Safety and preliminary efficacy of ATG-022 in patients with advanced/metastatic gastric cancer (CLINCH).

456 Background: ATG-022 is an antibody-drug conjugate (ADC) targeting Claudin 18.2 (CLDN 18.2) tumor antigen broadly expressed in gastric and other solid tumors. ATG-022 consists of a humanized monoclonal antibody that binds to CLDN 18.2 with high affinity of sub-nM grade and a conjugated linker-payload VC-MMAE, demonstrating activity across a wide range of CLDN18.2 expression levels, including both high and low/ultra-low expression levels. Methods: The CLINCH study included dose escalation phase and dose expansion phase. In the dose escalation, patients(pts) with advanced solid tumors regardless of CLDN 18.2 expression received ATG-022 once every three weeks (0.3-3.0 mg/kg Q3W) to evaluate the safety, tolerability, and pharmacokinetics. CLDN 18.2-positive patients were enrolled in dose expansion to receive ATG-022 at recommended phase 2 doses (RP2D) to evaluate the efficacy and safety. The primary endpoints included dose-limiting toxicity (DLT) and adverse events (AEs). The efficacy endpoints included objective response rate (ORR) and disease control rate (DCR), evaluated per RECIST1.1 criteria. Results: As of Aug 21, 2024, 16 pts with advanced solid tumors, including 7 gastric cancer (GC), were treated with ATG-022 from 0.3 to 3.0 mg/kg in dose escalation, with 1 DLT of grade 3 nausea found at 3 mg/kg among 6 pts, and 21 GC pts were enrolled in dose expansion to receive RP2D of 2.4 mg/kg Q3W. Among all 37 pts, median age was 61 years. Baseline ECOG were 0 (9 pts) and 1 (28 pts); 33 (89.2%) pts had stage IV disease; 26 (70.3%) pts had received ≥ 2 prior lines of systemic therapy and 14 (37.8%) pts had prior anti-PD-1/L1 therapy. At 2.4 mg/kg in expansion, 3 (14.3%) pts had ≥ 1 Serious TRAEs; 8 (38.1%) pts had grade ≥ 3 TRAEs; the most common TRAEs included neutrophil count decreased (47.6%), nausea (38.1%) and white blood cell count decreased (33.3 %). In dose escalation, 7 GC pts were enrolled, including 3 CLDN 18.2-positive pts. One PR and 1 CR was observed in pts with GC at the dosage of 1.8 mg/kg and 2.4 mg/kg, respectively. Among 12 GC pts who had at least 1 tumor evaluation in dose expansion, 5 PR and 7 SD were observed, resulting in an ORR of 41.7%, and a DCR of 100%. One CR and 1 PR were observed among 3 GC pts receiving 2.4 mg/kg and with CLDN 18.2 expression < 2+, 5%. The Cmax of both total antibody and ADC drug is increased as dose increased from dose 0.3 – 3.0 mg/kg. No pronounced exposure accumulation was found after multiple dose treatment. Preliminary data showed Dose-Normalized AUC of MMAE for ATG-022 is comparable with other vcMMAE ADC drugs. Conclusions: ATG-022 demonstrated a manageable safety profile, comparable PK properties in current dosing levels, and encouraging preliminary antitumor effects in GC pts from high CLDN 18.2 expression to low CLDN 18.2 expression, suggesting further clinical investigation in pts with variable CLDN 18.2 expression. The enrollment of GC and other solid tumors are ongoing. Clinical trial information: NCT05718895 .