Vyloy (zolbetuximab-clzb)

Herein, we summarize CLDN18.2 expression in cancer along with clinical trials of zolbetuximab and other CLDN18.2-directed therapies. Given the variability in CLDN18.2 expression within and between tumor types, biomarker-driven approaches will be critical for patient selection in clinical trials and therapeutic approaches.

h1D6 was generated by immunizing CLDN18.2 knockout mice followed by humanization; it exhibited high specificity for CLDN18.2 (no cross-reactivity with CLDN18.1) and improved binding affinity and in vivo efficacy vs. existing antibodies (e.g., IMAB362)...In vivo, 89Zr-labeled h1D6-ADC-5 showed prolonged tumor accumulation in CLDN18.2-positive xenograft, with significant tumor regression (nearly complete regression at 10 mg/kg) while no overt toxicity was observed based on body weight and histology. These preclinical data demonstrate that h1D6-ADC-5 is a promising candidate for treating CLDN18.2-positive cancers.

Zolbetuximab, a CLDN18.2-targeted monoclonal antibody, has been approved in combination with chemotherapy as a first-line treatment option for patients with HER2-negative and CLDN18.2-positive gastric adenocarcinoma...In conclusion, precision targeting of CLDN18.2 represents a promising approach in GC therapy, shifting from conventional chemotherapy to biomarker-guided strategies. Continued development of next-generation agents and rational combination therapies may enhance outcomes and expand benefit.

A 59-year-old man with CLDN18.2-positive stage IV gastric cancer and suspected peritoneal dissemination received zolbetuximab with capecitabine and oxaliplatin. This case suggests that zolbetuximab-based chemotherapy may enable conversion surgery in selected patients. Careful perioperative management is essential, and further studies are needed.

Claudin-18 isoform 2 (CLDN18.2) has rapidly moved from a gastric-lineage surface antigen to an actionable therapeutic target in advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, following the SPOTLIGHT and GLOW Phase 3 trials, which established zolbetuximab plus fluoropyrimidine-platinum chemotherapy as a first-line option for patients with CLDN18.2-positive, HER2-negative disease...Collectively, current evidence supports a reassessment-based rather than assumption-based approach to CLDN18.2 sequencing. However, key gaps remain, including the optimal interface with PD-1-based first-line therapy, the geographic generalizability of several next-generation datasets, standardized retesting strategies at progression, and prospective validation of modality-specific sequencing after target modulation.

We further discuss emerging triplet strategies and next-generation CLDN18.2-targeted platforms. Rather than considering CLDN18.2 as an isolated biomarker, we propose a treatment-oriented framework for integrating zolbetuximab into contemporary first-line management of HER2-negative advanced gastric cancer.

P2, N=143, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: May 2027 --> Nov 2027 | Trial primary completion date: Jul 2026 --> Dec 2026

P2/3, N=126, Not yet recruiting, AstraZeneca AB

Background: Claudin 18.2 (CLDN18.2) has become a clinically relevant therapeutic target in gastric adenocarcinoma (GC), with zolbetuximab now approved for use in CLDN18.2-positive, HER2-negative advanced disease... CLDN18.2 shows excellent intratumoral reproducibility and a stable biological profile in GC, supporting its diagnostic reliability in biopsies and value as a predictive biomarker. A subset with extreme expression demonstrated aggressive features, suggesting a potential "claudin-driven" phenotype requiring further study.

Following multidisciplinary evaluation, irinotecan combined with zolbetuximab was initiated on the basis of individualized adjustment of the hemodialysis schedule. The regimen was well tolerated, associated with stabilization of renal function, and resulted in a marked decline in serum CA19-9 accompanied by a significant shrinkage of peritoneal metastatic lesions on CT imaging, with sustained disease control during treatment. This case highlights that in patients with advanced gastric cancer undergoing hemodialysis, CLDN18.2-targeted therapy combined with chemotherapy may be feasible and safe with close laboratory monitoring and individualized dialysis management and may serve as a valuable reference for personalized treatment in gastric cancer complicated by renal failure.

Zolbetuximab-based chemotherapy may facilitate conversion-intent or response-adapted surgical intervention, including metastasectomy, in carefully selected patients with CLDN18.2-positive gastric and GEJ adenocarcinoma. A biomarker-driven, response-adapted multidisciplinary strategy may help identify candidates for surgery following CLDN18.2-targeted therapy, but larger studies are required to determine whether this approach improves survival outcomes.

Zolbetuximab was launched in June 2024 as an anticancer drug useful for patients with CLDN18.2 positive and HER2 negative curatively unresectable advanced or recurrent gastric cancer. The mechanism and response to side effects such as hypoalbuminemia are still unclear, and more cases need to be accumulated.