1039P - First-in-human phase I study of givastomig, a novel Claudin 18.2/4-1BB bispecific antibody in advanced solid tumors

Background

Givastomig is a first-in-class bispecific antibody designed to target tumors with a wide range of Claudin 18.2 (CLDN18.2) expression and engage 4-1BB through a unique conditional activation mechanism at the tumor sites to avoid systemic toxicities.

Methods

This study evaluates safety, clinical response (RECIST v1.1), pharmacokinetics (PK), soluble 4-1BB (s4-1BB) levels, serum cytokines and immunophenotypes. Givastomig was administered intravenously every 2 weeks (Q2W) across 8 dose levels (0.1-15mg/kg) in patients with advanced solid tumors. The Bayesian Optimal Interval design was utilized during dose escalation without CLDN18.2 preselection. Additionally, 6 CLDN18.2+ patients per dose level were enrolled at 5, 8, and 12mg/kg in parallel expansions. CLDN18.2+ is defined as ≥1% of tumor cells with ≥1+ intensity by immunohistochemistry.

Results

As of 18 April 2023, 50 patients were enrolled (32 in the dose escalation and 18 in the parallel expansions) with a median age of 66 years, ECOG 0/1 (34%/66%), and a median of 3 prior lines of therapy. No dose-limiting toxicity was observed up to 15 mg/kg, and maximum tolerated dose was not reached. The most common treatment-related adverse events (TRAEs) were Grade 1/2 nausea (22%), fatigue (14%), and vomiting (12%) with 7 sporadic Grade 3 TRAEs, and no Grade ≥4 TRAEs. Givastomig exhibited a linear PK at doses ≥5 mg/kg and a dose-dependent increase of s4-1BB levels reaching a plateau at doses ≥8 mg/kg. Among 18 efficacy-evaluable patients with CLDN18.2+ gastroesophageal cancer (GEC) at 5, 8, and 12mg/kg, partial response (PR) in 1 patient each at 5 and 8 mg/kg, unconfirmed PR in 2 patients at 12 mg/kg, and stable disease in 2 patients were observed. An additional PR was observed in 1 patient with head and neck cancer at 12mg/kg. CLDN18.2 expression among the responders ranged from 11% to 100%.

Conclusions

Givastomig is well tolerated up to 15 mg/kg Q2W. Encouraging monotherapy activity was observed in heavily pre-treated GEC patients with a wide range of CLDN18.2 expression, including low CLND18.2 tumors. The PK profile, s4-1BB induction, and efficacy signal support 12 mg/kg as an optimal dose. Further development of givastomig mono- and combo- therapy in GEC and other cancers is planned.

Clinical trial identification

NCT04900818.

Editorial acknowledgement

Legal entity responsible for the study

I-Mab Biopharma.

Funding

I-Mab Biopharma.

Disclosure

G. Ku, S.J. Klempner, S. Kim: Financial Interests, Personal, Advisory Board: i-mabbiopharma. M.T. Nguyen, V. Wang, C. Xu: Financial Interests, Personal and Institutional, Full or part-time Employment: i-mabbiopharma. A. Zhu: Financial Interests, Institutional, Full or part-time Employment: i-mabbiopharma. All other authors have declared no conflicts of interest.