Development of antibody-drug conjugates in gastric cancer: an overview of clinical trials from 2005 to 2025

Abstract

Antibody-drug conjugates (ADCs) have emerged as a novel class of therapeutics for gastric cancer. This study systematically analyzed 294 clinical trials of ADCs conducted from 2005 and April 2025, highlighting key trends, therapeutic advancements, current challenges and future directions in ADC development. The comprehensive analysis encompassed target antigens, linker and payload technologies, geographic distribution, sponsorship patterns, and emerging innovative strategies, offering valuable insights for clinicians, researchers, and pharmaceutical developers.

Introduction

Gastric cancer remains a major global health burden, ranking fifth in both incidence and mortality among all cancers worldwide^[1]. Current therapeutic approaches are often inadequate in advanced stages of the disease, emphasizing the need for more effective treatment strategies. Antibody-drug conjugates (ADCs), which selectively target tumor cells while minimizing systemic toxicity, have emerged as a promising class of therapeutics^[2]. Several ADCs have shown encouraging clinical activity in gastric cancer; however, a comprehensive overview of their clinical development is still lacking. This study is the first to systematically analyze and characterize the current clinical trial landscape of ADCs in gastric cancer, identifying key therapeutic trends, novel strategies, and ongoing challenges in their development. We declare that no artificial intelligence has been used in the research and manuscript development^[3].

Methods

We conducted a comprehensive search using the TrialTrove databases, with the following query: “(Drug Type is Biological > Protein > Antibody > Antibody-drug conjugate) AND (Disease is Oncology: Gastric).” We included interventional clinical trials that specifically investigated ADC therapies across all histological and molecular subtypes of gastric cancer. Exclusion criteria comprised observational studies and trials evaluating agents that were not ADCs. As of 30 April 2025, a total of 330 clinical trials had been identified. After checking by two investigators, 294 trials met the above criteria, which are listed in the Supplementary Digital Content Table, available at: http://links.lww.com/JS9/E649. Key parameters extracted included the trial phase, trial status, trial start date, geographic distribution, sponsor characteristics, primary endpoints, targeted antigens, linker type and payload.

HIGHLIGHTS

• First comprehensive overview of antibody-drug conjugate (ADC) clinical trials specifically in gastric cancer spanning 2005-2025.

• Analysis reveals significant growth in clinical trials, particularly in China and the United States, underscoring strong market interest and clinical need.

• HER2, Claudin 18.2, Trop-2 remain the predominant ADC target, with emerging targets such as ITGB6, 5T4, and STEAP1, and DKK1 gaining research focus.

• Cleavable linkers and topoisomerase I inhibitor (TOP1i) payloads dominate recent ADC designs.

• Bispecific ADCs, dual-drug ADCs and probody-drug conjugates (PDCs) are emerging ADCs format.

• Future development will focus on refinement of ADC design including searching for new molecular targets, developing new linker technologies and diversifying payloads. Combination therapies and tumor microenvironment modulation are also potential strategies.

Results

This study analyzed the landscape of ADCs clinical trials in gastric cancer over a 21-year period from 2005 to 2025, revealing a steadily increasing trend, with the number of trials peaking in 2024. The majority of these trials were early phase studies (Phase I and II) (Fig. 1A), mainly in an open status (Fig. 1B), reflecting vigorous and accelerating efforts in ADC innovation. Geographically, trials were predominantly conducted in China and the United States, highlighting both the unmet clinical need and significant investment in these countries (Fig. 1C). The majority of studies were industry-sponsored, indicating the strong commercial interest and market potential for ADC therapies (Fig. 1D). Regarding primary endpoints, the most commonly assessed indicators were safety and tolerability, adverse events and dose-limiting toxicities (DLTs) (Fig. 1E).

Figure 1.

