Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of cancer-related death worldwide (Sung et al., 2021; Morgan et al., 2022). Given the subtle nature of its symptoms, most patients with GC are diagnosed at an advanced or metastatic stage (Hundahl et al., 2000). For early-stage GC, therapeutic options include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) (Sundar et al., 2025). Advanced cases, however, typically require a combined approach of surgery and chemotherapy to improve 5-year survival. Patients with unresectable GC often receive concurrent radiotherapy and chemotherapy, which has been shown to enhance survival outcomes (López et al., 2023; Guan et al., 2023). HER2 (human epidermal growth factor receptor 2) represents an established therapeutic target in GC management. The large-scale, international HER-EAGLE study revealed a global HER2-positivity rate of 10%–20% in GC, defined as immunohistochemistry (IHC) 3+ or IHC 2+ with positive in situ hybridization (ISH) (Kim et al., 2018). HER2-low expression was defined as IHC 2+/ISH-negative or IHC 1+. For locally advanced or metastatic HER2-positive disease, first-line trastuzumab-based regimens represent standard therapy (Bang et al., 2010). Immune checkpoint inhibitors combined with platinum-based doublet chemotherapy have become standard first-line treatment for HER2-negative advanced GC (Janjigian et al., 2021; Rha et al., 2023; Kang et al., 2022; Shitara et al., 2020a). Ramucirumab, administered either as monotherapy or combined with paclitaxel, constitutes an established second-line option (Wilke et al., 2014; Fuchs et al., 2014).

Recent advances in clinical oncology drug development have witnessed the approval of novel antibody-drug conjugates (ADCs) including disitamab vedotin (RC48) (Peng et al., 2021) and trastuzumab deruxtecan (T-DXd) (Shitara et al., 2020b), expanding therapeutic options for advanced-stage disease. ADCs represent a powerful class of cancer drugs. They combine the precision of monoclonal antibodies with potent cytotoxic agents, linked together to deliver the payload directly to tumor cells. A key advantage of many ADCs is their bystander-killing effect. This occurs when the cytotoxic drug escapes the initial target cell and enters neighboring cells, triggering cell death (apoptosis) and helping to overcome challenges posed by tumor heterogeneity. Currently, global clinical trials involve more than 100 ADC candidates; so far, 15 have gained regulatory approval. Significantly, agents like T-DXd, RC48, and IMMU-132 are now options for treating advanced GC (Peng et al., 2021; Shitara et al., 2020b; Hao et al., 2024). Pushing forward with next-generation ADCs and exploring novel treatment approaches is therefore vital. These efforts offer fresh hope for advanced GC patients whose current choices are limited. Recent years have witnessed increasing clinical recognition of HER2-low breast cancer as a distinct therapeutic subtype, stimulating interest in exploring this entity within the GC landscape (Modi et al., 2022; Tara et al., 2020; Yu et al., 2023). Patients with HER2-low GC derive limited benefit from conventional HER2-targeted monoclonal antibodies (Bang et al., 2010), necessitating novel therapeutic strategies. Evidence suggests ADCs may exhibit antitumor activity in this population, potentially mediated through the bystander effect inherent to certain ADC constructs. This phenomenon-whereby cytotoxic payloads released from dying tumor cells exert cytotoxic effects on adjacent cells-proves particularly valuable for eliminating HER2-low cells and addressing tumoral heterogeneity (Li et al., 2016). The phase II C013 trial demonstrated efficacy of RC48 plus toripalimab in pretreated HER2-low gastric/gastroesophageal junction cancer (GC/GEJC) patients (IHC2+/ISH- or IHC1+), reporting an objective response rate (ORR) of 46%, median progression-free survival (PFS) of 5.1 months, and median overall survival (OS) of 14.0 months (Wang et al., 2024).

Contemporary clinical development of ADCs in advanced GC includes ongoing trials evaluating monotherapy and combination regimens. This complex disease exhibits substantial intratumoral genomic and phenotypic heterogeneity, which poses therapeutic challenges. Consequently, clinical outcomes demonstrate significant variability across studies-with some meeting primary endpoints while others report non-significant results. Addressing the unmet need for synthesized evidence, this systematic review and meta-analysis comprehensively assesses ADC efficacy and safety profiles in advanced GC/GEJC. Additionally, we characterize clinical and molecular subpopulations exhibiting differential responses to ADC therapies.

This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and registered prospectively with PROSPERO (International Prospective Register of Systematic Reviews) (CRD420251066208).

