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Complete Mechanism Overview

ZELVARA (celdatuzumab) targets CLDN18.2 exposed on gastric/GEJ tumor cells, engaging dual mechanisms of tumor destruction: ADCC via NK cell degranulation releasing perforin and granzymes, and CDC via C1q-initiated complement cascade assembling the membrane attack complex (MAC, C5b-9) to induce osmotic lysis.

About CLDN18.2

Claudin 18.2 is a tight junction protein normally expressed in differentiated gastric epithelial cells but hidden within intact tight junctions. In gastric and GEJ adenocarcinomas, loss of cell polarity exposes CLDN18.2 on the tumor cell surface, creating a highly selective therapeutic target with limited expression in normal tissues.

Target Selectivity

CLDN18.2 expression has been detected in approximately 60% of gastric adenocarcinomas and 18% of GEJ tumors. In the BEACON-1 and BEACON-2 trials, CLDN18.2 positivity was defined as ≥75% of tumor cells showing moderate-to-strong membranous staining by immunohistochemistry (IHC 2+/3+).

Dual Mechanism of Tumor Cell Destruction

Antibody-Dependent Cellular Cytotoxicity (ADCC)

Upon binding CLDN18.2, the Fc region of celdatuzumab engages FcγRIIIa (CD16) on natural killer (NK) cells, triggering degranulation and release of cytotoxic mediators (perforin and granzymes) that directly lyse the target tumor cell.

Complement-Dependent Cytotoxicity (CDC)

The Fc region simultaneously activates the classical complement cascade by binding C1q, initiating a proteolytic cascade that culminates in assembly of the membrane attack complex (MAC, C5b-9), forming pores in the tumor cell membrane and inducing osmotic lysis.

Expert Commentary

Hear from leading investigators on the clinical significance of CLDN18.2 targeting in gastric and GEJ adenocarcinoma.

4:32

MOA Deep Dive

Understanding the Dual ADCC/CDC Mechanism

Dr. Sarah Chen, MD PhD — Stanford Cancer Institute

6:15

Clinical Perspective

BEACON Trial Results: What They Mean for Practice

Dr. James Nakamura, MD — Memorial Sloan Kettering

3:48

Biomarker Testing

CLDN18.2 Testing in Clinical Practice

Dr. Maria Rodriguez, MD — MD Anderson Cancer Center

Video content is illustrative of a typical KOL video library. Speakers and institutions are fictional.

Important Safety Information

The most common adverse reactions (≥20%) with ZELVARA plus chemotherapy were nausea, vomiting, decreased appetite, fatigue, diarrhea, and peripheral neuropathy. Severe nausea and vomiting can occur; administer antiemetic prophylaxis prior to and during treatment. See Full Prescribing Information.

Important Safety Information

INDICATIONS AND USAGE

ZELVARA (celdatuzumab-mkrz) is indicated, in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative, claudin 18.2 (CLDN18.2)-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. CLDN18.2 positivity should be determined by an FDA-approved test.

Warnings and Precautions

Nausea and Vomiting: ZELVARA can cause severe nausea and vomiting. In the BEACON-1 trial, nausea occurred in 70.2% of patients treated with ZELVARA plus chemotherapy, including Grade 3 events in 14.8%. Vomiting occurred in 64.8%, including Grade 3 events in 12.1%. Administer antiemetic prophylaxis prior to and during treatment. Withhold, dose reduce, or permanently discontinue based on severity. Infusion-Related Reactions: Infusion-related reactions have been reported. Monitor patients during and after infusion. Interrupt or slow the rate of infusion for mild to moderate reactions. Permanently discontinue for severe or life-threatening reactions. Embryofetal Toxicity: Based on its mechanism of action and findings from animal studies, ZELVARA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose.

Adverse Reactions

The most common adverse reactions (≥20%) in patients receiving ZELVARA plus chemotherapy were nausea (70.2%), vomiting (64.8%), decreased appetite (42.1%), fatigue (38.4%), diarrhea (28.7%), and peripheral neuropathy (22.5%). Serious adverse reactions occurred in 42% of patients treated with ZELVARA plus chemotherapy, including vomiting (8.2%), nausea (4.1%), dehydration (3.8%), and decreased appetite (2.4%). Fatal adverse reactions occurred in 2.1% of patients.

Drug Interactions

No formal drug interaction studies have been conducted with ZELVARA. No clinically significant pharmacokinetic interactions are expected based on the known elimination pathways of celdatuzumab.

Use in Specific Populations

Pregnancy: ZELVARA can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Lactation: Advise women not to breastfeed during treatment and for 3 months after the last dose. Females and Males of Reproductive Potential: Verify pregnancy status prior to initiation. Advise females to use effective contraception during treatment and for 3 months after the last dose. Pediatric Use: The safety and efficacy of ZELVARA have not been established in pediatric patients. Hepatic Impairment: No dose adjustment is recommended for patients with mild hepatic impairment. ZELVARA has not been studied in patients with moderate or severe hepatic impairment.

Mechanism of Action

Complete Mechanism Overview

About CLDN18.2

Target Selectivity

Dual Mechanism of Tumor Cell Destruction

Antibody-Dependent Cellular Cytotoxicity (ADCC)

Complement-Dependent Cytotoxicity (CDC)

Expert Commentary

Understanding the Dual ADCC/CDC Mechanism

BEACON Trial Results: What They Mean for Practice

CLDN18.2 Testing in Clinical Practice

Important Safety Information

WARNING: NAUSEA AND VOMITING

Important Safety Information

INDICATIONS AND USAGE

Warnings and Precautions

Adverse Reactions

Drug Interactions

Use in Specific Populations