A novel anti-HER2 monoclonal antibody IAH0968 in HER2-positive, heavily pretreated solid tumors: Results from a phase Ia/Ib, first-in-human, open-label, single-center study.

e15098 Background: IAH0968 is an afucosylated anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody which possessing the same binding properties to HER2 as trastuzumab and improving antibody-dependent cellular cytotoxicity (ADCC) activity and superior anti-tumor efficacy. We present results from patients with advanced HER2 positive malignant solid tumors including trastuzumab resistant and ineffective patients to establish the recommended dose of IAH0968 for phase II trials, as well as to investigate the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of the drug. Methods: This was a single institution investigator-initiated phaseⅠa/Ⅰb study, using 3+3 design. The primary endpoint was safety, tolerability and preliminary clinical activity. Secondary endpoints included PK, recommended phase II dose, and anti-drug antibody (ADA). PK detection used ELISA to quantitatively determine blood drug concentration of IAH0968. Results: Eighteen pts were evaluable for safety and fifteen pts were suitable for efficacy analysis. The primary cancer sites included breast (8/18), colon (3/18), stomach (2/18), rectum (2/18), biliary tract (2/18), and pancreas (1/18). Median age was 54.2±9.7, ECOG 1/2 = 17/1, and 72.2% received anti-HER2 therapy in prior lines. Doses escalation were 6mg/kg (N = 3), 10mg/kg (N = 6), 15mg/kg (N = 5), and tolerable up to 20mg/kg (N = 4). Only one DLT was found at dosage 10mg/kg, and no MTD was reached. No ADA against IAH0968 was detected. The main PK parameters included mean T 1/2 for doses 6~20 mg/kg ranging from 105 to 118 hours. The volume of distribution (Vz -obs ) ranged from 4110.16 mL to 5395.64 mL. EC 50 of ADCC activity of IAH0968 was 17.75~63.25 ×10 -3 µg/mL. All grade treatment-related adverse events (TRAEs) occurred in 100% of pts, including grade 3 in 16.7%, and grade 4 in 5.6% of pts. The most common grade 3 TRAEs were hypokalemia (5.6%), arrhythmia (5.6%), QTC interval extension (5.6%), and infusion reaction (5.6%). The grade 4 TRAE was arrhythmia (5.6%). No serious TRAE or G5 were reported. 22.2% of pts had a TRAE leading to dose adjustment and 16.7% leading to discontinuation of IAH0968. After a median follow-up of 56.5 days (range, 0-479), objective response rate (ORR) was 13.3% (2/15), disease control rate (DCR) was 53.3% (8/15), and median progression-free survival (PFS) was 57.5 days (range, 42-236), with 4/15 responses ongoing. Conclusions: In heavily pretreated metastatic pts with HER2 positive, IAH0968 demonstrated promising clinical activity and tolerable safety profiles. IAH0968 will be further assessed in Phase Ⅱ study in combination treatment. Clinical trial information: NCT04934514 .