HER2 represents the earliest and best-characterized biomarker in GC, remaining a major research focus for ADC-targeted therapies. Trastuzumab emtansine (T-DM1) received FDA (Food and Drug Administration) approval in 2013 for HER2-positive metastatic breast cancer (Verma et al., 2012). However, the GATSBY trial demonstrated no OS or PFS benefit with T-DM1 versus taxanes in HER2-positive advanced GC patients, likely attributed to HER2 heterogeneity within these tumors (Thuss-Patience et al., 2017). Consequently, characterizing heterogeneous HER2 expression emerges as a critical research priority. Compared to T-DM1, T-DXd exhibits potent bystander effects due to enhanced membrane permeability, enabling targeting of GC with low HER2 expression or heterogeneity. RC48, another ADC, received NMPA (National Medical Products Administration) China approval in 2021 and demonstrates promising antitumor activity in GC. Furthermore, investigational ADCs including ARX788 show considerable therapeutic promise.

ADCs enhance the therapeutic index of anticancer treatments by combining the precision of monoclonal antibodies with the potency of cytotoxic agents, thereby reducing off-target toxicity (Staudacher and Brown, 2017; Kalim et al., 2017). An ADC consists of three key elements: an antibody, a linker, and a cytotoxic payload. The antibody, typically a humanized IgG isotype (often IgG1 for its strong effector functions), confers target specificity and must exhibit low immunogenicity, high affinity, and efficient internalization (Khongorzul et al., 2020; Beck et al., 2017). The linker ensures stability in circulation and enables specific payload release at the tumor site; it may be cleavable or non-cleavable, influencing both stability and potential bystander effects (Kalim et al., 2017). The payload, which is highly potent and stable, causes cell death through mechanisms such as microtubule disruption or DNA damage (Li et al., 2016; Puthenveetil et al., 2016).

Following the ToGA trial, trastuzumab combined with chemotherapy became the standard first-line treatment for HER2-positive advanced GC. The ToGA results demonstrated that adding trastuzumab to chemotherapy significantly improved median OS (13.8 months vs. 11.1 months) and median PFS (6.7 months vs. 5.5 months) in patients with HER2-positive metastatic GC, alongside an enhanced ORR (47% vs. 35%; p = 0.0017) (Bang et al., 2010). Subsequently, the KEYNOTE-811 study showed that adding pembrolizumab to trastuzumab and chemotherapy further extended median OS (20.0 months vs. 16.8 months) and PFS (10.0 months vs. 8.1 months) compared to trastuzumab and chemotherapy alone. The overall ORR also increased by 12.5% (72.6% vs. 60.1%). However, patients with PD-L1 combined positive score (CPS) < 1 derived no significant benefit in OS, PFS, or ORR from the addition of pembrolizumab (Janjigian et al., 2024b). Pooled analysis of included studies revealed that first-line ADCs for HER2-positive advanced GC achieved integrated efficacy outcomes: ORR 67% (95% CI: 53%–82%), median OS 19.67 months (95% CI: 15.79-23.55), and median PFS 10.57 months (95% CI: 6.37-14.77). Compared to historical controls, these meta-analysis findings indicate superior clinical benefits.

Effective standard second-line anti-HER2 therapies remain limited for patients with advanced HER2-positive GC following progression on first-line anti-HER2 treatment. Results from three phase 3 trials demonstrated that second-line docetaxel or irinotecan improves OS compared with best supportive care in advanced GC (Thuss-Patience et al., 2011; Kang et al., 2012; Ford et al., 2014). A separate phase 3 trial reported comparable OS benefits between irinotecan and paclitaxel (Hironaka et al., 2013). Collectively, these findings have established irinotecan, docetaxel, and paclitaxel as viable second-line chemotherapy options. Ramucirumab, administered either as monotherapy or in combination with paclitaxel, has also demonstrated OS prolongation in the second-line setting for previously treated advanced GC (Wilke et al., 2014; Fuchs et al., 2014). Specifically, the combination of ramucirumab plus paclitaxel significantly extended PFS (4.4 months vs. 2.9 months; p < 0.0001) and OS (9.6 months vs. 7.4 months; p = 0.0169) compared to placebo, with an ORR of 28%. Results from the present meta-analysis indicate that when used as second-line treatment, the ADC was associated with a pooled median OS of 11.65 months (95% CI: 8.05-15.22), a pooled median PFS of 4.13 months (95% CI: 2.43-5.83), and a pooled ORR of 40% (95% CI: 29%–51%). While PFS showed no improvement, both OS and ORR demonstrated clinically meaningful improvements in indirect comparisons with established regimens. Treatment options for third-line advanced GC remain highly limited. Irinotecan, taxanes, trifluridine/tipiracil, and ICIs (immune checkpoint inhibitors) represent alternative therapeutic approaches (Muro et al., 2019). This meta-analysis demonstrated that for patients receiving the ADC as third-line therapy, the pooled median OS was 9.37 months (95% CI: 7.38-11.37) and the pooled median PFS was 4.50 months (95% CI: 3.51-5.50). The pooled ORR was 27% (95% CI: 16%–38%).

