ASKB589 Plus CAPOX and Sintilimab Demonstrates Early Efficacy in Gastric/GEJ Cancers

The humanized IgG1 monoclonal antibody against CLDN18.2 ASKB589 demonstrated anti-tumor activity and a good safety profile in combination with capecitabine and oxaliplatin (CAPOX) plus the PD-1 inhibitor sintilimab (Tyvyt) in patients with gastric or gastroesophageal junction cancers (GEJ), according to data from an ongoing phase 1/2 trial (NCT05632939) presented during the 2024 Gastrointestinal Cancers Symposium.¹

In the dose-escalation and dose expansion study, the disease control rate among patients with measurable CLDN18.2 moderate or high disease who received 6 mg/kg of ASKB589 plus CAPOX and sintilimab (n = 45) was 100%. Additionally, 80% of patients achieved a partial response and 20% of patients experienced stable disease. At the data cutoff, among patients who received ASKB589 at 6 mg/kg (n = 53), 77.3% were ongoing treatment and there were no treatment discontinuations due to adverse effects (AEs) related to ASKB589 in the trial.

Patients with locally advanced, relapsed and metastatic gastric or GEJ adenocarcinoma who were not candidates for surgery or radical radiotherapy received ASKB589 at 10.0 mg/kg (n = 6) or 6.0 mg/kg (n = 3) plus CAPOX and sintilimab in the dose-escalation 3+3 designed portion of the study. No dose-limiting toxicities (DLTs) were observed, and patients received the agent at 6 mg/kg in the dose-expansion portion of the trial.¹

A phase 3 trial has also been approved for initiation in China to the evaluate this combination in patients with gastric or GEJ cancers.²

The primary end points of the study included identification of the maximum tolerated dose and recommended phase 3 dose, safety and tolerability, and DLTs. Secondary end points included characterization of the pharmacokinetics, progression-free survival, and overall survival. Patients enrolled had an ECOG performance score of 0 or 1; adequate bone marrow, heart, liver, and renal function; an expected survival of at least 3 months; and had CLDN18.2-positive disease. Further, chemotherapy plus immunotherapy had to be suitable as a first-line treatment or patients could have experienced progression following 6 months of chemotherapy.¹

The median age of all patients in the trial (n = 62) was 59.0 years (range, 30-75) and most patients were male (66.1%). Additionally, most patients had an ECOG performance score of 1 (66.1%), 0 to 2 sites of metastases (75.8%), gastric cancer (87.1%) as opposed to GEJ (12.9%), and had not received prior gastrectomy (88.7%). Lauren types included diffuse (17.7%), intestinal (14.5%), mixed (8.1%), and unknown (59.7%), and patients had PD-L1 combined positive scores of less than 1 (40.3%), 1 to 5 (22.6%), and 5 or higher (37.1%).¹

Patients had CLDN18.2 expression that was low (16.1%), moderate (21.0%), and high (62.9%) and was assessed using the IHC DS-3 LDT assay on the Leica BOND-III autostainer platform. Investigators noted that high comparability was observed with CLDN18.2 staining by DS-3 and 43-14A.

At the 6 mg/kg dose, 94.6% of patients expereinced an any grade treatment-emergent AE (TEAE) and 42.9% experienced a grade 3 or higher TEAE; these respective rates were 100.0% and 16.7% at the 10 mg/kg dose. The most common any-grade TEAEs occurring at the 2 dose levels were hypoalbuminemia (76.8% vs 83.3%, respectively), nausea (66.1% vs 66.7%), anemia (55.4% vs 66.7%), decreased neutrophil count (55.4% vs 50.0%), vomiting (53.6% vs 33.3%), hypocalcemia (42.9% vs 50.0%), decreased leukocyte count (37.5% vs 50.0%), decreased weight (33.9% vs 50.0%), increased aspartate aminotransferase level (33.9% vs 16.7%), and decreased platelet count (26.8% vs 66.7%), among others.

TEAEs of grade 3 or greater in the 6 mg/kg group included decreased neutrophil count (16.1%), vomiting (7.1%), hypocalcemia (5.4%), decreased platelet count (5.4%), fatigue (3.6%), hypokalemia (3.6%), anemia (3.6%), decreased appetite (3.6%), and decreased leukocyte count (1.8%). The only grade 3 or higher TEAE patients who received the 10 mg/kg dose experienced was decreased neutrophil count (16.1%).¹

References

1. Peng Z, He Y, Chen J, Hickingbottom B, Lu J, Shen L. A phase lb/ll study of ASKB589 (anti-CLDN18.2 monoclonal antibody) in combination with CAPOX and PD-1 inhibitor as a first-line treatment of locally advanced, relapsed and metastatic G/GEJ cancer (NCT05632939). J Clin Oncol. 2024;42(suppl 3):317. doi:10.1200/JCO.2024.42.3_suppl.317
2. AskGene Pharma received clearance to commence pivotal phase III clinical trial in China for ASKB589. News release. AskGene Pharma. October 16, 2023. Accessed January 18, 2024. https://ask-gene.com/askgene-pharma-received-clearance-to-commence-pivotal-phase-iii-clinical-trial-in-china-for