Editor’s Note:

From November 22 to 24, 2024, the CSCO Gastric Cancer Committee Annual Meeting convened in Beijing, gathering leading experts to discuss the latest advancements, challenges, and opportunities in gastric cancer management. Dr. Ting Deng from Tianjin Medical University Cancer Institute and Hospital delivered a keynote presentation titled "ADC Combination Strategies for Gastric Cancer: Directions and Advances."

The Era of Precision Medicine for Advanced Gastric Cancer

Advancements in molecular profiling have ushered gastric cancer into the age of precision therapy, uncovering new actionable targets such as CLDN18.2, FGFR2b, and cMET. This has facilitated the development of targeted therapies ranging from monoclonal antibodies (mAbs) to antibody-drug conjugates (ADCs) and CAR-T therapies.

ADC therapies, which combine antibodies with potent cytotoxic payloads, have emerged as one of the fastest-growing areas in oncology. Two HER2 ADCs—trastuzumab deruxtecan (T-DXd) and RC48—are now recommended by the 2024 CSCO guidelines for third-line and beyond therapy in HER2-positive gastric cancer.

Current Landscape of ADC Combination Therapies

Despite the progress, unmet clinical needs remain. Combination strategies are essential to optimizing ADC therapy, and approaches include combining ADCs with:

1. Immune checkpoint inhibitors (ICIs)
2. Chemotherapy
3. Targeted therapies
4. Anti-angiogenic agents

1. Key Findings from DESTINY-Gastric03 (DG-03)

• Study Design: Explored T-DXd combinations in HER2-positive advanced gastric cancer (GC). Patients were randomized into three groups: standard of care (SOC), T-DXd monotherapy, or T-DXd-based combinations.
• Results: The combination of T-DXd with fluoropyrimidine and pembrolizumab (pembro) demonstrated significantly improved PFS and OS. A reduced dose of T-DXd (5.4 mg/kg) combined with fluoropyrimidine and pembrolizumab showed manageable safety and promising early anti-tumor activity. Follow-up studies are planned for HER2-positive GC/GEJA patients with CPS ≥1.

2. RC48 in Combination Therapies

At the 2024 ASCO meeting, RC48 combined with tislelizumab and S-1 achieved a remarkable 94.3% ORR in HER2-positive advanced GC/GEJC.

• Notable Findings: Promising activity was also observed in HER2 IHC2+/FISH-negative populations. Ongoing studies, such as RC48-027, aim to expand the evidence base for this combination in various HER2 expression subgroups.

3. Expanding Frontline and Perioperative Use

• HER2 ADCs: While post-line treatment often involves monotherapy, frontline strategies are exploring combinations. T-DXd in perioperative settings achieved an MPR of 14.8% in neoadjuvant therapy, underscoring the limited efficacy of ADC monotherapy. RC48 combined with camrelizumab and S-1 achieved a neoadjuvant ORR of 80.0% and pCR of 30.0%, with all patients undergoing successful R0 resection.

4. Targeting Claudin18.2

Claudin18.2 (CLDN18.2) has emerged as a pivotal target in gastric cancer.

• Approved Therapies: Zolbetuximab combined with chemotherapy is the first approved regimen for CLDN18.2-positive, HER2-negative advanced GC.
• Ongoing Trials: Multiple ADCs targeting CLDN18.2 are in Phase III trials. Combinations with PD-1 inhibitors and chemotherapy are under Phase II investigation.

Challenges in ADC Combination Therapies

1. Tumor Heterogeneity

• Spatial and Temporal Variability: Variability in HER2 and other targets complicates patient stratification. Redefining HER2 positivity and expanding studies to low-expression populations are critical.

2. CPS Expression in Immunotherapy Combinations

• DG-03 Findings: CPS ≥1 correlated with better outcomes in T-DXd and pembrolizumab combinations, while chemotherapy-based combinations showed no CPS-dependent differences.

3. Safety Concerns in Combinations

• ADCs inherently cause adverse events; combining therapies may exacerbate toxicities. Mitigation Strategies: Dose optimization (e.g., intermittent dosing). Drug engineering (e.g., prodrug designs, Fc silencing to reduce Fc receptor-mediated toxicity). Biomarker-based toxicity prediction using wearable biosensors.

Conclusion

ADCs have transformed the therapeutic landscape of advanced gastric cancer, particularly in HER2-positive settings. The paradigm is shifting from late-line monotherapy to frontline combinations. Key developments include:

• Enhanced Efficacy: Combination strategies with immunotherapy and chemotherapy are promising.
• Safety Optimization: Innovative approaches are crucial to balance efficacy with safety.

As research progresses, ADC combinations targeting diverse pathways, including HER2 and CLDN18.2, offer hope for improving survival outcomes in gastric cancer patients.

Dr. Ting Deng

• Deputy Chief Physician, Master’s Supervisor
• Department of Gastrointestinal Oncology, Tianjin Medical University Cancer Institute and Hospital
• Chair, Tumor Nutrition and Supportive Therapy Committee, Tianjin Anti-Cancer Association
• Standing Committee Member, CSCO Youth Expert Committee
• Member, CSCO Gastric Cancer and Chemotherapy Committees