The novel approach with antibody-drug conjugate targeting CLDN18.2 trial’s insights and future perspectives

Stomach-specific tight junction protein, claudin18.2 (CLDN18.2), is the newly emerging therapeutic target in advanced gastric cancer (AGC) (1). Lineage-specific expression and exposure through loss of polarity make it an attractive therapeutic target. High expression tends to be enriched in patients with early-onset or diffuse-type gastric cancer who are not eligible for existing targeted treatments (2).

In this issue of the Lancet Oncology, the primary results of a phase 1 KYM901 trial of CMG901 were reported (3). CMG901 is an antibody-drug conjugate (ADC) consisting of a humanized immunoglobulin G1 (IgG1) antibody against CLDN18.2, conjugated to monomethyl auristatin E via a cleavable linker, with a drug-to-antibody ratio of ~4. This study assessed safety and efficacy in patients with solid tumors (dose-escalation) and in metastatic gastric cancer (mGC)/gastroesophageal junction cancer (GEJC) (dose-expansion). The efficacy analysis focused on AGC. CMG901 was administered intravenously every three weeks at 0.3–3.4 mg/kg (dose-escalation) and 2.2–3.0 mg/kg (dose-expansion). Primary endpoints were adverse events (AEs) and dose-limiting toxicity in dose-escalation, and objective response rate (ORR) and recommended phase II dose in dose-expansion. No formal hypothesis testing for ORR was prespecified. In total, 27 patients (including 14 with pancreatic cancer) were enrolled in dose-escalation and 107 with AGC in dose-expansion. Gastrointestinal (GI) and hematologic toxicities were common (50–70%), but mostly grade <3; dose reduction was required in <15% and discontinuation in <10%. Among 113 patients with mGC/GEJC, investigator-assessed ORR was 28% [95% confidence interval (CI): 20–38%]. Considering efficacy and safety, 2.2 mg/kg was selected as the recommended phase II dose.

Given the ORRs of current standard agents (4–15%) (4-6), CMG901 shows potential as a ≥3rd-line option for human epidermal growth factor receptor 2 (HER2)-negative AGC. However, compared with trastuzumab deruxtecan (T-DXd), an anti-HER2 ADC, its outcomes appear modest (7,8). Future directions include combining cytotoxic agents or other ADCs. Efficacy in patients with ≥2+ staining in ≥20% of tumor cells suggests broader applicability beyond the current CLDN18.2-positive definition. CMG901 can induce a bystander effect, which may explain its activity in gastric cancers (GCs) with lower CLDN18.2 expression (9).

The present study was conducted exclusively at Chinese centers. The global phase III CLARITY study (NCT06346392) is going on. IBI343, a humanized Fc-silenced anti-CLDN18.2 ADC with a topoisomerase inhibitor payload, showed comparable efficacy, and its Fc-silencing design may reduce GI toxicity (10). A randomized phase III G-HOPE trial (NCT06238843) is underway (Table 1). Bispecific antibodies are another promising approach, but current ORR is lower than with ADCs (11). CAR-T therapy is also attractive, though cost and complexity remain major challenges (12).

The KYM901 trial underscores a new avenue for targeting CLDN18.2. Finding the optimal cutoff, selecting the appropriate payload, and refining antibody design will likely be key challenges in future development.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-39/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-39/coif). I.N. reports research funding from Astellas, Ono, MSD, Boehringer Ingelheim, Daiichi Sankyo, and Chugai Pharmaceutical Co., Ltd. and Honoraria from Taiho, MSD, Astellas, Daiichi Sankyo, Ono, and Bristol-Myers Squibb. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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