirm the efficacy of this combination. Clinical trial information: NCT03259867 . Best overall response in all evaluable patients. mRECIST n=18 (%) RECIST n=18 (%) RR 10 (55.6%) 3 (16.7%) CR 4 (22.2%) 0 (0%) PR 6 (33.3%) 3 (16.7%) SD 5 (27.8%) 11 (61.1%) DCR 15 (83.3%) 14 (77.8%) PD 3 (16.7%) 4 (22.2%)