Comparison of CLDN18/CLDN18.2 IHC assays (43-14A vs EPR19202) and the correlation with clinical efficacy in patients with gastric/gastroesophageal junction adenocarcinoma treated by the novel antibody-drug conjugate XNW27011.

4061 Background: Claudin 18.2 (CLDN18.2), the dominant isoform of CLDN18 in gastric tissues, is a highly specific tight junction protein of the gastric mucosa with considerably retained expressions in gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, making it a clinically actionable therapeutic target. Accurate immunohistochemical (IHC) assessment of CLDN18.2 expression is critical for patient selection in CLDN18.2-targeted therapies. Here, we report the findings of the analytical comparability, concordance and clinical efficacy outcomes between two CLDN18/CLDN18.2 antibodies (VENTANA CLDN18 43-14A and Abcam CLDN18.2 EPR19202), from a Phase I/II study of a novel antibody-drug conjugate XNW27011 (NCT06792435). Methods: This retrospective study utilized formalin-fixed paraffin-embedded (FFPE) samples of 121 patients with G/GEJ adenocarcinoma enrolled in the Phase I/II study of XNW27011. Each sample was stained with CLDN18 (43-14A) and CLDN18.2-specific (EPR19202) antibodies. Efficacy in objective response rate (ORR) was evaluated across CLDN18/CLDN18.2 expression strata defined by each assay antibody in patients treated with XNW27011 at doses of 2.4–6.0 mg/kg administered intravenously every 3 weeks. Concordance between the two assay antibodies was assessed by the percentage of the overall agreement (positive or negative) primarily at the cutoff of ≥20% tumor cells with 2+ to 3+ membranous staining. Results: Therapeutic efficacy outcomes of XNW27011 in ORR were highly consistent across expression strata defined by either 43-14A or EPR19202 assay antibody. In patients with CLDN18/CLDN18.2 expression defined as IHC ≥2+ in ≥20% of tumor cells, ORRs were 45.5% and 45.3% using EPR19202 and 43-14A assay antibody, respectively. EPR19202 and 43-14A IHC assays demonstrated high concordance, with an overall agreement of 90.1%. Conclusions: The IHC assays of CLDN18.2 expression with EPR19202 or CLDN18 expression with 43-14A demonstrate comparable analytical performance with high concordance. The alignment of efficacy outcomes across the two antibody-defined strata supports that CLDN18 and CLDN18.2-specific antibodies can identify patient populations with similar clinical benefit. Both antibodies can support the clinical development of XNW27011 in the treatment of patients with G/GEJ adenocarcinoma.