The management of gastrointestinal malignancies has evolved from a predominantly histology-based approach toward increasingly refined molecular stratification. This shift has been particularly evident in gastric, gastroesophageal junction, colorectal, and biliary tract cancers, where actionable biomarkers have progressively changed treatment algorithms. Despite these advances, many patients still experience disease progression after standard chemotherapy, immunotherapy, and targeted therapies.
Antibody-drug conjugates (ADCs) represent one of the most dynamic developments in contemporary oncology. They combine a monoclonal antibody directed against a tumor-associated antigen, a linker, and a cytotoxic payload. Newer ADCs may also exert a bystander effect, allowing activity in tumors with heterogeneous antigen expression—an important consideration in gastrointestinal malignancies.
HER2-directed ADCs have already entered clinical practice in selected settings, while agents targeting CLDN18.2, TROP2, CEACAM5, and other antigens are advancing through clinical development. Further progress will depend on refining biomarkers, treatment sequencing, toxicity management, and rational combination strategies.
Rationale for ADCs in gastrointestinal oncology
GI tumors are biologically heterogeneous and often evolve under therapeutic pressure. Resistance to chemotherapy may emerge through clonal selection, drug efflux mechanisms, impaired apoptosis, or changes in the tumor microenvironment. ADCs may help overcome some of these limitations by increasing intratumoral drug delivery and exploiting antigen expression as a therapeutic entry point.
Several features make GI malignancies particularly suitable for ADC development. Validated or emerging surface targets such as HER2, CLDN18.2, TROP2, and CEACAM5 are expressed in clinically relevant subsets of disease. Target heterogeneity may also be partially mitigated by payload diffusion and bystander killing, particularly with membrane-permeable topoisomerase I inhibitor payloads. In addition, molecular testing is already part of routine care in many GI cancers, allowing ADC biomarkers to be integrated into existing diagnostic pathways.
However, ADCs are not simply “targeted chemotherapy.” Their clinical activity depends on antigen density, internalization kinetics, linker stability, payload potency, the tumor microenvironment, prior therapies, and host factors. Their development in GI oncology therefore needs to be accompanied by translational research aimed at identifying predictive biomarkers, resistance mechanisms, and rational combination strategies.
HER2-directed ADCs
HER2 remains the most established ADC target in GI oncology. HER2 overexpression or amplification is detected in a clinically relevant proportion of gastric and gastroesophageal junction adenocarcinomas and in a smaller but therapeutically important subset of metastatic colorectal cancers. HER2 alterations are also observed in biliary tract cancers, particularly gallbladder cancer and extrahepatic cholangiocarcinoma.
The clinical success of trastuzumab deruxtecan (T-DXd) has redefined HER2-directed therapy in GI malignancies. T-DXd combines a humanized anti-HER2 antibody with a cleavable linker and a potent topoisomerase I inhibitor payload. Its high drug-to-antibody ratio and bystander effect are central to its activity, particularly in tumors with heterogeneous HER2 expression.
T-DXd in Gastric and GEJ Cancer
The pivotal DESTINY-Gastric01 trial was a landmark in ADC development for GI cancers. In this randomized phase II study, patients with HER2-positive advanced gastric or gastroesophageal junction cancer previously treated with at least two prior regimens, including trastuzumab, received trastuzumab deruxtecan or physician’s choice chemotherapy. T-DXd significantly improved objective response rate compared with chemotherapy (51% vs 14%) and median overall survival (12.5 vs 8.4 months; HR for death, 0.59). These results established T-DXd as a new standard for previously treated HER2-positive gastric cancer and demonstrated that HER2 remained actionable after trastuzumab exposure (Shitara K et al, NEJM, 2020).
Subsequent studies expanded this evidence base. DESTINY-Gastric02 evaluated T-DXd in a Western population and confirmed clinically meaningful activity after progression on trastuzumab-based therapy. More recently, DESTINY-Gastric04 compared T-DXd with ramucirumab plus paclitaxel in the second-line setting for HER2-positive unresectable or metastatic gastric/GEJ adenocarcinoma. The study showed a statistically significant and clinically meaningful overall survival benefit with T-DXd, supporting its earlier integration after first-line trastuzumab-based therapy (Shitara K et al, NEJM, 2025).
