1017P - Updated safety and efficacy from the phase I study of givastomig, a novel claudin 18.2/4-1BB bispecific antibody, in claudin 18.2 positive advanced gastroesophageal carcinoma (GEC)

Background

Givastomig/ABL503 (Giva) is a first-in-class, bispecific antibody targeting Claudin (CLDN) 18.2 and engaging 4-1BB through a unique conditional activation mechanism in tumor sites to avoid systemic toxicities. A phase 1 study was designed to evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics of Giva.

Methods

The study included a dose escalation following the Bayesian Optimal Interval design and a dose expansion. During dose escalation, patients with solid tumors, irrespective of CLDN18.2 expression were administered Giva intravenously every 2 weeks (Q2W) across 8 dose levels (0.1, 0.3, 1, 3, 5, 8, 12, 15mg/kg). During dose expansion, patients with CLDN18.2 positive (+, ≥1% of tumor cells with ≥1+ intensity by immunohistochemistry) GEC were included. The outcomes from patients with CLDN18.2+ GEC at doses ≥5mg/kg are reported here.

Results

As of February 1, 2024, 39 patients with CLDN18.2+ GEC were enrolled at Giva 5 mg/kg (n=7), 8 mg/kg (n=5), 12 mg/kg (n=21), and 15mg/kg (n=6) Q2W. Patients had a median of 3 prior lines of therapy, including 74% with prior programmed death-(ligand) 1 inhibitor therapy. Common treatment-related adverse events (≥15%, any grade/grade 3) included white blood cell count decreased (26%/8%), anemia (23%/8%), nausea (21%/0%), and vomiting (15%/3%). No dose limiting toxicities were observed. Linear PK was observed at doses ≥5mg/kg. Soluble 4-1BB induction was dose-dependent and plateaued at doses ≥8 mg/kg. Partial response (PR) was observed in 5 patients (1 PR each at 5 and 8mg/kg and 3 PRs at 12mg/kg) with objective response rate of 13%. CLDN18.2 expression in responders ranged from 11% (1+, 10%; 2+, 1%) to 100% (2+, 10%; 3+, 90%). Stable disease was observed in 13 patients (disease control rate = 46.2%). 8 (20.5%) patients are ongoing including one PR in 8 mg/kg at 471 days and one PR in 12 mg/kg at 127 days.

Conclusions

Giva was well tolerated up to 15 mg/kg Q2W and has shown encouraging activity in heavily pre-treated GEC patients with a wide range of CLDN18.2 expression. The current optimal dose range was determined to be 8-12 mg/kg Q2W. A study of Giva in combination with standard of care treatment in 1L metastatic GEC is ongoing.

Clinical trial identification

NCT04900818.

Editorial acknowledgement

Legal entity responsible for the study

I-Mab Biopharma, US, Limited.

Funding

I-Mab Biopharma, US, Limited.

Disclosure

S.J. Klempner: Financial Interests, Personal, Advisory Board, Stomach Cancer Advisory Board: Merck, Bristol Myers Squibb, Astellas, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, One Time Advisory Board: Natera; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x 1, 2023: Mersana; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x 1: Sanofi-Aventis; Financial Interests, Personal, Advisory Board, Stomach Cancer consulting, ended in 1/2024: Novartis; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x1 in 1/2024: AstraZeneca; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x1 in 3/2024: I-Mab Therapeutics; Financial Interests, Personal, Advisory Board, Stomach cancer consulting: Taiho Oncology; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x1, planned for 6/2024: Eisai; Financial Interests, Personal, Stocks/Shares, Stock Ownership, ended in 6/2022: Turning Point Therapeutics; Financial Interests, Personal, Stocks/Shares, Early investor, company is not public: Mbrace; Financial Interests, Institutional, Coordinating PI, National PI for trial: Leap Therapeutics; Financial Interests, Personal and Institutional, Local PI, Local PI for trial, also served on advisory board as noted above: Astellas; Financial Interests, Institutional, Local PI, Ended in 2022: Macrogenics; Financial Interests, Institutional, Coordinating PI, Trial PI, ended in 2023: Silverback; Financial Interests, Institutional, Local PI, Site PI for phase III trials: Arcus; Financial Interests, Personal and Institutional, Local PI, Site PI for trial, as disclosed above was a one-time advisory board participant: I-Mab; Non-Financial Interests, Advisory Role, Medical-Scientific Advisory Board Member: Debbies Dream Foundation; Non-Financial Interests, Advisory Role, Member of Scientific Advisory Board: Hope for Stomach Cancer; Non-Financial Interests, Other, Member of Gastric and Esophageal NCCN Guideline Committees: NCCN; Other, Participant in gastroesophageal CME activities, compensated, last in 3/2024: Research to Practice. L. Shen: Financial Interests, Personal, Advisory Board: MSD, BI, Servier, AZ, Transcenta Holding Limited; Financial Interests, Institutional, Funding: BeiGene, Ltd.; Financial Interests, Institutional, Trial Chair: Rongchang Pharmaceutical, Roche, Innovent, BeiGene, Ltd., NovaRock Biotherapeutics Limited. F. Dayyani: Financial Interests, Personal, Advisory Board: Eisai, AstraZeneca; Financial Interests, Personal, Invited Speaker: Ipsen, Sirtex, Takeda; Financial Interests, Institutional, Local PI: AstraZeneca, BMS, Bayer, Roche, Ipsen, Merck; Financial Interests, Institutional, Coordinating PI: Exelixis, Signatera, Taiho. J. Kratz, S. Kim: Financial Interests, Institutional, Advisory Board: I-Mab Biopharma. E. Girda: Financial Interests, Institutional, Advisory Board: Merck, Immunogen. C. Xu, M.T. Nguyen: Financial Interests, Institutional, Full or part-time Employment: I-Mab Biopharma. J. Xia, X. Wang: Financial Interests, Institutional, Full or part-time Employment: TJBio. G.Y. Ku: Financial Interests, Personal and Institutional, Advisory Board: I-Mab Biopharma; Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca, BMS, CARsgen, Daiichi Sankyo, Jazz, Merck, Pieris, Zymeworks, Astellas, Bayer; Financial Interests, Institutional, Sponsor/Funding: Oncolys. All other authors have declared no conflicts of interest.