Abstract P3-14-21: Phase II Study of Single Agent Trifunctional Antibody Ertumaxomab (Anti-HER-2 & Anti-CD3) in HER-2 Low Expressing Hormone-Refractory Advanced Breast Cancer Patients (ABC)
Authors: Cardoso F , Dirix L , Conte PF , Semiglazov V , de Placido S , Jaeger M , Mueller C , Eschenbach B , Klunker D , Lindhofer H , Cortes J. 
Published: April 2011

Abstract
Background: Ertumaxomab is an intact bispecific trifunctional antibody targeting HER-2 and CD3 as well as activating Fcγ receptors on accessory cells. Trifunctional Abs mediate the elimination of cancer cells by simultaneous binding and activation of T-cells and accessory cells at the tumor site. A phase I study with ertumaxomab showed encouraging efficacy results in MBC patients (Kiewe et al., 2006). Another trifunctional Ab of the same class, catumaxomab, was recently approved in Europe for the treatment of Malignant Ascites.
Materials & Methods: This was an open-label, non-randomized, single agent phase II study. Enrolled pts had ER and/or PgR positive ABC with low HER-2 expression (defined as IHC 1+ or 2+ and FISH negative). Pts had to have PD after hormonal therapy including at least one aromatase inhibitor but no prior chemotherapy for advanced disease. Ertumaxomab was given i.v. once a week on days 0, 7, and 14 over three hours according to the schedule: 10 μg (day 0), 100 μg (day 7) and 100 μg (day 14). Primary endpoint was objective response rate (ORR) according to RECIST. Tumor response evaluation was performed at 4 and 8 weeks after the last dose of ertumaxomab, then every 2-3 months until PD. Secondary efficacy endpoints were time to progression (TTP), time to and duration of response, clinical benefit, and tumor marker levels. Safety and tolerability were also secondary endpoints.
Results: Of the planned 40 pts, 28 were enrolled. Recruitment was prematurely terminated due to a strategic change in the sponsor's clinical development program. No CR was observed. One patient had PR at follow up (FUP) 3, but this finding was not confirmed due to lack of further FUP data. 14 of 26 evaluable pts (53.8%) had SD at FUP 2 (day 42) and 8 of 26 patients (30.8%) had SD at FUP 3 (day 70). In one patient SD was sustained beyond 10 months. The median TTP in the evaluable population was 65.5 days (95%, CI: 43-98). Fourteen pts (51.9%) had at least one treatment-related adverse event (AE) after the 1st infusion (10μg), and 25 pts (92.6%) had at least one AE after administration of 100μg. The most frequently observed AEs were pyrexia (74.1%), headache (40.7%), chill (33.3%), and vomiting (29.6%). AEs were mostly of mild or moderate intensity and the majority (73.8%) resolved within one day. Mean plasma concentrations of IL-10, IL-2, IL-6, TNF-α and IFN-α markedly increased after infusion 2 and 3 and returned to baseline levels 24 hours later. Discussion: The safety and tolerability profile of ertumaxomab in Her2 low expressing pts was similar to the profile of other immunotherapeutic Abs and to the results of the previous phase I study. The observed symptoms are most likely due to the release of cytokines and in line with the mode of action of ertumaxomab. They indicate a strong immunologic response. The clinical benefit obtained and safe toxicity profile support further clinical development of ertumaxomab. Further dose optimization studies as a single-agent and in combination as well as studies in HER-2 + pts are warranted.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-21.