Abstract 3477: Pertuzumab in combination with trastuzumab enhanced the anti-tumor activity in HER2-positive human gastric cancers

Abstract

Abstract Objective: Gastric cancer has a poor prognosis. HER2 targeting therapy for gastric cancer would be considered important, because HER2 protein in gastric cancer is reported to be prognosis factor as well as breast cancer. Recently, trastuzumab has provided benefits for patients with HER2-positive gastric cancer in the ToGA trial (a phase III study of trastuzumab in HER2-positive advanced gastric cancer). On the other hand, pertuzumab, a new anti-HER2 antibody, can bind a different HER2 domain from trastuzumab and inhibits tumors by preventing the dimerization of HER2 and other HER family proteins. In this study, we investigated the efficacy of pertuzumab in combination with trastuzumab to consider a new approach to HER2-positive gastric cancers. Results: We examined the anti-tumor activity of pertuzumab in combination with trastuzumab in the mouse xenograft models of HER2-positive human gastric cancer, NCI-N87 and 4-1ST. Pertuzumab and trastuzumab were administered once a week i.p. for 3 weeks. The combination group showed a significant anti-tumor activity (tumor growth inhibition (TGI) % = 145 % and 105 % in NCI-N87 and 4-1ST, respectively) compared with the group treated only with pertuzumab (TGI % = 31 % and 29 %) or that treated only with trastuzumab (TGI % = 52 % and 55 %). In addition, the anti-tumor activity was higher than the maximum anti-tumor activities in either of those monotherapy groups. Furthermore this combination effect was also observed in vitro. Phosphorylation of HER2 was strongly blocked by exposure of these antimodies in combination. EGF-stimulated phosphorylation of EGFR was also down-regulated. As other mechanisms of the combination effect, we examined the ADCC activity of pertuzumab and trastuzumab by means of a real-time cell analyzer. Pertuzumab and trastuzumab had ADCC activity and that activity was enhanced when both of them were exposed. In addition we examined micro-vessel density (MVD) change after treatment in NCI-N87 tumor tissues with CD31-immunostaining. We observed MVD inhibition only in the tumor tissues treated with both pertuzumab and trastuzumab and not in the tissues treated with the drugs separately. VEGF levels in tumor tissues were reduced by pertuzumab or trastuzumab. The present results suggest that pertuzumab in combination with trastuzumab shows significant anti-tumor activity in HER2-positive human gastric cancers not only by directly inhibiting cell growth through down-regulation of HER2/EGFR signaling but also by enhancing ADCC activity and reducing MVD. Conclusion: The anti-tumor activity of pertuzumab and trastuzumab was higher than the maximum anti-tumor activity showed when pertuzumab or trastuzumab were used as single agent. The present study suggests that this combination therapy may provide greater benefits for patients with HER2-positive gastric cancers. Clinical evaluation is expected. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3477.