The DESTINY-Gastric program also highlights important practical considerations. HER2 expression can be heterogeneous and may change after treatment, making re-biopsy, archival tissue review, or liquid biopsy-based strategies increasingly relevant. Interstitial lung disease/pneumonitis also remains an important safety consideration with T-DXd and requires early recognition, treatment interruption, and prompt corticosteroid therapy when suspected.
T-DXd in Colorectal and Biliary Tract Cancer
The activity of T-DXd extends beyond gastric cancer. In HER2-positive metastatic colorectal cancer, the DESTINY-CRC program showed that HER2 is an actionable therapeutic target. DESTINY-CRC02, a multicenter randomized phase II trial, evaluated two T-DXd doses in previously treated HER2-positive metastatic colorectal cancer and confirmed promising antitumor activity, supporting continued development of HER2-directed ADC strategies in this setting (Raghav K et al, Lancet Oncology, 2024).
Biliary tract cancer represents another area of interest. The HERB trial evaluated T-DXd in HER2-expressing unresectable or recurrent biliary tract cancer and showed promising activity in HER2-positive disease, with an additional signal in HER2-low tumors. Although biliary tract cancer remains molecularly diverse and treatment options after progression are limited, these data support HER2 testing and further ADC development in biomarker-selected patients (Ohba A et al, JCO, 2024; Ohba A et al, 2022).
Disitamab vedotin and the broadening of HER2 targeting
Disitamab vedotin (RC48) is a HER2-directed ADC consisting of an anti-HER2 antibody linked to monomethyl auristatin E. It has generated substantial interest because of its potential activity across a broader spectrum of HER2 expression, including HER2-low or HER2-expressing tumors that may not meet traditional criteria for HER2 positivity.
Early clinical development in gastric cancer has demonstrated encouraging response rates in HER2-expressing disease. Combination approaches are also being explored. RC48 combined with toripalimab has been evaluated in advanced gastric/gastroesophageal junction cancer, based on the hypothesis that ADC-induced immunogenic cell death and antigen release may enhance antitumor immunity.
First-line disitamab vedotin-based therapy is now being evaluated in randomized studies, including a seamless phase II/III strategy in HER2-expressing gastric/GEJ cancer (Shen L et al, J Clin Oncol, 2024). Perioperative studies combining RC48 with sintilimab and XELOX in resectable HER2-overexpressing gastric/GEJ adenocarcinoma are also exploring whether ADCs can move into earlier disease stages (Liu Y et al, J Clin Oncol, 2026).
The RC48 program may also help redefine HER2 not as a binary biomarker, but as a spectrum. If validated, this concept could increase the number of patients eligible for HER2-directed ADC therapy.
CLDN18.2-directed ADCs
CLDN18.2 is one of the most compelling emerging targets in GI oncology. It is a tight-junction protein normally expressed in gastric mucosa and aberrantly exposed or overexpressed in several gastrointestinal tumors, particularly gastric and gastroesophageal adenocarcinomas. Its clinical validation as a therapeutic target has accelerated the development of antibodies, bispecifics, cellular therapies, and ADCs (Wiscovitch AD et al, Cancers, 2025).
Arcotatug tavatecan (IBI343) is among the most advanced CLDN18.2-directed ADCs. It carries a topoisomerase I inhibitor payload and has demonstrated promising activity in advanced gastric/GEJ adenocarcinoma. In a phase I study, the confirmed objective response rate was approximately 29%, with a median progression-free survival of 5.5 months at the recommended phase II dose in CLDN18.2-high gastric/GEJ adenocarcinoma. Activity has also been explored in pancreatic and biliary tract tumors, supporting broader development across CLDN18.2-expressing GI malignancies (Liu J et al, Nat Med, 2025).
The global phase III G-HOPE-001 program is evaluating IBI343 in CLDN18.2-high gastric/GEJ adenocarcinoma. As of June 2026, a company announcement reported that the study met its primary endpoint and that a new drug application had been accepted in China. These findings remain emerging regulatory data pending full peer-reviewed publication (Shen L et al, JCO, 2025; Innovent Biologics, press release, 2026).