Analysis of ADCs clinical trials in gastric cancer. A. The annual distribution of clinical trials of ADCs in gatric cancer by Phase. B. Status of ADCs trials in gastric cancer. C. Top 10 countries by number of ADCs trials in gastric cancer. D. Sponsor types of ADCs trials in gastric cancer. E. Top 10 primary endpoints of ADCs trials in gastric cancer. F. Top 10 target antigens in gastric cancer ADCs trials. G. Types and evolving trend of payloads in gastric cancer ADCs trials. H. Linker types in gastric cancer ADCs trials.

Among target antigens, HER2 was the most frequently investigated, followed by Claudin 18.2 and Trop-2 (Fig. 1F). In terms of cytotoxic payloads, tubulin inhibitors and topoisomerase I inhibitors (TOP1i) were the most commonly used. Notably, there has been a recent shift toward increasing use of TOP1i-based ADCs (Fig. 1G). Most ADCs employed cleavable linkers, favored for their ability to facilitate payload release and bystander effect (Fig. 1H).

Discussion

ADCs have emerged as a promising therapeutic approach for gastric cancer. In the DESTINY-Gastric01 trial, trastuzumab deruxtecan (T-DXd), a HER2-targeted ADC, achieved an objective response rate (ORR) in advanced HER2-positive gastric cancer of 51.3% compared to 14.3% in the chemotherapy group, with a median overall survival (OS) of 12.5 months compared to 8.4 months. The safety profile was generally manageable, with interstitial lung disease being the most notable but largely controllable adverse event^[4]. In the KYM901 trial, CMG901, a Claudin18.2-targeted ADC, achieved an ORR of 28% in patients with advanced gastric and gastro-esophageal junction cancer, with manageable gastrointestinal and hematological toxicities^[5]. These encouraging results have spurred a wave of clinical trials investigating a wide range of ADCs for gastric cancer.

The large number of early-phase trials reflects the active and growing interest in ADC development. However, many candidates have remained in Phase I or Phase I/II trials without progressing to later-phase studies. This discontinuation is primarily attributed to insufficient efficacy and safety concerns^[6]. Key barriers include the development of resistance, tumor heterogeneity, and inter-patient variability, which contribute to reduced therapeutic effectiveness. Off-target and on-target toxicities are the principal safety challenges. To overcome these challenges, current research is increasingly focused on enhancing ADC design, including optimization of target selection, linker stability, and payload potency.

The selection of tumor-associated antigens remains a key determinant of the success of ADCs. Although well-characterized targets such as HER2 and Claudin 18.2 continued to play a vital role, novel candidates, including ITGB6, 5T4, and STEAP1, have entered clinical trials and are garnering increasing attention. In addition, preclinical studies have identified emerging targets such as DKK1, which is overexpressed in gastric cancer tissues and implicated in tumor progression and immune evasion^[7]. DKN-01, a monoclonal antibody targeting DKK1, has demonstrated preliminary antitumor activity in combination therapies^[8]. In addition to the exploration of novel targets, the development of bispecific ADCs and strategies to increase antigen copy numbers have emerged as promising approaches to overcome drug resistance and mitigate toxicities^[9].

Currently, IgG1 remains the predominant type of antibody applied in ADC development. However, next-generation ADCs are incorporating advanced antibody engineering to overcome limitations of conventional formats. Nanobody-based ADCs, due to their smaller size, offer enhanced tumor penetration and reduced immunogenicity. Probody-drug conjugates (PDCs), which remain inactive until cleaved by tumor-specific proteases, provide improved specificity and reduced off-target toxicities^[10]. Furthermore, the use of naked antibodies conjugated to cytotoxins ex vivo through click chemistry presents a promising platform for flexible and modular ADC design^[6]. These innovations hold great potential to refine the therapeutic index of ADCs, ultimately paving the way for more personalized and effective treatment regimens.

