Safety, anti-tumour activity, and biomarker results of the HER2-targeted bispecific antibody ZW25 in HER2-expressing solid tumours

Abstract

Background: ZW25, a novel IgG1 bispecific antibody, targets HER2 domains ECD2 and ECD4, resulting in multiple differentiated and unique mechanisms of action, including improved receptor internalization and downregulation relative to trastuzu-mab. Safety, anti-tumor activity, and biomarker data from an ongoing phase 1 trial of ZW25 monotherapy in solid tumors other than breast cancer, are presented here. Methods: Eligible patients with HER2 IHC 3þ, IHC 2þ/FISHþ, or IHC 2þ/FISH-tumors confirmed by central review of fresh or archival biopsies, who had progressed on all standard therapies, were enrolled. Assessments included tumor evaluations (RECIST 1.1 Q8W), circulating tumor DNA (ctDNA; pre-dose C1 D1, C2 D15, treatment end), and standard safety evaluations. Results: A total of 43 patients, including 17, 6, 10, and 10 with gastroesophageal adeno-carcinoma (GEA), biliary tract cancers, colorectal cancer, and other cancers, respectively , received single agent ZW25 at 10 mg/kg QW or 20 mg/kg Q2W. The median number of prior therapies was 3 (range 1-6) for all patients. For GEA and non-GEA patients, 88% and 35% respectively received at least one unique prior HER2 therapy. The most common treatment-related adverse events (all Grade 1 or 2) were diarrhea (49%) and infusion related reaction (34%). The objective response rate (all partial response (PR)) for response evaluable patients was 41% (14/34), stable disease (SD) in 38% (13/34), and progressive disease in 21% (7/34). The majority of patients (74%; 25/ 34) experienced a decrease in the sum of diameters for their target lesions. Compared to FISH, the positive predictive value of HER2 amplification in pre-dose C1D1 ctDNA was 90% (95% CI 79-96%), negative predictive value 45% (25-67%), and diagnostic accuracy 79% (63-90%). Disease control (PR or SD) > 5 months was associated with lower level of copy number adjusted mutational variant allele frequency in pre-treatment ctDNA (Mann Whitney p ¼ 0.0085). Conclusions: ZW25 has been well tolerated with promising single agent activity in heavily pre-treated patients. These data support further clinical development of this bispecific antibody in HER2-expressing solid tumors.