Abstract 986P
Background
Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to Claudin 18.2 and mediates cancer death via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Phase III studies of zolbetuximab plus chemotherapy (fluoropyrimidine and oxaliplatin) are ongoing. Along with chemotherapy, immunotherapy is becoming standard of care for gastric cancer. The beneficial effect of zolbetuximab plus chemotherapy or anti-mouse PD-1 (anti-mPD-1) antibody is presented here.
Methods
In this study, we examined the effect of zolbetuximab plus 5-fluorouracil + oxaliplatin (chemotherapy; Study 1) or an anti-mPD-1 antibody (Study 2) in a syngeneic mouse tumor model with mouse Claudin 18.2-expressing CLS-103 gastric carcinoma cells. Tumor cells were inoculated into immune-competent NMRI mice. Rituximab, PBS + 5% glucose, and anti-trinitrophenol antibody were used as isotype controls or vehicle (Table). Tumor volumes were assessed in both studies. In Study 1, flow cytometry was used to analyze the frequency of immune cells in tumor tissues.
Results
In Study 1, tumor growth was inhibited by 65%, 42%, or 93%, in the zolbetuximab, chemotherapy, or combination groups, respectively. Tumor volume was significantly lower with the combination versus zolbetuximab (P < 0.05) or chemotherapy alone (P < 0.01). The frequency of tumor-infiltrating CD8+ T-cells was significantly higher with the combination versus control (P < 0.05). In Study 2, tumor growth was inhibited by 50%, 60%, or 91%, in the zolbetuximab, the anti-mPD-1 antibody, or combination groups, respectively. Tumor volume was significantly lower with the combination versus zolbetuximab (P < 0.01) or anti-mPD-1 antibody (P < 0.05).
Conclusions
Zolbetuximab combined with chemotherapy or an anti-mPD-1 antibody more potently inhibited tumor growth, compared with each treatment alone, in a syngeneic tumor model. Table: 986P
Study groups
| Study 1, n=15 each group | Study 2, n=12 each group |
| Group 1: control (rituximab + PBS + 5% glucose) | Group 1: control (rituximab + anti-trinitrophenol antibody) |
| Group 2: zolbetuximab (zolbetuximab + PBS + 5% glucose) | Group 2: zolbetuximab (zolbetuximab + anti-trinitrophenol antibody) |
| Group 3: chemotherapy (rituximab + 5-FU + oxaliplatin) | Group 3: anti-mPD-1 antibody (rituximab + anti-mPD-1 antibody) |
| Group 4: combination (zolbetuximab + 5-FU + oxaliplatin) | Group 4: combination (zolbetuximab + anti-mPD-1 antibody) |
Abbreviations: 5-FU, 5-fluorouracil; anti-mPD-1, anti-mouse PD-1.
Clinical trial identification
Editorial acknowledgement
Medical writing/editorial support was provided by Cathy R. Winter, PhD, Patrick Tucker, PhD, and Elizabeth Hermans, PhD, from Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and funded by the study sponsor.
Legal entity responsible for the study
Astellas Pharma, Inc.
Funding
This study was funded by Astellas Pharma, Inc.
Disclosure
T. Yamada: Other, Institutional, Funding, Inventor of WO/2021/025177: Astellas. All other authors have declared no conflicts of interest.