Encouraging efficacy of anti-claudin 18.2 ADC in G/GEJ cancer

In a phase 1 trial, IBI343, a monoclonal antibody-drug conjugate (ADC) targeting claudin 18.2, was well-tolerated and demonstrated encouraging efficacy in heavily pretreated patients with advanced unresectable or metastatic gastric or gastro-oesophageal junction (G/GEJ) cancer.

Claudin 18.2 is a tight-junction molecule predominantly found in the non-malignant gastric epithelium that becomes accessible on the tumour cell surface during malignant transformation, providing an appealing target for cancer therapy [1]. IBI343 is an ADC targeting claudin 18.2-expressing tumour cells. After claudin 18.2-dependent internalisation, the payload (exatecan, a topoisomerase inhibitor) induces apoptosis of the tumour cells. The released drug can also diffuse across the plasma membrane to reach and kill the neighbouring cells, resulting in a "bystander killing effect".

A phase 1 trial (NCT05458219) evaluated the safety and efficacy of IBI343 in 159 patients with heavily pretreated advanced G/GEJ cancer with confirmed claudin 18.2 expression. Dr Jia Liu (St Vincent’s Hospital Sydney, Australia) presented the results [2].

Safety findings showed that grade ≥3 treatment-related adverse events (AEs) occurred in 37.7% of the participants treated with 6 or 8 mg/kg IBI343. Gastrointestinal AEs of grade ≥3 occurred at low rates: vomiting 1.9%; nausea 1.3%; decreased appetite 1.3%. Hypoalbuminemia occurred in 24.5% of the participants and was of grade 1–2; no cases of interstitial lung disease (ILD) were reported.

In participants with moderate-to-high (≥40%) claudin 18.2 expression, the overall response rate was 31.2% and 41.4% in the 6 and 8 mg/kg IBI343 groups, respectively, with an associated disease control rate of 89.6% and 82.8% (see Figure). No response was observed in participants with low (<40%) claudin 18.2 expression.

Figure: Efficacy with IBI343 in G/GEJ cancer patients with moderate-to-high claudin 18.2 expression [2]



PD, progressive disease; PR, partial response; SD, stable disease.

Based on these results, Dr Liu concluded that “IBI343 is well-tolerated and has an encouraging efficacy in patients with G/GEJ cancer with moderate or high claudin 18.2 expression.” A registrational phase 3 clinical trial (NCT06238843) is being initiated.

1. Nakayama I, et al. Nat Rev Clin Oncol. 2024;21:354-369.
2. Liu JJ, et al. Anti-claudin 18.2 (CLDN18.2) antibody-drug conjugate (ADC) IBI343 in patients (pts) with solid tumors and gastric/gastro-esophageal junction adenocarcinoma (G/GEJ AC): A phase 1 study. Abstract 396MO, ESMO Gastrointestinal Cancers Congress 2024, 26–29 June, Munich, Germany.

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Posted on 21 August 202421 August 2024