Conversion surgery following zolbetuximab-based chemotherapy for CLDN18.2-positive gastroesophageal junction cancer.

Abstract

Gastric cancer remains a major cause of cancer-related mortality worldwide. Systemic chemotherapy is the primary treatment strategy for unresectable or metastatic gastric cancer, but long-term survival remains poor. Zolbetuximab, a monoclonal antibody targeting claudin-18 isoform 2 (CLDN18.2), has demonstrated efficacy in combination with chemotherapy for CLDN18.2-positive gastric and gastroesophageal junction (GEJ) adenocarcinomas. In select cases, systemic therapy can lead to a significant reduction in tumor burden, enabling conversion surgery, which has been associated with favorable outcomes. However, reports on zolbetuximab-based regimens facilitating conversion surgery remain scarce. A 27 year-old man presented with progressive dysphagia, nausea, and weight loss. Endoscopy revealed a type 3 GEJ adenocarcinoma (Siewert type II), and imaging confirmed liver and lymph-node metastases. Pathological analysis identified CLDN18.2 positivity, HER2 negativity (score 1 +), mismatch repair proficiency, and CPS 1 ≤ 5. The patient was treated with six cycles of zolbetuximab-CAPOX (zolbetuximab, capecitabine, and oxaliplatin), resulting in complete regression of liver metastases and significant tumor shrinkage. PET-CT showed no distant metastases, and endoscopic evaluation confirmed tumor regression with resolution of treatment-related gastritis. Given the disappearance of non-curative factors, conversion surgery was performed. The patient underwent robot-assisted proximal gastrectomy with lower esophagectomy, D2 lymphadenectomy, and esophagogastrostomy with Delta anastomosis. Histopathological examination revealed a moderately differentiated adenocarcinoma (tub2 > por2) with residual tumor cells, classified as ypT3N1. Significant fibrosis and necrosis were observed within the tumor, with a histological response grade of 2a, indicating viable tumor cells with extensive treatment-induced changes. Surgical margins were negative, and no lymphovascular invasion was detected. The patient recovered uneventfully and was able to resume chemotherapy early, on postoperative day 20. This case demonstrates the potential of zolbetuximab-based chemotherapy in facilitating conversion surgery for CLDN18.2-positive GEJ adenocarcinoma. While clinical trials suggest reduced efficacy of zolbetuximab in GEJ cancer compared to gastric cancer, our case highlights the possibility of exceptional responses in select patients. Additionally, transient treatment-related gastritis observed during therapy raises questions about the effects of CLDN18.2 inhibition on gastric mucosal integrity. Further research is warranted to refine patient selection for CLDN18.2-targeted therapy and investigate its broader physiological effects.