ATG-022 Demonstrates Safety, Preliminary Efficacy in Advanced CLDN18.2+ Gastric Cancer

Treatment with antibody-drug conjugate (ADC) ATG-022 demonstrated a manageable safety profile with preliminary antitumor effects in patients with gastric cancer with high claudin18.2 (CLDN18.2) expression and low/ultra-low CLDN 18.2 expression, according to data from the phase 1 CLINCH trial (NCT05718895) presented at the 2025 Gastrointestinal Cancers Symposium.1

At the data cutoff of November 22, 2024, the dose-escalation portion of the study included 16 patients, 8 of whom had gastric cancer, and these patients were treated with ATG-022 at doses of 0.3 to 3.0 mg/kg. Those with gastric cancer enrolled in the dose-expansion portion (n = 37) received 2.4 mg/kg of ATG-022 once every 3 weeks. Among patients in the dose-escalation cohort, only 1 dose-limiting toxicity of grade 3 nausea in 6 patients occurred at 3.0 mg/kg.

In the dose-expansion cohort evaluating ATG-022 at 2.4 mg/kg, 32.4% of patients experienced at least 1 serious treatment-emergent adverse effect (TEAE), and 40.5% had grade 3 or greater TEAEs. The most common TEAEs included decreased neutrophil count (51.1%), nausea (48.6%), and decreased white blood cell count (43.2%). Of note, no ophthalmological or neurological toxicities were observed.

Regarding efficacy, among patients with gastric cancer (n = 21) who underwent at least 1 tumor evaluation and had high CLDN 18.2 expression (≥immunohistochemistry [IHC] 2+), 9 patients experienced partial responses (PRs), and 11 had stable disease, translating to an overall response rate (ORR) of 42.9% and a disease control rate (DCR) of 95.2%.

Additionally, 10 patients with gastric cancer with low CLDN18.2 expression (<IHC 2+) treated with the efficacious dosage of 1.8 to 2.4 mg/kg of ATG-022; of these patients, 1 achieved a complete response (CR) and 2 had PRs. The ORR was 30%, and the DCR was 50%. Of note, the patient with a CR demonstrated a durable response and was on the study for more than 14 months as of the cutoff date.

“ATG-022 demonstrated a manageable safety profile and encouraging preliminary antitumor effects in [patients with] gastric cancer with high CLDN18.2 expression and low/ultralow CLDN18.2 expression, suggesting further clinical investigation in patients with variable CLDN18.2 expression,” lead study author Jinfeng Ma, MD, of Shanxi Cancer Hospital in China, and colleagues wrote in a poster presentation of the data. “The enrollment of [patients with] gastric cancer for dose optimization and [patients with] other solid tumors is ongoing.”

Background and CLINCH Trial Design

ATG-022 is an ADC that targets CLDN18.2 expressed in gastric and solid tumors. The agent has demonstrated activity across CLDN18.2 expression levels, including moderate to high (≥20%), low (5%-20%), and ultralow (≤5%) expression levels.

The phase 1 CLINCH study included dose-escalation and -expansion phases. Eligibility criteria included patients at least 18 years of age; histological or cytological confirmation of a solid tumor that progressed on standard therapies or intolerance to/not applicable for standard therapies; at least 1 measurable lesion per RECIST 1.1 criteria; and an ECOG performance status of 0 or 1.2

Patients from the dose-expansion phase had advanced solid tumors regardless of CLDN18.2 expression and were treated with 0.3 to 3.0 mg/kg of ATG-022 once every 3 weeks.1 The agent was evaluated for safety, tolerability, and pharmacokinetics. Patients who were CLDN18.2-positive (≥ IHC 1+) were enrolled in the dose-expansion phase to receive 2.4 mg/kg or 1.8 mg/kg of ATG-022 once every 3 weeks. This portion of the phase evaluated the efficacy and safety of the respective dose levels.

The primary end point of the study included the incidence of DLTs and AEs; secondary end points included ORR and DCR per RECIST 1.1 criteria.

Additional Safety Findings

Regarding safety, patients with at least one TEAE included 100% treated with 0.3 mg/kg of ATG-022 (n = 1), 100% treated with 0.9 mg/kg (n = 3), 100% treated with 1.8 mg/kg (n = 3), 100% treated with 2.4 mg/kg (n = 3), 100% treated with 3.0 mg/kg (n = 6), and 89.2% in the dose-expansion phase treated with 2.4 mg/kg (n = 37). In each respective dose cohort, serious TEAEs occurred in 100%, 0%, 33.3%, 33.3%, 83.3%, and 32.4% of patients; grade 3 or 4 TEAEs occurred in 0%, 33.3%, 66.7%, 66.7%, 100%, and 40.5% of patients, respectively.

TEAEs leading to dose interruption in the cohorts evaluating ATG-022 at 0.3 mg/kg, 0.9 mg/kg, 1.8 mg/kg, 2.4 mg/kg, 3.0 mg/kg, and 2.4 mg/kg occurred in 0%, 33.3%, 33.3%, 33.3%, 83.3%, and 24.3% of patients, respectively; TEAEs leading to patients withdrawing from treatment were reported in 0%, 0%, 33.3%, 0%, 33.3%, and 8.1% of patients, respectively. TEAEs leading to dose reduction occurred in 13.5% of patients in the 2.4 mg/kg cohort, and TEAEs leading to death occurred in 1 patient (33.3%) in the 3.0-mg/kg cohort and 3 patients (8.1%) in the 2.4-mg/kg cohort.

Among the 37 patients in the dose-expansion phase receiving 2.4 mg/kg of ATG-022, the most common TEAEs included decreased neutrophil count (any-grade, 51.4%; ≥grade 3, 18.9%), nausea (48.6%; 2.7%), decreased white blood cell count (43.2%; 2.7%), decreased weight (40.5%; 0%), decreased appetite (37.8%; 8.1%), hypoalbuminemia (37.8%; 0%), anemia (37.8%; 5.4%), vomiting (21.6%; 2.7%), alopecia (16.2%; 0%), diarrhea (16.2%; 0%); fatigue (13.5%; 2.6%), malaise (13.5%; 0%), increased blood lactate dehydrogenase levels (10.8%; 0%), increased blood alkaline phosphatase levels (10.8%; 0%), increased gamma-glutamyl transferase levels (10.8%; 0%), hypokalemia (10.8%; 0%), and pyrexia (10.8%; 0%).

References

1. Ma J, Cao D, Zhao Q, et al. Safety and preliminary efficacy of ATG-022 in patients with advanced/metastatic gastric cancer (CLINCH). J Clin Oncol. 2025;43(suppl 4):456. doi: 10.1200/JCO.2025.43.4_suppl.456
2. A study of ATG-022 in patients with advanced/metastatic solid tumors (CLINCH). ClincialTrials.gov. Updated April 10, 2014. Accessed January 28, 2025. https://clinicaltrials.gov/study/NCT05718895