Antibody-Drug Conjugates in Gastric Cancer: Clinical Progress, Resistance, and the Road Ahead

Gastric cancer, the fifth most common cancer and the third most common cause of cancer death globally, continues to pose a formidable clinical challenge, marked by its late detection, complex molecular landscape, and poor prognosis. [1] And while, over the past 5 years, the treatment landscape of gastric cancer has rapidly evolved with the integration of biomarker-informed strategies designed to guide the use of immune checkpoint inhibitors and targeted therapies in molecularly defined subgroups, including microsatellite-unstable, PD-L1-expressing, human epidermal growth factor-2 (HER2)-positive, and claudin 18.2-positive disease, the current standard of care remains based on fluoropyrimidine-platinum chemotherapy backbones, usually combined with capecitabine or 5-FU with oxaliplatin/cisplatin.[2]

Traditional chemotherapy offers only modest benefit, sparking an urgent need for more precise and effective treatment strategies. In this context, antibody-drug conjugates (ADCs)—engineered molecules that deliver cytotoxic payloads directly to cancer cells via antigen-specific antibodies—have emerged as a transformative therapeutic class, combining potent efficacy with reduced off-target toxicity.

Clinical Advances and Novel Targets
Recent years have witnessed remarkable progress in the development of ADCs for gastric cancer for targeting HER2, CLDN18.2, TROP2, CEACAM5/6, and HER3 [3], with several agents demonstrating significant therapeutic activity:

• HER2: ADCs such as trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca), a topoisomerase I inhibitor ADC, and disitamab vedotin (Aidixi®; RemeGen), a HER2-targeting ADC, have redefined the standard of care in pretreated HER2-positive gastric cancer, offering improved survival and response rates.
• CLDN18.2 and TROP2: Early clinical data on ADCs targeting CLDN18.2 (including CMG901) and TROP2 (including investigational ADCs such as SKB264 (MK-2870), a novel ADC with a topoisomerase I inhibitor payload, and OBI-992, a highly specific TROP2 ADC shown in preclinical studies to produce superior tumor reduction, are equally promising, and these agents are now being evaluated in earlier lines of therapy and in combination regimens.[3]
• Additional Targets: Ongoing research is exploring ADCs against CEACAM5/6, HER3, and other markers, expanding the therapeutic arsenal for advanced disease.

Redefining HER2: HER2-Low and Combination Strategies
HER2-positive gastric cancer is a distinctive molecular subtype, often exhibiting chromosomal instability and heterogeneous HER2 expression. While HER2-targeted therapies have improved outcomes, resistance remains a persistent challenge. One key advance is the recognition of HER2-low tumors—previously overlooked by earlier therapies. New-generation ADCs, such as trastuzumab deruxtecan, with high drug-to-antibody ratios, cleavable linkers, and a potent bystander effect, now extend treatment benefits to a broader population and have set a new standard for patients previously treated for HER2-positive disease.[4]

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Preclinical studies further suggest that combining HER2-targeted ADCs with other ADCs, such as the anti-nectin-4-targeting ADC enfortumab vedotin (Padcev®; Astellas Pharma and Pfizer), approved for the treatment of advanced urothelial cancer, can synergistically enhance antitumor efficacy and overcome resistance in both breast and gastric cancer models because HER2-positive breast and gastric cancers frequently express nectin-4. These rationally designed ADC combinations represent a promising direction for future therapy.[4][5]

Claudin Proteins: A New Frontier in Precision Oncology
Claudins (CLDNs), a family of transmembrane proteins critical for tight junction integrity, are frequently over-expressed in various solid tumors—including gastric cancer. Their expression is closely linked to tumor subtype, grade, and prognosis. [5] Studies have shown that dysregulated CLDN expression modulates oncogenic signalling, which, in turn, contributes to tumor proliferation, epithelial-mesenchymal transition, stemness, fibrosis, immune modulation, and therapeutic resistance. [6]

• CLDN18.2 has emerged as a particularly attractive therapeutic target. Monoclonal antibodies and ADCs directed against CLDN18.2 have achieved clinical approval, validating this precision approach.
• Innovative strategies—including bispecific antibodies and CAR T-cell therapies—are in development, offering new hope for biomarker-selected patients and further expanding the landscape of targeted therapy.

