Gastrointestinal (GI) cancers remain a major global health burden, necessitating the development of novel therapeutic strategies. Bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs) have emerged as promising approaches for targeted treatment. The 2024 ASCO Gastrointestinal Cancers Symposium featured a presentation by Dr. Colin D. Weekes, highlighting the latest clinical advancements and research findings on these emerging therapies.

Antibody-Drug Conjugates in GI Cancers

ADCs are designed to enhance the precision of chemotherapy by selectively delivering cytotoxic payloads to tumor cells while minimizing systemic toxicity. The presentation emphasized key ADC candidates under investigation, demonstrating their potential to improve outcomes in various GI malignancies.


Key Findings in Bispecific Antibodies and ADCs

Zanidatamab, a bispecific HER2-targeting antibody, demonstrated an objective response rate (ORR) of 41.3% and a disease control rate (DCR) of 74.3% in patients with HER2-amplified biliary tract cancer (BTC). The median progression-free survival (PFS) was 5.5 months, highlighting its potential as a targeted therapy. Another study, the Phase III COMPASSION-15 trial, evaluated cadonilimab (a PD-1/CTLA4 bispecific antibody) combined with chemotherapy for advanced gastric cancer. The median overall survival was 15 months with the combination therapy versus 10.8 months with chemotherapy alone (HR 0.62, p<0.001), with improved PFS of 7 months versus 5.3 months (HR 0.53, p<0.001). The combination therapy showed an ORR of 65.2% compared to 48.9% with chemotherapy alone, though higher rates of grade 3 adverse events (65.9% vs. 53.6%) were observed.


Promising ADCs in GI Cancers

ADCs in Colorectal and Pancreatic Cancer

ABBV-400, a c-MET-targeting ADC, demonstrated an ORR of 37.5% in colorectal cancer patients with high c-MET expression compared to 14% in those with lower expression. The median PFS was 4.6 months, increasing to 5.4 months in high-expression patients. Similarly, MRG004A, a tissue factor (TF)-targeting ADC, showed promising results in pancreatic ductal adenocarcinoma (PDAC), particularly in patients with high TF expression, with an ORR of 80%, a DCR of 100%, and a median PFS of 5.5 months.


ADCs in Gastric and Gastroesophageal Cancer

Sacituzumab Tirumotecan (MK2870/SKB264), studied in second- and third-line treatment settings for gastric and gastroesophageal carcinoma, demonstrated an ORR of 22% and a median duration of response of 7.5 months. Patients treated in the second-line setting achieved an ORR of 22% with a DCR of 77.3%, whereas those in the third-line or later setting had an ORR of 15.8% with a DCR of 84.2%. Response rates were also influenced by TROP2 expression, with ORR reaching 25% in high-IHC cases and 21.7% in low-to-medium IHC cases. The overall DCR across all groups was 80%, showing significant disease stabilization. The safety profiles of these ADCs were consistent with previous reports, with manageable toxicity.


Challenges and Resistance Mechanisms

Despite ADC potential, resistance remains a major challenge. Mutations in TACSTD2/TROP2 and TOP1 were identified as key factors reducing drug efficacy, altering antigen expression or disrupting ADC internalization. Cross-resistance among ADCs with similar payloads underscores the need for new drug development strategies. Functional imaging, including 64Cu-FBP8 fibrin-targeted PET/MRI and NOTA-Granzyme B PET/CT, is emerging as a clinical biomarker to assess treatment response, refine patient selection, and optimize interventions.


Neoadjuvant Therapy and Future Perspectives

Neoadjuvant therapy incorporating ADCs and bispecific T-cell engagers (BiTEs) is being explored to improve surgical outcomes, particularly in metastatic colorectal cancer. Administering ADCs or BiTEs before surgery, followed by adjuvant therapy, aims to enhance long-term remission rates and bridge the gap between systemic therapy and curative surgery.


Conclusion

The ASCO 2024 presentation highlighted the evolving role of ADCs and bispecific antibodies in GI oncology. While these therapies offer new hope for patients with limited options, overcoming resistance mechanisms and refining biomarker-driven strategies will be crucial. Future research will focus on enhancing drug design, improving patient selection, and integrating functional imaging for personalized treatment.