A phase 1 study of LB4330, a peptide fused to CLDN18.2 antibody targeting the tumor antigen associated (TAA) CD8+T cells in patients with advanced solid tumors.

e15074 Background: PD-1/PD-L1-targeted immunotherapies have become critical in the treatment for many tumors. However, there has been limited progress in low immunogenic cancers such as pancreatic ductal adenocarcinoma (PDAC) or CRC. LB4330 is a novel, bi-functional molecule targeting Claudin18.2 and IL-10 with high affinity anti-CLDN18.2 (14pM). It may activate TAA CD8+ T cells in the tumor microenvironment (TME) and has potential alone or in combination with immunotherapeutic agents, including PD-1/PD-L1 mAbs, for the treatment of advanced solid tumors. A FIH, phase 1 study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of LB4330 in patients with advanced solid tumors (MEETCD8-001) is ongoing in China. Methods: Eligible patients were ≥ 18 years old with ECOG PS 0-1. Dose cohorts ranged from 0.001 mg/kg to1 mg/kg IV QW: 0.001mg/kg-0.05mg/kg in an accelerated titration design, and 0.2mg/kg-1 mg/kg using traditional 3+3 design. The primary objective is safety, including dose-limiting toxicities (DLTs). The secondary/exploratory objectives include efficacy, pharmacokinetics (PK), and immunogenicity. Results: As of January 5, 2024, 30 patients with advanced solid tumors who have failed standard treatments or who did not have standard treatments available or applicable at this stage were recruited, including 17 PDAC, 6 GC, 3 CRC and 4 other solid tumor patients. All patients enrolled had multiple organ metastases. Treatment emergent AEs (TEAEs) occurred in 90.3% of patients. The most common Treatment related AEs (TRAE) were thrombocytopenia, anemia, fever, rash/itching, and fatigue. 7 patients (23.3%) had grade 3 TRAE which were infusion reaction, skin itching, rash, fever, abdominal distension, anemia, and thrombocytopenia. 1 patient (3.2%) had grade 4 AE, thrombocytopenia. On-treatment scan for efficacy was available for 20 patients, and 7 had stable disease. Target lesion shrinkage was observed in 2 pts, including one PDAC patient whose sum of target lesion reduced by 32.9% from baseline. PK was generally dose proportional, with t½ ~2 days. The immune activating Th1 cytokine IL-18 was elevated in 77.8% of patients treated with LB4330. Updated data will be presented. Conclusions: LB4330 has manageable safety and shows preliminary efficacy at tolerable doses. Dose and efficacy expansion study is ongoing in more PDACs and other solid tumors. In the meantime, Phase I study of LB4330 in combination with PD1/TIM-3 bispecific antibody LB1410 has been initiated in different tumor types as well. Clinical trial information: NCT05707676 .