Background: For patients with human epidermal growth factor receptor 2 (HER2)-overexpressing GEA, trastuzumab in combination with chemotherapy is the only approved HER2-targeted therapy, and they have limited treatment options after progression. Zanidatamab, a HER2-targeted bispecific antibody, has shown durable anti-tumor activity with good tolerability in a range of HER2-expressing cancers. Methods: In this 3-part Phase 1 study (NCT02892123), zanidatamab (10 mg/kg QW, 20 mg/kg Q2W, or 30 mg/kg Q3W) is administered as a single agent (Parts 1 & 2; QW or Q2W) or in combination with chemotherapy (Part 3; Q2W or Q3W). Eligibility criteria includes GEA with HER2 expression as assessed by immunohistochemistry (IHC) 3+ or IHC 2+, progression after standard of care therapy, and measurable disease per RECIST 1.1 (Part 2 requirement only). Results: In Parts 1 and 2, 36 GEA patients have been treated with zanidatamab (QW [n = 5]; Q2W [n = 31]). In Part 3, 26 GEA patients have been treated (zanidatamab Q2W + (paclitaxel [n = 11] or capecitabine [n = 6]); zanidatamab Q3W + capecitabine [n = 9]). Conclusions: Zanidatamab, both as a single agent and in combination with chemotherapy, is well tolerated with promising and durable anti-tumor activity in heavily pretreated GEA patients (including prior HER2-targeted therapy). These data support further investigation of zanidatamab as a novel therapeutic for patients with HER2-expressing GEA. Clinical trial information: NCT02892123

Note: Data cutoff: Jul 28, 2020. *, 35 patients had prior systemic therapy;^**, all were Grade 3 except for one Grade 4 neutropenia event in Part 3; ^#, includes one patient with complete response; ^‡, in response evaluable patients who had a confirmed complete or partial response followed by ≥1 response assessment The most common (occurring in ≥ 20%) zanidatamab-related AEs were: diarrhea (44%) and infusion-related reaction (36%) in Parts 1 & 2 (all Grade 1/2 except one Grade 3 diarrhea event); and diarrhea (58%) and fatigue (27%) in Part 3 (all Grade 1/2 except one Grade 3 fatigue event).