Abstract B001: Safety and efficacy of ZW25, a HER2-targeted bispecific antibody, in combination with chemotherapy in patients with locally advanced and/or metastatic HER2-expressing gastroesophageal cancer

Background: Up to 30% of gastroesophageal adenocarcinoma (GEA) overexpress HER2. ZW25 is a novel bispecific antibody that targets HER2 domains ECD2 and ECD4, resulting in multiple differentiated and unique mechanisms of action, including increased antibody binding density and improved receptor internalization and downregulation relative to trastuzumab. In an ongoing phase 1 trial (ZWI-ZW25-101; NCT02892123), single-agent ZW25 was well tolerated and showed promising anti-tumor activity across HER2-expressing solid tumors. This abstract presents data for GEA patients treated with ZW25 in combination with chemotherapy in Study ZWI-ZW25-101. Methods Eligible patients had HER2-expressing (IHC 3+, IHC 2+/FISH+, or IHC 2+/FISH-) GEA and had disease progression after 1–3 lines of prior chemotherapy for advanced and/or metastatic disease. Fresh or archived tumor tissue was required for central review of HER2 status, although patients could be enrolled based on local results. Patients received ZW25 in combination with paclitaxel or capecitabine. Evaluations included standard safety assessments, tumor re-staging (Q8W by RECIST 1.1), and assessment of peak/trough pharmacokinetic (PK) levels during each cycle. Results To date, 14 patients have been enrolled, with safety and efficacy data available for 11. ZW25 was administered in combination with paclitaxel (n=5) or capecitabine (n=6). The median age was 62 yrs (range, 26-80). The median number of prior anti-cancer regimens was 3 and the median number of prior HER2-targeted therapies was 1. Six patients (55%) were HER2 IHC3+ or IHC2+ and FISH+ per central review. The most common adverse events (AEs) considered related to ZW25 or ZW25 and chemotherapy were diarrhea (n=5; 45%), fatigue (n=3; 27%), and nausea (n=3; 27%); the majority of events were Grade 1 or 2. Grade 3 or higher events considered related to ZW25 or ZW25 and chemotherapy occurred in 3 patients (27%), including fatigue, hypokalemia, and neutropenia (n=1 each). One additional patient experienced a Grade 5 serious adverse event of pneumonitis, reported as related to the combination of ZW25 and paclitaxel. This patient had been previously treated with trastuzumab, cisplatin, and capecitabine; pembrolizumab and margetuximab; and most recently DS8201, and had asymptomatic interstitial lung disease at study entry. A total of 9/11 patients (82%) had measurable disease and 8/9 (89%) were response-evaluable. The objective response rate was 63% (95% CI: 25, 92) (5/8 patients; all partial responses, with 4 confirmed to date) and the disease control rate was 75% (6/8 patients). Responses were seen in patients with FISH+ and FISH- disease, as well as in combination with either paclitaxel or capecitabine. Patients have received between 1 and 12 cycles of treatment and 4 patients remain on treatment. PK data will be presented at the meeting. Conclusions The combination of ZW25 with chemotherapy was generally well tolerated in heavily pre-treated patients with HER2 high- and low-expressing GEA and the preliminary anti-tumor activity is promising. Further evaluation of the safety and efficacy of ZW25 in combination with standard of care chemotherapy regimens has been initiated in frontline GEA (ZW25-201; NCT03929666). Citation Format: Funda Meric-Bernstam, Jorge Chaves, Do-Youn Oh, Jeeyun Lee, Yoon-Koo Kang, Erika Hamilton, Jose Mayordomo, Melody Cobleigh, Christos Vaklavas, Elena Elimova, Jaffer Ajani, Jordi Rodon, Gerry Rowse, Todd Gray, Rose Lai, Diana Hanna. Safety and efficacy of ZW25, a HER2-targeted bispecific antibody, in combination with chemotherapy in patients with locally advanced and/or metastatic HER2-expressing gastroesophageal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B001. doi:10.1158/1535-7163.TARG-19-B001