Linker technology represents another fundamental pillar in the design of ADCs. Cleavable linkers are commonly employed to facilitate the efficient release of the cytotoxic payload upon internalization into target cancer cells, thereby enhancing the potency of ADCs. In gastric cancer, cleavable linkers are particularly favored due to their ability to induce the “bystander effect,” a phenomenon where the released payload diffuses into adjacent tumor cells, including those with low or heterogeneous antigen expression^[11]. This feature is particularly relevant in gastric tumors, which are characterized by pronounced intratumoral heterogeneity. Recent advances in linker chemistry have led to the development of hydrophilic linkers, which enhance intracellular delivery while mitigating resistance mechanism mediated by efflux proteins^[10].

Regarding cytotoxic payloads, there is a growing preference for TOP1i, which exhibits a favorable potency-to-toxicity ratio and is effective against both proliferative and quiescent tumor cells. Tubulin inhibitors and DNA-targeting payloads have also been widely utilized. In addition, novel classes of payloads are being explored, including immune stimulatory payloads such as toll-like receptor (TLR) agonists, stimulator of interferon genes (STING) activator and RNA-II polymerase, thereby expanding the therapeutic potential of ADCs^[6]. Given the molecular heterogeneity of gastric cancer cells, diversifying payload is crucial for promoting the efficacy of ADCs. Dual-drug ADCs, which incorporate two distinct payloads, are emerging as a promising strategy to overcome resistance and target heterogeneous tumor cell populations.

The conjugation method, how and where the linker-payload moiety is attached to the antibody, is another critical factor influencing ADC performance. Conventional non-site-specific conjugation approaches, typically involving lysine or interchain cysteine residues, often yield heterogeneous drug-to-antibody ratios (DAR), potentially compromising the efficacy and safety of ADCs. In contrast, site-specific conjugation techniques, such as THIOMAB, engineered cysteines, and enzymatic methods (e.g., transglutaminase or sortase) enhance the consistency, stability and therapeutic index of ADCs^[12].

Geographically, the majority of clinical trials were conducted in China and the United States. In support of the growing ADC landscape, the U.S. FDA released the Clinical Pharmacology Considerations for Antibody-Drug Conjugates Guidance for Industry in 2024, while China’s NMPA issued the Technical Guidelines for Clinical Development of Antitumor Antibody-Drug Conjugates in 2023. This highlights the commitment of regulatory bodies to advancing ADC development, providing substantial guidance and impetus for continued innovation.

This study has several limitations. First, classification bias may be inherent in the database used. Second, there may be delays in the inclusion of newly registered clinical trials, potentially limiting the comprehensiveness of the analysis.

Conclusion

This study highlights the substantial progress in the development and clinical trials of ADCs. Innovative ADC formats, such as bispecific ADCs, dual-drug ADCs and PDCs, suggest that future research will continue to focus on refining ADC design to overcome drug resistance and enhance tumor specificity. Promising strategies include the identification of novel molecular targets, optimization of linker chemistry and conjugation techniques to minimize off-target effects, development of new payloads to enhance efficacy, and fine-tuning antibody-antigen affinity to enhance tumor uptake. Furthermore, combination therapies and tumor microenvironment modulation approaches are being explored to improve delivery and sustain antitumor activity. Continued international collaboration and regulatory support will be essential to fully realize the clinical potential of ADCs and improve outcomes for patients with gastric cancer.

Ethical approval

This article does not include any human/animal subjects to acquire such approval.

Consent

Not applicable.

Sources of funding

This study received no specific grant from any funding agency in the public, commercial, or not-for profit sectors.

Author contributions

Ran Duan: Conceptualization, data curation, visualization, writing (original draft), and writing (review and editing).

Conflicts of interest disclosure

None.

Guarantor

Ran Duan.

Research registration unique identifying number (UIN)

Not applicable.

Provenance and peer review

Not commissioned, internally peer-reviewed.

Data availability statement

All the source data in this work are based on the Trialtrove database, with clinical trial details derived from clinical trial publicity platforms.

Assistance with the study

We thank EditSprings (https://www.editsprings.cn) for the assistance with language editing.

Presentation

None.