Antibody-drug conjugates (ADCs) have emerged as a promising treatment modality for pancreaticobiliary cancers, offering targeted delivery of cytotoxic agents while minimizing systemic toxicity. Dr. Lei Zheng’s presentation at the ASCO Gastrointestinal Cancers Symposium explores the mechanisms, key selection criteria, and ongoing clinical trials evaluating ADCs in pancreatic and biliary tract cancers (BTC).Mechanism of ADCs and Antigenic Targets
ADCs function through a three-component system, comprising a monoclonal antibody (mAb) targeting a tumor-specific antigen, a cytotoxic payload, and a linker that facilitates payload release. Effective ADCs require highly expressed and tumor-specific antigenic targets to maximize efficacy and minimize off-target effects.
Key antigenic targets under investigation include HER2, CLDN18.2, TROP-2, B7-H3, and mesothelin, which are overexpressed in pancreatic and biliary tract cancers. Among FDA-approved ADC targets for solid tumors, HER2, TROP2, and Nectin-4 have demonstrated clinical relevance, with new agents like Datopotamab Deruxtecan (DATO-DXd) targeting TROP2 and Telisotuzumab Vedotin (ABBV-399) targeting c-MET.
DESTINY-PanTumor02: Trastuzumab Deruxtecan (T-DXd) in Pancreaticobiliary Cancers
One of the most significant studies, DESTINY-PanTumor02, evaluates trastuzumab deruxtecan (T-DXd), a HER2-directed ADC, in HER2-expressing solid tumors. The Phase II trial demonstrated:
The study reported an Objective Response Rate (ORR) of 24.4% (95% CI: 16.9–32.9), indicating that nearly a quarter of patients demonstrated a measurable response to treatment. The Disease Control Rate (DCR) was 71.3% (95% CI: 63.1–78.6), reflecting the proportion of patients who experienced either a response or stable disease. In terms of survival outcomes, the Median Progression-Free Survival (mPFS) was 6.9 months (95% CI: 5.6–8.0), while the Median Overall Survival (mOS) reached 13.4 months (95% CI: 11.3–15.6), demonstrating the potential of trastuzumab deruxtecan in extending survival for patients with HER2-expressing tumors.
For biliary tract cancers (BTC), the study found that HER2 IHC 3+ patients showed significant response to T-DXd, reinforcing the necessity of biomarker selection for optimal therapeutic outcomes.
Selected ADCs in Clinical Trials for Biliary Tract Cancers (BTC)
Several ADCs are in various stages of clinical development for BTC, focusing on tumor-specific antigens such as HER2, TROP-2, and B7-H3. Key trials include:
BL-B01D1, an EGFR × HER3 bispecific ADC, demonstrated an ORR of 28.6% (6/21) and a DCR of 76.2% (16/21) in BTC patients. Adverse events included anemia (67%), thrombocytopenia (62%), and leukopenia (48%).
Sacituzumab govitecan (SG, TROP-2-targeted ADC) is also under investigation with promising results in BTC treatment.
Other ADCs in trials for BTC include TQB2102 (Her2-targeted, TOP1 inhibitor), RC48-ADC (Her2-targeted, MMAE payload), and MRG003 (EGFR-targeted, MMAE payload).
Selected ADCs in Clinical Trials for Pancreatic Adenocarcinoma (PDAC)
PDAC presents additional challenges due to its desmoplastic microenvironment limiting ADC penetration. Key ADCs in development include:
IBI343, an anti-CLDN18.2 ADC, showed an ORR of 28.0% and a DCR of 80.0% in a trial with 35 patients (28 PDAC, 7 BTC). Notable grade 3/4 adverse events included neutropenia (25.7%).
Other ADCs targeting mesothelin, CEACAM5/6, MUC1, and c-MET are also in early-phase clinical trials for pancreatic cancer.
Specific ADCs in PDAC trials include TORL-2-307-ADC (CLDN18.2-targeted, MMAE payload), Anetumab ravtansine (Mesothelin-targeted, DM4 payload), and ABBV-400 (c-MET-targeted, TOP1 inhibitor payload).
Biomarker Selection and Companion Diagnostics
Accurate biomarker selection is essential to identify patients most likely to benefit from ADC therapy. Immunohistochemistry (IHC)-based assays for HER2, CLDN18.2, and TROP-2 play a crucial role in patient stratification. Studies highlight that HER2 IHC 3+ expression correlates with enhanced ADC efficacy, reinforcing the need for companion diagnostic tools in treatment decision-making. CLDN18.2 expression is highly heterogeneous in gastric and pancreatic adenocarcinomas, with positivity rates of 56.3% at ≥50% cutoff and 44.4% at ≥75% cutoff, indicating the potential role of CLDN18.2-targeting ADCs in these malignancies.
Biomarker Assays for CLDN18.2
Table 1 outlines the prevalence of CLDN18.2 positivity in study samples, with staining ≥50% observed in 64.4% of gastric adenocarcinomas and 44.9% of GEJ adenocarcinomas, with an overall total of 56.3%. Using a more stringent cutoff of ≥75%, the prevalence drops to 51.4% for gastric adenocarcinomas, 34.6% for GEJ adenocarcinomas, and 44.4% overall. These findings highlight the heterogeneous expression of CLDN18.2 and emphasize the need for optimized biomarker-driven selection of patients for CLDN18.2-targeted ADC therapy.
Conclusion
Antibody-drug conjugates hold significant potential in the treatment of pancreaticobiliary cancers, offering a precision medicine approach that enhances efficacy while reducing systemic toxicity. The DESTINY-PanTumor02 trial underscores the clinical benefits of trastuzumab deruxtecan in HER2-positive patients, while emerging ADCs targeting TROP-2, B7-H3, and CLDN18.2 provide additional avenues for therapeutic development. BL-B01D1 and IBI343 show promising results in BTC and PDAC, respectively, highlighting the importance of continued biomarker-driven research. Rational ADC design and biomarker-driven patient selection will be critical in unlocking the full therapeutic potential of ADCs in these challenging malignancies.
