Gastric cancer is one of the most common malignancies worldwide and is characterized by pronounced molecular and phenotypic heterogeneity.

In 2020, there were approximately 1.089 million new cases and 769,000 deaths globally, ranking fifth in incidence and fourth in cancer-related mortality.

Its pathogenesis is associated with multiple genetic and molecular alterations, including aberrant growth factor and receptor signaling, defects in DNA damage repair pathways, and increased genomic instability. These changes provide a biological basis for targeted therapies.

Currently, several key therapeutic targets have been identified or are under active investigation, including HER2, CLDN18.2, FGFR, VEGFR, TROP2, PD-L1, and DKK1.

Among targeted therapeutic strategies, antibody–drug conjugates (ADCs) have become a major focus in gastric cancer research due to their dual mechanism of “precise targeting + potent cytotoxicity.”

More than 100 ADCs are currently in clinical development, and approximately 15 have been approved globally. Among them, trastuzumab deruxtecan (DS-8201a, T-DXd), disitamab vedotin (RC48), and sacituzumab govitecan (IMMU-132) have been used in the treatment of advanced gastric cancer.

The global pharmaceutical distributor DengYueMed plays an important role in oncology drug supply chain integration and clinical information connectivity, supporting global accessibility and research collaboration for complex solid tumors such as gastric cancer.

I. Main Targets of ADCs in Gastric Cancer

1. HER2

HER2 is one of the most established targets in gastric cancer.

Early ADC therapy with ado-trastuzumab emtansine (T-DM1) showed significant efficacy in breast cancer; however, it failed to demonstrate meaningful benefit in gastric cancer, likely due to marked HER2 heterogeneity (as observed in the GATSBY study).

In contrast, the next-generation HER2-targeting ADC trastuzumab deruxtecan (DS-8201a, T-DXd) has shown substantial clinical advantages. Its high membrane permeability enables a “bystander effect,” allowing activity against tumors with low or heterogeneous HER2 expression.

In addition, disitamab vedotin (RC48) has been approved in China for gastric cancer and continues to demonstrate encouraging antitumor activity in multiple clinical studies.

Other investigational HER2 ADCs, including ARX788 and PF-06804103, have also shown promising antitumor potential.

2. EGFR and HER3

EGFR and HER3 are also overexpressed in subsets of gastric cancer.

● MRG003: the first EGFR-targeting ADC evaluated in clinical studies, currently in Phase II trials for advanced gastric cancer

● BL-B01D1: a bispecific EGFR/HER3 ADC representing a next-generation dual-target design

● AMT-562: demonstrates durable antitumor responses in HER3-expressing tumor models

These agents represent a transition from single-target to dual-target ADC development.

3. CLDN18.2

CLDN18.2 is one of the most promising recent breakthroughs in gastric cancer, stably expressed in approximately 60% of cases.

● CMG901 (AZD0901) demonstrated an objective response rate (ORR) of approximately 33% in early studies

● EO-3021 (SYSA1801) showed an ORR of 47.1% in gastric cancer patients

Additionally, LM-302 and TORL-2-307 are being further evaluated as monotherapy or in combination with immunotherapy.

4. GCC

Guanylyl cyclase C (GCC) is highly expressed in gastrointestinal tumors. However, ADCs targeting GCC, such as TAK-264, have shown limited clinical efficacy. Despite this, GCC remains a promising long-term target due to its broad expression profile.

5. TROP2

TROP2 is currently one of the most actively investigated ADC targets.

●       IMMU-132 (sacituzumab govitecan): has demonstrated clinical activity in gastric cancer

●       SKB264 (sacituzumab tirumotecan): being evaluated in multiple tumor types, including treatment-resistant patients

●       DS-1062 (datopotamab deruxtecan): shows strong antitumor activity in gastric cancer models

TROP2 ADCs typically use topoisomerase I inhibitors as payloads, contributing to strong cytotoxic effects.

6. SLC44A4

SLC44A4 is clearly expressed in gastric cancer. The ASG-5ME study demonstrated a disease control rate of approximately 47% in gastric cancer patients, suggesting it as a potential emerging therapeutic target.

II. Combination Strategies of ADCs in Gastric Cancer

With increasing therapeutic demands, ADCs are shifting from monotherapy toward combination strategies.

1. Combination with monoclonal antibodies (mAbs)

Studies have shown that ADCs combined with antibodies significantly improve efficacy:

● ARX788 +      trastuzumab: significantly prolonged progression-free survival (PFS) and overall survival (OS)

● T-DXd + trastuzumab: improved ORR and survival outcomes

Ongoing trials such as DESTINY-Gastric04 are further evaluating optimized regimens.

2. Combination with immunotherapy

ADCs can enhance tumor immunogenicity by:

● promoting dendritic cell activation

● upregulating PD-L1 expression

● increasing CD8+ T-cell infiltration

Examples include:

● RC48 + PD-1 inhibitor (JS001): ORR 43%, median OS 16.8 months

● T-DXd +      durvalumab: currently under evaluation for safety and preliminary efficacy

3. Combination with chemotherapy and other targeted agents

● RC48 + chemotherapy showed ORR of approximately 24.8% in advanced gastric cancer

●       Pyrotinib enhances HER2 internalization and increases T-DXd uptake

● WEE1 inhibitor + T-DXd increases DNA damage accumulation and enhances cytotoxicity

● Lovastatin may increase HER2 surface expression, improving ADC binding efficiency

These strategies reflect a combined mechanism of “enhanced internalization + impaired DNA repair + increased payload release.”

III. Challenges and Future Perspectives of ADCs in Gastric Cancer

Despite major progress, several challenges remain:

● Tumor heterogeneity leading to variable responses

● Complex mechanisms of drug resistance

● Need for improved toxicity management

● Lack of established optimal combination strategies

Future directions may include:

● Development of next-generation linkers with improved stability and controlled release

● Novel high-potency payloads

● Bispecific ADCs

● More precise patient stratification strategies

● Deeper integration with immunotherapy

Conclusion

ADCs represent a major breakthrough in precision treatment of gastric cancer, particularly targeting HER2, CLDN18.2, and TROP2, where significant clinical benefits have been observed.

With ongoing advances in drug development and combination strategies, ADCs are expected to further transform the treatment landscape of advanced gastric cancer.

In parallel, research into multi-target strategies and combination optimization continues to accelerate. Further details can be found in:

“2026 Gastric Cancer Treatment Drug Guide: Latest Dual-Target Therapies, 12 Approved Treatments, and 5 Emerging Technologies”, which provides an overview of the latest approved therapies and emerging technologies.

The global pharmaceutical distributor DengYueMed continues to monitor and integrate global advances in ADC and innovative oncology drug development, supporting clinical research, drug accessibility, and international collaboration.