Sonesitatug vedotin is another CLDN18.2-directed ADC under active clinical investigation. On July 27, 2026, AstraZeneca announced positive high-level results from the phase III CLARITY-Gastric01 trial. The study met its primary overall survival endpoint in the third-line-or-later population, with an OS benefit also reported across the overall second-line-or-later population. Progression-free survival favored sonesitatug vedotin but did not reach statistical significance.
Key clinical questions remain, including the optimal expression threshold, reproducibility of immunohistochemistry testing, activity in lower-expression tumors, mechanisms of resistance, and safety across different CLDN18.2-expressing tumor types.
TROP2-directed ADCs
TROP2 is a transmembrane glycoprotein overexpressed in multiple epithelial malignancies and involved in tumor growth, invasion, and metastasis. TROP2-directed ADCs have already demonstrated activity in other solid tumors and are now being explored in GI malignancies.
Sacituzumab tirumotecan (MK-2870/SKB264) is a TROP2-directed ADC carrying a topoisomerase I inhibitor payload. In advanced gastric and gastroesophageal junction adenocarcinoma, preliminary data from the phase I/II KL264-01 study showed encouraging antitumor activity in previously treated patients, including those treated in later lines, with a manageable safety profile. These findings supported the launch of a phase III program evaluating sacituzumab tirumotecan versus physician’s choice of treatment in advanced/metastatic gastroesophageal adenocarcinoma (Rodon J et al, AACR, 2024; MK-2870-015 trial program).
TROP2-directed strategies are also being explored in metastatic colorectal cancer. Although the data remain earlier and less definitive than in HER2-positive disease, the future role of TROP2 ADCs will depend on whether target expression, tumor type, prior therapy, and payload sensitivity can identify patients most likely to benefit.
CEACAM5-directed ADCs in metastatic colorectal cancer
CEACAM5, commonly recognized as carcinoembryonic antigen (CEA), is highly expressed in many colorectal cancers and has long been used as a clinical biomarker. Its cell-surface expression makes it a rational ADC target.
Precemtabart tocentecan (Precem-TcT, previously M9140) is an anti-CEACAM5 ADC with an exatecan topoisomerase I inhibitor payload. Early clinical data in heavily pretreated metastatic colorectal cancer demonstrated a manageable safety profile and antitumor activity, including confirmed partial responses in a refractory population. The PROCEADE CRC program has advanced this strategy, with PROCEADE-CRC-03 designed as a pivotal phase III trial in previously treated metastatic colorectal cancer (Kopetz S et al, Nat Med, 2025; PROCEADE CRC-03 trial program).
CEACAM5-directed ADCs are particularly interesting because CEACAM5 expression is common in colorectal cancer. If efficacy is confirmed in randomized studies, this approach could become one of the broadest ADC strategies in mCRC. However, optimal CEACAM5 expression thresholds, on-target off-tumor toxicity, and the clinical relevance of serum CEA levels versus tissue expression require further investigation.
Emerging ADC targets beyond HER2, CLDN18.2, TROP2 and CEACAM5
The ADC pipeline in GI oncology extends beyond the leading programs. HER3-directed ADCs may be relevant in tumors where HER3 signaling contributes to growth or resistance. B7-H3 is broadly expressed in several solid tumors and is associated with aggressive biology and immune modulation. c-MET represents a biologically attractive target in tumors with MET overexpression or pathway activation. Guanylyl cyclase C (GCC) is highly lineage-associated with intestinal epithelial tumors and may provide a more selective approach in colorectal cancer. Mesothelin is also being investigated, particularly in pancreatic cancer and other aggressive GI malignancies.
These programs remain at earlier stages but expand ADC development beyond single biomarker niches. The key challenge will be to determine which targets are truly predictive, which are simply expressed, and which can provide a therapeutic index sufficient for sustained clinical benefit.
Biomarker strategy and clinical implementation
The success of ADCs depends on accurate patient selection. For HER2, testing algorithms are well established but still face challenges in gastric cancer because of spatial heterogeneity and changes after anti-HER2 therapy. For CLDN18.2, assay standardization, cut-off definitions, and inter-laboratory reproducibility remain central issues. For TROP2 and CEACAM5, the predictive value of target expression is still under active investigation.