In an ideal scenario, ADCs deliver cytotoxic payloads directly to tumor cells via antibody-mediated targeting, potentially reducing adverse events associated with conventional chemotherapy. However, due to current technological and manufacturing limitations, coupled with variations in antibody specificity, linker stability, and the nature of the cytotoxic payload among different ADC types, significant adverse events may still occur (Wolska-Washer and Robak, 2019). ADC-related toxicities can be categorized based on target antigen involvement: on-target and off-target toxicity. On-target toxicity arises when the ADC specifically binds to and is internalized by antigen-expressing normal tissues, leading to payload release and subsequent cytotoxicity. While the ideal target antigen is highly expressed on tumor cells with minimal or no expression on normal cells, low-level expression on healthy tissues can result in misdelivery of the payload, causing on-target effects. Off-target toxicity refers to damage inflicted by the ADC on organs or cells lacking target antigen expression (Kang and Kim, 2025). Furthermore, adverse events are also intrinsically linked to the payload’s mechanism of action. In HER2-targeting ADCs for GC, common payloads include microtubule inhibitors (e.g., DM1/DM4, MMAE/MMAF) and DNA topoisomerase I inhibitors (e.g., DXd, SN-38).

In this meta-analysis, the pooled incidence rates for any-grade TRAEs and grade 3–5 TRAEs were 98% (95% CI: 96%–100%) and 60% (95% CI: 52%–69%), respectively. The safety profile of ADCs in GC/GEJC generally aligned with established profiles in breast cancer. Subgroup analysis of grade 3–5 TRAEs revealed a higher incidence with combination therapy versus monotherapy (65%, 95%CI: 51%–79% vs. 57%, 95%CI:47%–67%). ADC combination regimens-typically incorporating chemotherapy, ICIs, or both-are associated with heightened toxicity. Notably, the observed incidence of grade ≥3 TRAEs in this analysis is comparable to that of established standard regimens in GC/GEJC, such as trastuzumab plus chemotherapy (68% in the ToGA study (Bang et al., 2010)) and pembrolizumab plus trastuzumab and chemotherapy (58% in the Keynote-811 trial (Janjigian et al., 2024b)). Despite the encouraging antitumor activity demonstrated by ADCs in this setting, the considerable incidence of grade 3-5 toxicities cannot be overlooked and necessitates vigilant monitoring, proactive management, and thorough patient counseling to ensure a favorable risk-benefit profile. Comparative assessment of ADC agents indicated that ARX788 demonstrated a notably lower incidence of grade 3–5 TRAEs (13%, 95% CI: 4%–31%) than other evaluated drugs. However, the randomized phase III ACE-Breast-02 trial, comparing ARX788 to lapatinib plus capecitabine in HER2-positive advanced breast cancer, reported similar rates of any-grade and grade ≥3 TRAEs between treatment arms. Specifically, grade ≥3 TRAEs occurred in 41.4% (91/220) of ARX788 recipients (Hu et al., 2025). The incidence of grade 3–5 TRAEs observed with ARX788 in the GC/GEJC setting requires further validation in larger trials.

Several potential limitations warrant consideration. First, our meta-analysis is limited by the predominance of single-arm studies, given the nascent stage of ADC application in advanced GC and the scarcity of large-scale RCTs. This design lacks randomization and a control group, which introduces significant risks of selection bias and confounding. The patients enrolled in these trials are often highly selected based on strict eligibility criteria, such as good performance status and normal organ function, and therefore may not be representative of the broader patient population treated in real-world clinical practice. Consequently, the pooled efficacy outcomes may reflect an optimistic estimate of the treatment’s true effect size, as they could be influenced by a patient cohort with a more favorable prognosis. Furthermore, without a control group, it is challenging to distinguish the treatment effect from the natural disease course or effects of prior therapies. Smaller sample sizes in these studies also increase susceptibility to bias. Thus, the overall findings should be interpreted with caution and are best validated by future large-scale, prospective randomized controlled trials. Second, the paucity of studies within individual treatment lines-exemplified by only two trials in first-line therapy, seven in second-line, and four in third-line settings for ADCs in advanced gastric cancer-necessitated the inclusion of all therapy lines (first-, second-, third-, and later-line) in the pooled analysis. This heterogeneity may introduce confounding factors; thus, subgroup analyses stratified by treatment line were performed to examine potential outcome differences across these strata. Third, the overrepresentation of studies investigating a specific ADC agent, T-DXd, may limit the generalizability of our pooled estimates to other ADC agents. Among these agents, T-DXd represents a preferred therapeutic option where available, given its robust evidence base and superior survival outcomes observed in our analysis. Nevertheless, further studies are warranted to validate the efficacy of other ADC agents and to enable more comprehensive comparative assessments.

This meta-analysis demonstrates that ADC therapy confers meaningful clinical benefit in patients with advanced GC/GEJC, irrespective of HER2 status (positive or low). These agents maintained a manageable safety profile, which nevertheless requires vigilant monitoring and proactive management. Available evidence indicates that for HER2-positive patients in the first-line setting, conventional standard regimens remain the preferred option. For both HER2-positive and HER2-low populations in the second-line or later settings, ADC therapy emerges as a valuable treatment option.