Antibody–drug conjugates (ADCs) targeting Claudin18.2 (CLDN18.2) have gained increasing attention as a novel therapeutic approach for advanced gastric and gastroesophageal junction (GEJ) cancers. Here, we summarize the phase 1 trial results of SHR-A1904 published in Nature Medicine (July 2025) and discuss its clinical implications.
Background: Gastric Cancer Treatment and CLDN18.2 as a Target
Gastric and GEJ cancers remain among the deadliest malignancies worldwide, particularly prevalent in East Asia. Although HER2-targeted ADCs and immune checkpoint inhibitors have transformed treatment paradigms, therapeutic options are limited for patients who are HER2-negative or resistant to immunotherapy.
Within this context, the tight junction protein CLDN18.2, selectively expressed in gastric mucosa and exposed on tumor cell surfaces during malignant transformation, has emerged as a promising target. Following the approval of zolbetuximab, CLDN18.2-directed ADCs are rapidly entering clinical development.
Drug Profile: Structure and Features of SHR-A1904
SHR-A1904, developed by Jiangsu Hengrui Pharmaceuticals, is an ADC composed of a CLDN18.2-specific monoclonal antibody conjugated with a DNA topoisomerase I inhibitor payload via a peptide-based cleavable linker. This design enables targeted delivery and intracellular drug release, resulting in tumor cell apoptosis.
Unlike zolbetuximab, which relies on immune effector recruitment, SHR-A1904 offers the advantage of direct tumor cell killing independent of immune activation.
Phase 1 Trial Design
The first-in-human, three-stage phase 1 study (NCT04877717) included 95 patients with CLDN18.2-positive advanced gastric/GEJ cancers who had received prior therapies. Doses ranged from 0.6 to 8.0 mg/kg, with expansion cohorts at 6.0 and 8.0 mg/kg.
DLTs included febrile neutropenia at 4.8 mg/kg and gastric mucosal lesions at 6.0 mg/kg. The maximum tolerated dose was not reached.
Safety Profile
Treatment-emergent adverse events (TEAEs) were observed in all patients. The most frequent were:
- Anemia: 75.8%
- Nausea: 67.4%
- Hypoalbuminemia: 64.2%
- Leukopenia: 58.9%
Grade ≥3 AEs occurred in 62.1% of patients; no treatment-related deaths were reported.
Efficacy Outcomes
The confirmed objective response rates (ORR) were:
- 6.0 mg/kg: 24.2% (95% CI, 11.1–42.3)
- 8.0 mg/kg: 25.0% (95% CI, 12.1–42.2)
The median progression-free survival (PFS) was 5.6 months at 6.0 mg/kg and 5.8 months at 8.0 mg/kg.
Clinical Significance
SHR-A1904 demonstrated manageable safety and modest efficacy even in heavily pretreated patients. Although ORRs were in the 20% range, these results are comparable to or slightly better than existing late-line chemotherapies such as trifluridine/tipiracil. Importantly, the ADC mechanism offers potential benefits in patients who fail zolbetuximab, as tumor killing is independent of immune effector function.
My Perspective
The phase 1 results of SHR-A1904 provide important validation for the clinical development of CLDN18.2 ADCs. However, several challenges remain:
- Toxicity management: With >60% grade ≥3 AEs, optimization of dosing schedules and supportive care is crucial.
- Biomarker strategy: Distinguishing efficacy in high vs. moderate CLDN18.2 expression groups will refine patient selection.
- Comparative positioning: Head-to-head or cross-trial analyses against other ADCs such as IBI343 are needed to establish therapeutic roles.
- Combination approaches: Exploring combinations with chemotherapy or immune checkpoint inhibitors may enhance efficacy.
Overall, SHR-A1904 has successfully cleared the initial clinical hurdle and merits further development. Large-scale, international trials will be essential to determine its place within the treatment landscape of gastric and GEJ cancers.
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This article was edited by the Morningglorysciences team.
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