Clinical pharmacology profile of the claudin 18.2 antibody zolbetuximab.
Authors: Yang Jianning , Yamada Akihiro , Klempner Samuel J. , Lonardi Sara , Shitara Kohei , Xu Rui-Hua , Ilson David H. , Ueno Yoko , Takeuchi Masato , Pavese Janet , Wojtkowski Tomasz , Matsangou Maria , Poondru Srinivasu 
Published: January 2024

316

Background:
Zolbetuximab is an investigational first-in-class chimeric (mouse/human) monoclonal antibody directed against the tight junction protein claudin 18.2 (CLDN18.2). Zolbetuximab is currently being developed as first-line treatment of patients with locally advanced unresectable or metastatic HER2
–
gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, in combination with fluoropyrimidine- and platinum-containing chemotherapy.
Methods:
The clinical pharmacology of zolbetuximab (pharmacokinetics [PK] and impact of covariates, potential for drug-drug interactions and QTc prolongation, exposure-response [E-R] for efficacy and safety, immunogenicity [antidrug antibodies; ADAs]) was characterized from 9 studies in adults with advanced CLDN18.2-positive adenocarcinoma of the stomach, esophagus, or GEJ.
Results:
Zolbetuximab exhibited dose-proportional PK at doses of 33 to 1000 mg/m
2
. Based on population PK modeling using data from 714 participants, zolbetuximab exposure (Table) was not meaningfully affected by sex, race/ethnicity, age, mild/moderate renal impairment, or mild hepatic impairment. Gastrectomy was predicted to increase C
ave
by 36%. Coadministration of zolbetuximab with chemotherapy did not show clinically meaningful changes in drug exposures of zolbetuximab or chemotherapy. At therapeutic doses, zolbetuximab had no clinically meaningful effect on QTc prolongation. In phase 3 studies, zolbetuximab (800 mg/m
2
loading dose/600 mg/m
2
Q3W) had a manageable safety profile and was associated with significant prolongation of progression-free survival (PFS) and overall survival (OS). E-R analyses suggested that higher zolbetuximab exposure may further prolong PFS and OS but with increased probability of gastrointestinal events and infusion-related reactions. E-R model simulations suggested comparable zolbetuximab efficacy and safety between the 800/600 mg/m
2
Q3W regimen and an alternative 800/400 mg/m
2
Q2W regimen for use in combination with chemotherapy. ADAs were detected in 4.4% of patients in phase 3 studies with no apparent impact on zolbetuximab PK, efficacy, or safety.
Conclusions:
The clinical pharmacology of zolbetuximab was well characterized using data from 9 clinical trials. The integrated data support the proposed 800/600 mg/m
2
Q3W regimen as well as an 800/400 mg/m
2
Q2W regimen in combination with chemotherapy.
Clinical trial information: NCT00909025
,
NCT01671774
,
NCT03528629
,
NCT04086758
,
NCT01197885
,
NCT01630083
,
NCT03505320
,
NCT03504397
,
NCT03653507
.

Model-estimated exposure metrics of zolbetuximab.

Mean (SD)

First Dose(800 mg/m
2
)

Steady State(600 mg/m
2
Q3W)

C
max
(µg/mL)

434 (96)
425 (91)

AUC
21d
(day·µg/mL)

2164 (589)
3359 (1254)

C
trough
(µg/mL)

43.9 (25.1)
101 (51)

C
ave
(µg/mL)

–
140 (50)

First dose simulation was for a 3-week interval after the first dose. For steady state, simulation was for a 3-week interval from Weeks 28–31. Estimated terminal elimination half-life was 43.6 days. Q3W, every 3 weeks.