In clinical practice, ADC implementation will require a coordinated diagnostic workflow. Tissue availability, timing of biopsy, archival versus fresh tissue, liquid biopsy integration, and repeat testing after progression should all be considered. Molecular tumor boards may play an increasing role in selecting ADC therapy, particularly when multiple targets are present or patients may be eligible for clinical trials.
Another emerging question is sequencing. For HER2-positive gastric cancer, the optimal placement of T-DXd after trastuzumab-based first-line therapy is becoming clearer, but the sequence of ADCs, bispecific antibodies, and other HER2-directed strategies remains unsettled. In CLDN18.2-positive, HER2-negative gastric/GEJ disease, future algorithms will need to integrate zolbetuximab-based first-line therapy, CLDN18.2-directed ADCs, chemotherapy, and immunotherapy.
Toxicity considerations
ADCs have distinct toxicity profiles determined by the antibody target, linker, payload, and dose schedule. For T-DXd, interstitial lung disease/pneumonitis is a key adverse event of special interest. Early diagnosis is essential, and patients should be educated to report cough, dyspnea, or fever promptly. Treatment interruption and corticosteroids are recommended depending on severity.
Hematologic toxicity, nausea, fatigue, alopecia, and gastrointestinal adverse events are also common across topoisomerase I inhibitor ADCs. MMAE-containing ADCs may be associated with neuropathy and myelosuppression. For CLDN18.2-directed therapies, gastrointestinal toxicity requires particular attention because of target biology and expression in gastric tissue, although early IBI343 data suggest a manageable safety profile.
As ADCs move into earlier lines of therapy, perioperative settings, and combination regimens, tolerability will become increasingly important. The goal will shift from disease control in refractory settings toward durable benefit with preservation of quality of life, requiring proactive toxicity monitoring, dose modification, and multidisciplinary care.
Future perspectives
The future of ADCs in GI oncology will likely be defined by several major directions. First, ADCs are moving earlier in the disease course, including second-line, first-line, and perioperative settings. DESTINY-Gastric04 already supports earlier use of T-DXd in HER2-positive gastric/GEJ cancer, while RC48 and CLDN18.2 ADC programs are exploring strategies that may further alter treatment sequencing (Shitara K et al, NEJM, 2025).
Second, combination therapy is becoming increasingly important. ADCs may synergize with immune checkpoint inhibitors through immunogenic cell death, antigen release, and modulation of the tumor microenvironment. Combinations with chemotherapy, antiangiogenic agents, or other targeted therapies may also improve the depth and durability of response.
Third, next-generation ADC engineering may improve the therapeutic index. Site-specific conjugation, optimized linkers, novel payloads, and dual-payload or bispecific ADCs may enhance efficacy while reducing toxicity. Translational research will also be essential to define resistance mechanisms, including antigen loss, impaired internalization, lysosomal dysfunction, payload resistance, and drug efflux, and to guide rational sequencing strategies.
Expert take-home messages
ADCs are no longer experimental concepts in GI oncology; they are becoming a central component of precision treatment. HER2 remains the most clinically validated ADC target, with trastuzumab deruxtecan establishing a new benchmark in HER2-positive gastric/GEJ cancer and demonstrating activity across colorectal and biliary tract cancers. Disitamab vedotin may further broaden HER2 targeting to lower-expression populations and earlier disease settings.
CLDN18.2 represents a leading next-generation ADC target, with IBI343 and sonesitatug vedotin among the most advanced programs. TROP2-directed ADCs may expand treatment opportunities in gastroesophageal adenocarcinoma and potentially colorectal cancer, while CEACAM5-directed ADCs could provide a broader strategy in metastatic colorectal cancer if phase III studies confirm early signals. The next challenge is not only to develop more ADCs, but to use them effectively: selecting the right patient, at the right time, with the right biomarker, while ensuring careful toxicity management.
Takeaway
Antibody-drug conjugates are transforming the treatment landscape of gastrointestinal malignancies. HER2-directed ADCs have already demonstrated meaningful clinical benefit, while CLDN18.2, TROP2, and CEACAM5 programs continue to advance. Their integration into GI oncology will depend on robust biomarker testing, careful toxicity management, and continued clinical development. As the evidence matures, ADCs are likely to play an increasingly important role across gastric, gastroesophageal, colorectal, biliary, and pancreatic cancers.
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