Phase I study of Ori-C101, an armored GPC3-directed CAR-T, in patients with advanced hepatocellular carcinoma (HCC).

4084 Background: Previously, we reported the results of Ori-C101 from investigator initiated trial in China (ChiCTR1900028121). The data demonstrated that Ori-C101 owned a favorable safety profile and promising efficacy. Among 10 GPC3 + HCC patients (pts) treated with Ori-C101, 9 pts (90%) achieved disease control and 6 pts (60%) met partial response per RECIST 1.1. Two pts with PR attained progression-free survival of one and two years respectively, with an overall survival close to 3 years. These results implied that Ori-C101 potentially held significant clinical benefits. Subsequently, extensive optimizations and improvements in the manufacturing process were implemented to enhance its clinical efficacy and persistency. Hence, a multicenter registration study was launched in China (the BEACON study), and herein, we will present the preliminary results. Methods: This is an open-label, multi-center, dose-escalation (3+3 design) study. GPC3 + advanced HCC pts who failed at least 2 lines of systemic treatments received a single hepatic arterial infusion with a total dose of 0.9 to 6×10 8 CAR-T cells. Primary endpoints are rate of dose-limiting toxicities (DLTs) and safety with the aim to determine a recommended phase II dose (RP2D). Secondary endpoints are cellular kinetics, overall response rate by investigator assessment, duration of response, overall survival and overall safety. Results: As of Dec 17th, 2024, a total of 10 eligible pts received Ori-C101 infusion at 3 dose levels (DLs). All pts had BCLC stage B or C, with 20% (2/10) had extrahepatic metastasis. The median number of prior lines of therapy was 4.5 (range 2-9), 100% pts received immune checkpoint inhibitors and tyrosine kinase inhibitors. All pts were evaluable for safety. All adverse events were reported regardless of study drug relationship. Of 10 pts evaluable for safety, the most common ≥ grade (G) 3 AEs were lymphocyte count decreased (100%), neutrophil count decreased (60.0%), blood fibrinogen decreased (40.0%), transaminases increased (40.0%), platelet count decreased (20.0%), blood bilirubin increased (20.0%). CRS was observed in 10 (100%) pts with 3 (30.0%) ≥ G3 CRS. No ICANS was observed. One pt developed DLT event due to CRS and secondary disseminated intravascular coagulation. 9 pts were evaluable for efficacy per RECIST 1.1. While 6 pts (66%) achieved disease control at DL2 or higher, all pts at the DL3 achieved objective response. Particularly, one pt who achieved CR showed encouraging durability and no signs of relapse at 9 months follow up evaluation, and follow up is ongoing. Conclusions: These preliminary data showed Ori-C101 has manageable safety profile and exciting efficacy with encouraging sign of good durability. Currently, more pts have been enrolled at dose expansion to confirm the DLs of RP2D. More information will be presented at coming ASCO conference. Clinical trial information: NCT05652920 .