1556P - Pharmacokinetics, pharmacodynamics and exposure response analyses of osemitamab in patients with locally advanced or metastatic solid tumors

Background

Osemitamab, a humanized Claudin18.2 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) via improved binding affinity and reduced fucosylation, is being developed to treat metastatic gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Pharmacokinetics (PK), pharmacodynamics (PD) and exposure-response (ER) relationship of Osemitamab were evaluated in two phase I/IIa studies.

Methods

Osemitamab was administrated as monotherapy or in combination with standard of care (SOC) in patients. PK profiles of osemitamab were determined using non-compartmental analysis and population PK. The ADCC capacity of circulating osemitamab was tested in a subset of patients who received 3-10mg/kg Q3W. Relationships between PK and objective response rate (ORR) and safety were explored.

Results

A total of 2401 PK data were obtained from 248 patients from two clinical trials. Similar PK was observed between the US and Chinese patients. PK is dose proportional between 0.3 to 15 mg/kg. A two-compartment model with first-order elimination described the PK profile of osemitamab. Clearance (CL) was affected by body weight and gastrectomy history. Model simulated steady state trough concentration will achieve in vitro ADCC assay EC95 and in vivo MKN45-CLDN18.2 tumor growth inhibition model EC50 in most subjects following 6mg/kg Q3W and 4mg/kg Q2W. ADA incidence is less than 10%. Serum ADCC response remained at ∼ 50% of the maximum lysis up to 21 days following osemitamab 6 mg/kg Q3W. Anti-tumor activity data from 58 patients with 1L G/GEJ adenocarcinoma treated with osemitamab and capecitabine and oxaliplatin (CAPOX) showed patients with average concentration in 56 days above 24 μg/mL tended to have a better ORR. Grade 2+ nausea/vomiting are found to be associated with osemitamab exposure; however, simulations demonstrated the proportion of patients that developed Grade 2+ nausea or vomiting by 6 months were just slightly higher (< 10% in difference) following 6 mg/kg Q3W than 3 mg/kg Q3W.

Conclusions

Osemitamab at 6mg/kg Q3W or 4mg/kg Q2W are predicted to have favorable PK/PD/safety profiles and might be associated with better ORR in combination with SOC compared to the lower doses.

Clinical trial identification

NCT04396821, NCT04495296.

Editorial acknowledgement

Legal entity responsible for the study

Suzhou Transcenta Therapeutics Co., Ltd.

Funding

Suzhou Transcenta Therapeutics Co., Ltd.

Disclosure

J. Yao; D. Chen; X. Lin; C. Qi; Z. Xia; L. Zhang; S. Yu; C. Germa; Financial Interests, Personal, Full or part-time Employment: Transcenta. All other authors have declared no conflicts of interest.