A novel antibody-drug conjugate (ADC) targeting CLDN18.2 has demonstrated promising efficacy and a manageable safety profile in patients with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, according to results from a phase 1 study published in Nature Medicine. The study of IBI343 enrolled 127 patients and represents a significant advancement in targeting this validated therapeutic pathway.
Study Design and Patient Population
The multicenter, open-label phase 1 study was conducted across 32 centers in China and Australia, featuring both dose escalation and expansion phases. During dose escalation, 19 participants received IBI343 monotherapy intravenously at doses ranging from 0.3 mg/kg to 10 mg/kg once every 3 weeks. The dose expansion phase enrolled 108 participants with G/GEJ adenocarcinoma at doses of 6 mg/kg (n=60), 8 mg/kg (n=32), and other dose levels (n=16).
CLDN18.2 expression was evaluated using the Ventana CLDN18 (43-14A) IHC assay in 100 of 108 participants in the expansion phase. Of these, 57 (57.0%) had high expression (2+/3+ ≥75%), 33 (33.0%) had moderate expression (2+/3+: 40-74%), and 10 (10.0%) had low expression (2+/3+ <40%). The median treatment duration was 18.0 weeks (range 3.0-64.0) for all participants with G/GEJ adenocarcinoma.
Safety Profile and Dose Determination
The maximum tolerated dose was determined to be 8 mg/kg after dose-limiting toxicities were observed in two of six participants at 10 mg/kg, including grade 4 myelosuppression and grade 4 neutropenia with grade 3 febrile neutropenia. However, based on comprehensive safety, efficacy, and pharmacokinetic analyses, 6 mg/kg every 3 weeks was selected as the recommended phase 2 dose.
Among all 116 participants with G/GEJ adenocarcinoma, treatment-emergent adverse events occurred in 113 participants (97.4%), with 77 participants (66.4%) experiencing grade 3 or higher events. The most common adverse events included decreased white blood cell count (67.2%), anemia (64.7%), decreased neutrophil count (58.6%), decreased appetite (46.6%), and nausea (41.4%).
Notably, IBI343 demonstrated a favorable gastrointestinal safety profile compared to other CLDN18.2-targeting therapies. Nausea occurred in 41.4% of patients (1.7% grade 3+) and vomiting in 25% (2.6% grade 3+), substantially lower than rates observed with other agents in this class. Importantly, no interstitial lung disease of any grade was observed during the study period.
Efficacy Results
In patients with high CLDN18.2 expression (2+/3+ ≥75%), IBI343 demonstrated substantial antitumor activity. At 6 mg/kg, 31 evaluable participants showed an unconfirmed objective response rate (ORR) of 48.4% (95% CI: 30.2-66.9) and a confirmed ORR of 29.0% (95% CI: 14.2-48.0). The disease control rate was 90.3% (95% CI: 74.2-98.0), with a median duration of response of 5.6 months (95% CI: 2.8-7.0) in confirmed responders.
At 8 mg/kg, 17 evaluable participants with high CLDN18.2 expression achieved an unconfirmed ORR of 52.9% (95% CI: 27.8-77.0) and a confirmed ORR of 47.1% (95% CI: 23.0-72.2). The disease control rate was 88.2% (95% CI: 63.6-98.5), with a median duration of response of 5.7 months (95% CI: 2.7-NC).
The median progression-free survival was 5.5 months (95% CI: 4.1-7.0) at 6 mg/kg and 6.8 months (95% CI: 2.8-7.5) at 8 mg/kg. Overall survival data were not mature at the time of analysis.
Unique Design Features
IBI343 represents a next-generation CLDN18.2-targeting ADC with several distinctive features. The molecule employs an Fc-silenced design to reduce on-target, off-tumor gastrointestinal toxicities by decreasing binding affinity to Fc gamma receptors and significantly reducing ADCC and CDC activities. The glycan-based conjugation technology enables site-specific conjugation of the exatecan topoisomerase payload to the N-glycans (N297) of the anti-CLDN18.2 antibody.
Clinical pharmacology analyses revealed exceptional drug-antibody ratio (DAR) stability, with minimal payload loss in vivo. The half-life was approximately 2 weeks at 6 mg/kg, supporting the 3-week dosing interval. Population pharmacokinetic simulations demonstrated continuous and dose-proportional exposure across the 3-10 mg/kg dosage range.
Comparison with Other CLDN18.2-Targeting Agents
The study results compare favorably to other therapies in this space. Zolbetuximab monotherapy showed an ORR of 9% in participants with moderate-to-strong CLDN18.2 expression in phase 2a studies, while the recently published CMG901 ADC demonstrated an ORR of 29% in dose expansion, though with higher rates of gastrointestinal toxicity despite mandatory six-drug prophylaxis.
The lower rates of nausea and vomiting observed with IBI343 may relate to the recommended four-drug antiemetic prophylaxis (neurokinin-1 receptor antagonist, 5-HT3 receptor antagonist, dexamethasone, and proton pump inhibitor) or the unique Fc-silencing design.
Clinical Implications and Future Directions
The study reinforces CLDN18.2 as a validated therapeutic target in upper gastrointestinal cancers and highlights the importance of quantitative CLDN18.2 testing as a biomarker for treatment selection. More than 70% of participants had received two or more prior lines of treatment, and IBI343 compared favorably against standard third-line therapies.
Based on these encouraging results, a multicenter, randomized, open-label phase 3 study (G-HOPE-001 trial; NCT06238843) of IBI343 monotherapy versus investigator's choice chemotherapy in patients with previously treated, high CLDN18.2 expression, HER2-negative G/GEJ adenocarcinoma is being initiated.
The study authors noted several limitations, including the single-arm design and predominantly Chinese patient population, which may limit generalizability. Future directions include exploring combination therapy with checkpoint inhibitors and optimal sequencing of anti-CLDN18.2 therapies.
Conclusion
IBI343 represents a promising advancement in CLDN18.2-targeted therapy, demonstrating encouraging efficacy with a manageable safety profile and notably reduced gastrointestinal toxicity compared to other agents in this class. The upcoming phase 3 trial will provide definitive evidence of its potential role in treating advanced gastric and gastroesophageal junction cancers.