Overcoming Resistance: Mechanisms and Innovations
Despite notable advances, acquired resistance to ADCs remains a major obstacle. [7] Key resistance mechanisms include:

• Antigen Loss or Heterogeneity: Tumor cells may lose or vary expression of the target antigen, reducing ADC efficacy.
• Impaired Internalization/Lysosomal Processing: Defects in ADC uptake and payload release can limit therapeutic impact.
• Increased Drug Efflux: Enhanced export of cytotoxic agents diminishes intracellular drug concentrations.
• Tumor Microenvironment: Immunosuppressive factors can further impede ADC delivery.
• Signaling Pathway Reactivation: In HER2-positive cases, resistance can arise through alternative receptor signaling, reactivation of downstream pathways (PI3K-AKT, MAPK), or changes in HER2 expression.
• Transcriptional Reinforcement: Recent studies highlight the RUNX-SOS1 axis as a mechanism sustaining oncogenic signaling despite receptor inhibition [8]

Future Directions and Emerging Strategies
To address resistance and improve outcomes, [9] ongoing research is focused on:

• Deeper Mechanistic Understanding: Elucidating pathways that drive resistance for smarter therapy design.
• Biomarker-Guided Patient Selection: Refining criteria to match patients with the therapies most likely to benefit them.
• Innovation: Advancing ADC designs with novel targets, improved linkers, and cytotoxic payloads.
• Combination Approaches: Exploring synergy with chemotherapy, immunotherapy, and other targeted agents.
• Next-Generation Technologies: Leveraging circulating tumor DNA and theranostic agents for real-time monitoring, treatment selection, and early response assessment.

Antibody-drug conjugates have revolutionized the management of gastric cancer, particularly in molecularly defined subgroups. Continued progress in understanding resistance mechanisms, optimizing patient selection, and developing next-generation ADCs—alone or in combination—will be crucial for achieving better, more durable outcomes in this challenging disease.

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Note: * Disitamab vedotin (RC48) is approved in China for HER2-overexpressing cancers, particularly gastric and urothelial cancers being developed by RemeGen. In the United States, the drug is an investigational drug developed by Pfizer). The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to disitamab vedotin in September 2020 for the treatment of HER2-positive locally advanced or metastatic urothelial cancer (UC) in patients who progressed after platinum-based chemotherapy.

Highlights of prescription information
Trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Enfortumab vedotin (Padcev®; Astellas Pharma and Pfizer)[Prescribing Information]

References
[1] Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet. 2020 Aug 29;396(10251):635-648. doi: 10.1016/S0140-6736(20)31288-5. PMID: 32861308.
[2] Choo J, Sargsyan A, Khachatryan V, Lonardi S, Pietrantonio F, Sundar R, Klempner S, Janjigian Y. Advances in the management of metastatic gastric cancer: current strategies and emerging therapeutics. Nat Rev Clin Oncol. 2026 Mar 10. doi: 10.1038/s41571-026-01134-1. Epub ahead of print. PMID: 41807638.
[3] Li W, Cheng M, Han H, Xu M, Luo Y, Bi F, Liu M. Antibody-drug conjugates in gastric cancer: clinical advances and resistance mechanisms. Gastric Cancer. 2026 Mar;29(2):300-320. doi: 10.1007/s10120-025-01703-w. Epub 2026 Jan 4. PMID: 41484653.
[4] Yazdi N, Pourjamal N, Li H, Laakkonen P, Joensuu H, Barok M. Combining an anti-HER2 antibody-drug conjugate with an anti-nectin-4 antibody-drug conjugate enhances efficacy in breast cancer and gastric cancer models. Cancer Cell Int. 2026 Mar 3;26(1):125. doi: 10.1186/s12935-026-04246-x. PMID: 41776522; PMCID: PMC12980906.
[5] Zheng ZN, Ye XH, Shen XB, Li T, Guo J. Advances in Targeted Therapy for Human Epidermal Growth Factor Receptor 2-Low Tumors: From Trastuzumab to Antibody-Drug Conjugates. World J Oncol. 2026 Mar 5;17(2):129-142. doi: 10.14740/wjon2718. PMID: 41822315; PMCID: PMC12978402.
[6] Saviano A, Toso A, Klempner SJ, Baumert TF. Claudin proteins as emerging therapeutic targets for solid tumours. Nat Rev Cancer. 2026 Mar 2. doi: 10.1038/s41568-026-00913-3. Epub ahead of print. PMID: 41772030.
[7] Choo J, Sargsyan A, Khachatryan V, Lonardi S, Pietrantonio F, Sundar R, Klempner S, Janjigian Y. Advances in the management of metastatic gastric cancer: current strategies and emerging therapeutics. Nat Rev Clin Oncol. 2026 Mar 10. doi: 10.1038/s41571-026-01134-1. Epub ahead of print. PMID: 41807638.
[8] Masuda T, Watanabe T, Ozaki T, Kamikubo Y. Transcriptional Reinforcement of the HER2-RAS Network in HER2-Positive Gastric Cancer: The RUNX-SOS1 Axis in Context. Cancer Sci. 2026 Mar 17. doi: 10.1111/cas.70364. Epub ahead of print. PMID: 41845875.
[9] Troxell ML. Repurposing HER2 IHC: Pan-HER2 and Low-HER2. Appl Immunohistochem Mol Morphol. 2026 Mar 23. doi: 10.1097/PAI.0000000000001316. Epub ahead of print. PMID: 41873944.

Featured Image: Human stomach structure. Courtesy: 2016 – 2026 © Fotolia/Adobe. Used with permission.

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