Positioning Zolbetuximab in HER2-Negative Advanced Gastric Cancer: A Practical Framework for Treatment Selection in
Tamotsu Sagawa1, Koshi Fujikawa2
1Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo-shi, Hokkaido, 003-0804, Japan. stamotsu@jk9.so-net.ne.jp.
Abstract:
Claudin 18.2 (CLDN18.2) has rapidly evolved from a biologically attractive target to a clinically actionable biomarker in HER2-negative advanced gastric and gastroesophageal junction adenocarcinoma. Following the phase 3 SPOTLIGHT and GLOW trials, zolbetuximab plus fluoropyrimidine/platinum chemotherapy has become a valid first-line option for CLDN18.2-positive disease. However, first-line decision-making is now increasingly complex because treatment selection depends on the integration of HER2, CLDN18, PD-L1 combined positive score (CPS), and MSI/MMR, while no direct comparative trial has established the preferred sequence between zolbetuximab-based therapy and immune checkpoint inhibitor (ICI)-based therapy. In this review, we summarize the biological rationale and pivotal clinical evidence supporting CLDN18.2 targeting and focus on the issues most relevant to practice: the differing clinical roles of CLDN18 and PD-L1 CPS as biomarkers, treatment selection in biomarker-overlap cases, the possibility of deferring PD-1 blockade to later lines in selected patients, pathology and testing pitfalls, and the practical implementation of zolbetuximab-based therapy. 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.
Insights
Claudin 18.2 (CLDN18.2) is a key biomarker for advanced gastric cancer. Zolbetuximab plus chemotherapy is a new first-line option, but integrating it with other biomarkers like PD-L1 requires careful consideration for optimal patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Clinical Trials
Background:
- Claudin 18.2 (CLDN18.2) has emerged as a significant target and biomarker in HER2-negative advanced gastric and gastroesophageal junction adenocarcinoma.
- The approval of zolbetuximab plus chemotherapy marks a new first-line treatment option for CLDN18.2-positive patients, based on SPOTLIGHT and GLOW trials.
Purpose of the Study:
- To review the biological rationale and clinical evidence for CLDN18.2 targeting in gastric cancer.
- To address practical challenges in first-line treatment selection, biomarker interpretation (CLDN18.2, PD-L1 CPS), and treatment sequencing.
- To propose a framework for integrating zolbetuximab into current first-line management strategies.
Main Methods:
- Literature review of biological mechanisms and clinical trial data.
- Analysis of biomarker roles (CLDN18.2, PD-L1 CPS, HER2, MSI/MMR) in treatment selection.
- Discussion of clinical implementation, pathology, testing, and emerging therapeutic strategies.
Main Results:
- Zolbetuximab plus chemotherapy is a validated first-line therapy for CLDN18.2-positive gastric cancer.
- Treatment decisions are complex due to multiple biomarkers and lack of direct comparative trials between zolbetuximab and ICI-based therapies.
- Potential for deferring PD-1 blockade in select patients and emerging triplet strategies.
Conclusions:
- Integrating CLDN18.2 targeting requires a nuanced approach considering multiple biomarkers and treatment sequences.
- A treatment-oriented framework is proposed for optimizing zolbetuximab use in first-line HER2-negative advanced gastric cancer.
- Addressing pathology and testing pitfalls is crucial for successful implementation of CLDN18.2-targeted therapies.
Related Concept Videos
02:56Treatment Resistent Cancers
02:56Treatment Resistant Cancers
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...