Pharmacokinetics and Biomarker Analysis from a Phase 1/2 Open-Label Study of the Anti-Gpc3 T-cell Engager SAR444200, in Patients with Advanced Solid Tumors.

2579 Background: SAR444200 is a novel NANOBODY T cell engager that simultaneously binds TCRαβ and glypican-3 (GPC3) to co-engage T cells with GPC3-expressing tumor cells, resulting in T cell-dependent cellular cytotoxicity. Here we present updated safety, pharmacokinetics (PK) and biomarker data from 6 and 5 dose levels (DL), respectively in patients with advanced solid tumors in the dose escalation cohort (Part 1A) from the first-in-human Phase 1/2 trial (NCT05450562). Methods: This ongoing Phase 1/2 trial evaluated open label, intravenously administered SAR444200 (every week with lead-in doses) at DL1 (3 mg), DL1A (1 mg), DL2A (2.5 mg), DL3A (4.5 mg), DL4A (18 mg), and DL5A (36 mg) in adult patients with GPC3+ solid tumors. On study imaging was performed every 9 weeks after the date of first infusion of SAR444200. Whole blood samples were collected to assess the plasma concentrations of SAR444200 and for biomarker analysis. PK analysis was performed with electrochemiluminescence-based total PK assay using Meso Scale Discovery platform. Anti-drug antibody (ADA) monitoring was performed using a PandA assay. Results: As of 19 January 2024, a total of 24 patients with GPC3+ solid tumors received SAR444200, 4 patients per DL (DL1, DL1A, DL2A, DL3A, DL4A, DL5A). Most of the patients (17 patients, 71%) had hepatocellular carcinoma. No dose-limiting toxicities were observed. Twenty-two patients (92%) reported treatment-related adverse events (TRAEs) of any grade, including three patients with a serious TRAE (2 events with hospitalization prolongation for a Grade 1 and 2 cytokine release syndrome [CRS] that recovered completely without and with Tocilizumab, respectively, 1 event with pneumonitis Grade 3). All CRS (19 patients, 79%) and infusion-related reaction (7 patients, 29%) were Grade 1 or 2. Cmax was observed at the end or shortly after completion of infusion. The maximum ADA titer, though high, stabilized despite the target dose increased from Cycle 2. Biomarker analysis showed an increase of interleukin-6 and interferon gamma during lead-in doses, supporting CRS. Cytokines declined after Cycle 1. Among 14 HCC patients with baseline alpha-fatal protein (AFP) higher than 20 ng/ml, 4 (29%) had at least a 20% AFP decrease on treatment. Two patients (both with HCC) have been on study drug for more than 6 months. Conclusions: These results suggest that SAR444200 is tolerable at the tested dose levels in patients with GPC3+ advanced solid tumors. Dose escalation continues at this time. Clinical trial information: NCT05450562 .