Abstract 42P
Background
Zolbetuximab, a chimeric mouse/human IgG1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates cancer cell death via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. A phase II study of zolbetuximab plus chemotherapy with or without the anti-programmed cell death 1 (anti-PD-1) antibody nivolumab is ongoing. Here, the triple combination was evaluated in a syngeneic mouse model. In addition, a virtual preclinical trial was conducted using a QSP approach.
Methods
Immunocompetent mice were engrafted with gastric carcinoma cells lentivirally transfected with mouse CLDN18.2 (CLS-103 LVT-murinCLDN18.2) and randomized to treatment groups based on tumor volume at Day 2 (Table). Tumor growth inhibition (TGI, %) = 100 × (1 − increase of mean tumor volume of each group/increase in control group). A mouse QSP model was built based on a published QSP model with in-house/published data, and the antitumor effect of the triple combination was simulated. Table: 42P
| Groups (n=16 each) |
| Control –→Rituximab + vehicle + isotype control Ab |
| Dual anti-mPD-1 Ab + chemotherapy –→Rituximab + 5-FU + oxaliplatin + anti-mPD-1 Ab |
| Dual anti-CLDN18.2 Ab + anti-mPD-1 Ab –→Zolbetuximab + vehicle + anti-mPD-1 Ab |
| Dual anti-CLDN18.2 Ab + chemotherapy –→Zolbetuximab + 5-FU + oxaliplatin + isotype control Ab |
| Triple anti-CLDN18.2 Ab + chemotherapy + anti-mPD-1 Ab –→Zolbetuximab + 5-FU + oxaliplatin + anti-mPD-1 Ab |
| Administration: zolbetuximab/rituximab control, 800 μg/head; 5-FU, 10 mg/kg (3.33 mL/kg); oxaliplatin, 0.5 mg/kg (3.33 mL/kg); vehicle, PBS + 5% glucose (3.33 mL/kg); anti-mPD-1 Ab/control, 30 μg/head |
| 5-FU, 5-fluorouracil; Ab, antibody; anti-mPD-1, anti-mouse PD-1 |
Results
Day 20 TGI was 88% with the zolbetuximab triple combination. TGIs of dual combinations of chemotherapy plus anti-mPD-1 antibody, zolbetuximab plus anti-mPD-1 antibody, or zolbetuximab plus chemotherapy were 65%, 78%, and 54%, respectively. The triple combination was associated with a higher percentage of regressed tumors (50%) than the dual combinations (31% in each group) or control (0%). Results of the virtual trial simulation by the established QSP model showed that interanimal variability of TGI was less with the triple combination than with any dual combination.
Conclusions
Zolbetuximab triple combination showed a more potent antitumor effect in the mouse model. The QSP model was able to reproduce the observed results not only as mean profiles but as profiles with different interanimal variability among treatments.
Clinical trial identification
Editorial acknowledgement
Medical writing/editorial support was provided by Pamela Barendt, PhD, Cathy R. Winter, PhD, and Carol Cadmus, ELS, 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
T. Nakayama, M. Oishi, J. Weng, K. Omori, C. Kwon, T. Nakazawa, T. Nishibata, F. Kinugasa, T. Yoshida, Y. Nagasaka: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma, Inc.