Two phase 1 trials—SHR-A1904 and IBI343—have propelled the clinical development of CLDN18.2-directed ADCs. This article provides a head-to-head comparison of their design, efficacy, safety, and positioning relative to zolbetuximab and other existing therapies.
Trial Design and Patient Populations
Both trials enrolled heavily pretreated gastric/GEJ cancer patients but differed in scope and methodology:
- SHR-A1904: 95 patients, mostly ≥2 prior lines, dose range 0.6–8.0 mg/kg
- IBI343: 127 patients, stratified by CLDN18.2 expression, RP2D set at 6 mg/kg Q3W
IBI343 uniquely incorporated biomarker-based subgroup analyses, highlighting differential efficacy by expression levels.
Structural Differences
- SHR-A1904: Retains Fc activity, combines CLDN18.2 antibody with topoisomerase I inhibitor
- IBI343: Fc-silenced backbone, conjugated to exatecan, with stable DAR=4
These distinctions shape safety and efficacy: SHR-A1904 retains immune effector functions, while IBI343 minimizes on-target GI toxicity.
Efficacy Comparison
Both agents demonstrated modest but clinically meaningful activity:
- SHR-A1904: ORR 24–25%, median PFS ~5.6 months
- IBI343: ORR 29–47% in high-expression patients, median PFS 5.5–6.8 months
IBI343 exhibited stronger responses in high-expression cohorts, reinforcing the role of biomarker-guided therapy.
Safety Comparison
Adverse events were hematologic in both trials, but GI toxicity differed:
- SHR-A1904: frequent nausea and hypoalbuminemia, 62% grade ≥3 AEs
- IBI343: predominantly cytopenias, fewer GI events, 66% grade ≥3 AEs
The reduced GI toxicity with IBI343 likely reflects the Fc-silenced design.
Positioning Relative to Zolbetuximab
Zolbetuximab, FDA-approved in 2024, provides modest OS benefit but depends on immune effector engagement. ADCs, by contrast, achieve direct tumor cell killing and may benefit patients unresponsive to zolbetuximab, particularly in immunosuppressive tumor microenvironments.
Shared Challenges Across ADCs
- Response rates remain ~30% or less
- High incidence of grade ≥3 hematologic AEs
- Resistance mechanisms (poor internalization, payload efflux, DNA repair activation)
Future strategies must refine patient selection, leverage bystander effects, and explore rational combinations with chemotherapy or immunotherapy.
My Perspective
SHR-A1904 and IBI343 embody two distinct approaches—immune effector engagement vs. toxicity reduction through Fc silencing. My key perspectives:
- Biomarker optimization: Patient selection by CLDN18.2 expression is critical, especially for IBI343.
- Combination therapy: Standalone efficacy is limited; synergies with checkpoint inhibitors or anti-angiogenics should be pursued.
- Resistance mitigation: Overcoming topoisomerase I inhibitor resistance will require alternative payload strategies.
In sum, SHR-A1904 and IBI343 represent complementary strategies, together forming the cornerstone of future CLDN18.2-targeted therapy.
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This article was edited by the Morningglorysciences team.
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