Phase I study of ERY974 in patients with glypican-3 (GPC-3)-positive advanced solid tumors

Background: ERY974, a bispecific antibody targeting GPC3 and CD3, redirects T cells to GPC3+ tumors to enhance immune responses. GPC3 is highly expressed in solid tumors and minimally present in normal tissue, making it a promising target. ERY102JP (Phase I) evaluated ERY974 in patients (pts) with GPC3+ advanced/recurrent solid tumors. A prior study showed limited tolerability at doses ≥0.81 µg/kg due to cytokine release syndrome (CRS), prompting investigation of prophylactic strategies. Methods: Eligible pts had tumors with ≥1% GPC3 expression. Pts got ERY974 (0.12-4.0 µg/kg; dose escalation design) by IV once weekly (QW). Tocilizumab (toc), an IL-6 receptor antagonist, was given before ERY974 (all cohorts) to mitigate CRS. Steroids (Cohorts 5-10) and step-up dosing (SUD; Cohorts 6-10) were added to reduce CRS and hepatotoxicity. Endpoints included safety, PK and anti-tumor activity (RECIST 1.1). Results 38 pts were enrolled across 10 cohorts. Grade ≥3 adverse events (AEs) occurred in 61% (23/38) of pts; ALT increased was seen in 37% (14/38) and AST increased in 24% (9/38). Dose-limiting toxicities occurred in 1 of 3 pts in the 0.80 µg/kg QW cohort, 1 of 6 pts in 0.80 µg/kg QW + Steroid cohort, and 3 of 4 pts in 0.5/1.2/4.0 µg/kg QW + Steroid cohort. The maximum tolerated dose was 2.7 µg/kg. No responses were seen (Table). ERY974 exposure increased dose-dependently; higher exposure, including 4.0 µg/kg, was achieved using SUD with steroids. CRS occurred in 55% (21/38) of pts, most often in cohorts receiving ERY974 ≥0.80 µg/kg. CRS incidence was 0% at 0.24 µg/kg with toc alone, and lower at initial ERY974 dose of 0.50 µg/kg with steroids (33%) vs without (67%). Higher ERY974 plasma concentrations were associated with increased risk of CRS (p=0.01) and grade ≥3 liver toxicity (p=0.05). Conclusions: Use of SUD, steroid premedication and toc enabled escalation to higher ERY974 doses (up to 2.7 µg/kg was tolerated) with manageable safety profiles. Toc likely mitigated CRS. Anti-tumor activity was limited. Table ERY974 dose (µg/kg) 0.12 (n=3) 0.24 (n=4) 0.50 (n=3) 0.80 (n=3) 0.80 + Steroid (n=6) 0.50/1.20 + Steroid a (n=3) 0.50/1.80 + Steroid a (n=4) 0.50/1.20/1.80 + Steroid a (n=4) 0.50/1.20/2.70 + Steroid a (n=4) 0.50/1.20/4.0 + Steroid a (n=4) Related AEs, n (%) b All grade 3 (100) 1 (25) 1 (33) 3 (100) 6 (100) 3 (100) 4 (100) 4 (100) 4 (100) 4 (100) Grade 3/4 c 0 1 (25) 0 2 (67) 3 (50) 2 (67) 4 (100) 3 (75) 4 (100) 4 (100) Serious 0 0 0 0 0 0 1 (25) 2 (50) 1 (25) 1 (25) AEs leading to withdrawal from any treatment 0 0 0 0 0 0 0 1 (25) 0 0 Best overall response, n (%) CR/PR 0 0 0 0 0 0 0 0 0 0 SD 0 1 (25) 0 0 3 (50) 0 1 (25) 0 1 (25) 2 (50) jRCT2031200382. Clinical cutoff: Oct 18, 2024 AE, Adverse event; CR, complete response; PR, partial response; SD, stable disease; SUD, step-up dosing. a Weekly SUD regimen. b Multiple occurrences of the same AE in a person is counted once. c No grade 5 AEs were reported.