T32 Research Fellow The University of Texas MD Anderson Cancer Center Houston, Texas, United States
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Participants should be aware of the following financial/non-financial relationships:
Timothy P. DiPeri, MD: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Introduction: Zanidatamab is a novel bispecific human epidermal growth factor receptor 2 (HER2)-targeted antibody with biparatropic binding which has demonstrated anti-tumor activity in HER2-expressing solid tumors.We sought to investigate the efficacy of zanidatamab in vivo by utilizing patient-derived xenograft (PDX) models developed from patients who were enrolled in or screened for the zanidatamab phase I trial (NCT02892123).
Methods: Consenting patients evaluated for the zanidatamab phase I trial underwent an image-guided biopsy for PDX development.HER2 immunohistochemistry and fluorescence in situ hybridization were performed on corresponding patient biopsies. Tumor fragments from biopsy specimens were implanted in the flanks of NSG mice followed by implantation in athymic nu/nu mice.Treatment with zanidatamab monotherapy (4, 8, and 16 mg/kg) was administered twice per week via tail vein injection once tumors were an average of 200 mm3.Tumor growth and treatment responses were assessed by relative change in tumor volume, relative treatment-to-control ratio, and event-free survival (EFS-2) [event defined as day of tumor doubling].
Results: Of 31 tumors implanted from trial, 17 PDX models were successfully established (55% take rate) from 15 patients. Pre-treatment and post-progression PDX models were developed from 2 patients who achieved a partial response with zanidatamab.Established PDXs represented a broad range of cancers (breast, cholangiocarcinoma, gallbladder, colorectal, esophageal, gastric/gastroesophageal junction cancers).In one PDX, treatment with zanidatamab at all dose levels led to tumor growth inhibition.In another PDX, tumor regression was observed in all mice treated with zanidatamab at 8mg/kg and 16mg/kg, with growth inhibition at 4mg/kg.Another did not demonstrate a response to zanidatamab at any dose level.
Conclusions: PDXs can be developed from pre-treatment biopsies on clinical trials. Work is ongoing to determine if there is an association between patient response to zanidatamab and the response of the corresponding PDX model, as well as mechanisms of primary/acquired resistance to zanidatamab therapy.
Learning Objectives:
Upon completion, participant will be able to summarize results from in vivo experiments testing zanidatamab in HER2+ patient derived xenografts.
Upon completion, participant will be able to describe the concept of co-clinical trial modeling using patient derived xenografts.
Upon completion, participant will be able to theorize about the correlation of patient and xenograft responses to therapies.