38P - Effects of antiemetics on zolbetuximab-induced gastric injury and emesis frequency in ferrets

Background

Claudin 18.2 (CLDN18.2) is expressed in normal gastric tissue and gastric cancers. Zolbetuximab is a chimeric IgG1 monoclonal antibody that selectively targets CLDN18.2, inducing antibody- and complement-dependent cytotoxicity and cancer cell lysis. In phase 3 studies of zolbetuximab for HER2-negative, advanced gastric/gastroesophageal junction adenocarcinomas (SPOTLIGHT, GLOW), the most frequent adverse events were nausea and vomiting (N/V). We investigated the mechanism of zolbetuximab-induced N/V and effects of antiemetic agents on gastric injury and emesis frequency in ferrets.

Methods

Ferrets were administered zolbetuximab with/without single or combination antiemetic treatment (Table). Retching/vomiting were monitored for 6 hours, after which gastric tissues were sampled for histopathologic assessment. The study was conducted twice. Table: 38P

Study groups

DEX, dexamethasone; FOS, fosaprepitant; IM, intramuscular; IV, intravenous; OLA, olanzapine; OND, ondansetron.

Results

Zolbetuximab induced emesis within 30 minutes of administration. Singly, dexamethasone (DEX), ondansetron (OND), and fosaprepitant (FOS) significantly reduced emesis vs control (no antiemetic) in Study 1; olanzapine (OLA) did not. In Study 2, FOS alone (but not DEX, OND, or OLA) almost completely suppressed emesis. Further, both combination regimens containing FOS reduced emesis. Histopathologic analysis indicated that zolbetuximab induced gastric injury, evidenced by submucosal inflammation in the corpus and pylorus. DEX alone and the DEX-based combination regimen showed a tendency to alleviate submucosal inflammation in the corpus and pylorus, although the other antiemetics did not show any clear suppression of gastric mucosal damage. The combination of OND+FOS also tended to alleviate gastric mucosal abnormalities.

Conclusions

These findings in ferrets demonstrate that zolbetuximab-induced emesis may be associated with gastric mucosal damage. Further, antiemetics may have the potential to mitigate N/V in patients treated with zolbetuximab.

Clinical trial identification

Editorial acknowledgement

This study is funded by Astellas Pharma, Inc. Medical writing/editorial support was provided by Sandra Westra, PharmD, Pamela Barendt, PhD, and Cheryl Casterline, MA, from Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, and funded by the study sponsor.

Legal entity responsible for the study

Astellas Pharma, Inc.

Funding

Astellas Pharma, Inc.

Disclosure

All authors have declared no conflicts of interest.