Abstract B028: Claudin-18 expression (using the 43-14A antibody kit) in pancreatic ductal adenocarcinoma: Assessment of a potential clinical biomarker for immunotherapy with zolbetuximab
Authors: Arseneau Riley J , Kempster Emma , Bekkers Carley , Sampson Thomas , Gala-Lopez Boris L , Ramjeesingh Ravi , Boudreau Jeanette E , Arnason Thomas 
Published: October 2024

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy; despite efforts to improve outcomes, five-year survival remains below 15% and immunotherapies have largely been unsuccessful. Claudin-18.2 (CLDN18.2), overexpressed in some gastro-intestinal cancers, including PDAC, has emerged as a promising therapeutic target. Zolbetuximab, a monoclonal antibody targeting CLDN18.2, triggers antibody- and complement-dependent cytotoxicity. Zolbetuximab has demonstrated therapeutic benefit in locally advanced and metastatic gastric and gastroesophageal junction cancers in phase 3 clinical trials (SPOTLIGHT and GLOW). A phase 2 clinical trial of zolbetuximab for PDAC patients is underway, with patient eligibility dependent on the expression of CLDN18 in ≥75% of tumor cells. CLDN18 overexpression in PDAC has been reported in research studies using a variety of antibodies, methods, and positivity thresholds. However, minimal population-based expression data uses the 43-14A diagnostic kit from the zolbetuximab clinical trials. The 43-14A antibody will likely become the standard clinical companion diagnostic if PDAC therapeutic trials succeed; hence, understanding its utility for binding and clinical assessment is prescient. Herein, we report the expression of CLDN18 using the 43-14A antibody kit in a retrospective Atlantic Canadian cohort of patients with PDAC. Methods: Immunohistochemical staining of CLDN18 was performed using the 43-14A antibody on PDAC samples (n=121) collected from patients who underwent surgical resection between 2012 and 2024 in Nova Scotia. Formalin-fixed paraffin-embedded samples were stained by immunohistochemistry with the 43-14A clone, prediluted kit, according to the kit manufacturer’s recommended protocol on the recommended platform (Benchmark ULTRA), consistent with methods employed in clinical trials. A board- certified pathologist, blinded to clinical outcomes, assessed CLDN18 immunostaining. Tumor cell staining proportion and membranous intensity were evaluated, with positive cases defined as ≥ 75% of tumor cells exhibiting membranous staining with an intensity of ≥ 2. Results: Out of 121 PDAC tumors, 39 (32.2%) stained positive for CLDN18. Although no significant associations were identified between CLDN18 positivity and various clinical variables, there was a trend suggesting a potential correlation with lower tumor grade (p = 0.0738). The study was adequately powered to detect significant associations. Conclusions: Our findings indicate that 32.2% of PDAC tumors in this cohort are positive for CLDN18, suggesting that a significant proportion of patients in our population could benefit from zolbetuximab and other CLDN18.2 targeted immunotherapies.

Citation Format: Riley J Arseneau, Emma Kempster, Carley Bekkers, Thomas Sampson, Boris L Gala-Lopez, Ravi Ramjeesingh, Jeanette E Boudreau, Thomas Arnason. Claudin-18 expression (using the 43-14A antibody kit) in pancreatic ductal adenocarcinoma: Assessment of a potential clinical biomarker for immunotherapy with zolbetuximab [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B028.