Claudin18.2 (CLDN18.2)-directed ADCs are rapidly emerging as a cornerstone in the treatment of advanced gastric and gastroesophageal junction (GEJ) cancers. Beyond SHR-A1904 and IBI343, several other candidates such as CMG901, EO-3021, and XNW27011 are in clinical development. This article reviews the global landscape and provides perspective on future directions.
CMG901 (KYM Biosciences/AstraZeneca)
CMG901 is an ADC conjugated with MMAE (monomethyl auristatin E). Developed by KYM Biosciences in China and licensed to AstraZeneca, it has demonstrated promising tolerability and antitumor activity in phase 1 trials. With its microtubule-inhibiting payload, it may address resistance mechanisms distinct from topoisomerase-based ADCs.
EO-3021 (SYSA1801/Elevation Oncology)
EO-3021, also known as SYSA1801, is an MMAE-based ADC developed by CSPC and licensed to Elevation Oncology. Currently in phase 1 trials in China, it is advancing toward global expansion. Biomarker-based patient stratification is integral to its design, aiming to broaden applicability across varying CLDN18.2 expression levels.
XNW27011 (Evopoint/Astellas)
XNW27011, licensed by Astellas from Evopoint in 2025, reported a remarkable 51% ORR in early-phase studies among patients with ≥5% CLDN18.2 expression. This unprecedented response has positioned it as a strong next-generation candidate with ongoing plans for global multicenter trials.
Other Development Programs
- FG-M108: Afucosylated antibody ADC, aiming to fine-tune immune effector function.
- LM-302: CLDN18.2-targeted ADC under early-phase evaluation.
- IBI38: A bispecific antibody (BsAb) from Innovent, potentially synergistic with ADC strategies.
- CAR-T (satricabtagene autoleucel): A novel cell therapy approach targeting CLDN18.2, expanding beyond ADCs.
Global Development Trends and Regulatory Landscape
China remains the hub for CLDN18.2 ADC development due to high prevalence, but expansion into the US and EU is accelerating. The FDA granted Fast Track designation to IBI343 for pancreatic cancer in 2025, reflecting regulatory willingness to expedite development across indications.
Common Challenges
- Response ceiling: ORRs across trials hover at ~30%, requiring exploration of resistance biology.
- Toxicity management: High rates of grade ≥3 hematologic AEs pose challenges for long-term therapy.
- Biomarker harmonization: Standardization of IHC assays and global consensus on expression thresholds are needed.
My Perspective
Claudin18.2 ADCs are poised to redefine the treatment landscape for gastric and GEJ cancers. My perspective:
- Therapeutic positioning: Ideal in post-zolbetuximab settings and in patients resistant to ICIs.
- Resistance mitigation: Diversification of payloads (MMAE, exatecan, topo-I inhibitors) will help circumvent resistance pathways.
- Combination strategies: Pairing ADCs with ICIs or VEGF inhibitors could enhance efficacy and broaden indications.
- Global competition: While China currently leads, US and EU companies are entering, expanding trial scale and sophistication.
Overall, CLDN18.2-targeted ADCs represent a validated target with multiple innovative modalities under development, and are likely to become a central component of gastric cancer therapy in the coming decade.
MorningGlorySciences is provided a series of life science and therapeutics news.
This article was edited by the Morningglorysciences team.
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