Abstract 1761: Anti-tumor activity of trastuzumab-DM1 in combination with pertuzumab in a gastric cancer model

Abstract

Abstract Objective: Anti-HER2 therapy is considered to be important for gastric cancer as well as breast cancer. In a previous study, we showed the combinational efficacy of trastuzumab and pertuzumab (an anti-HER2 antibody which binds a different HER2 domain from trastuzumab) in HER2-positive gastric cancer models (AACR, 2010). In the present study, we investigated the usefulness of a HER2 antibody-cytotoxic drug conjugate, trastuzumab-DM1 (T-DM1) as monotherapy and in combination with pertuzumab for HER2-positive gastric cancer as a novel therapy. Methods: A HER2 over-expressing human gastric cancer, NCI-N87 mouse xenograft model was used for examining the efficacy. T-DM1 was administered intravenously once every 3 weeks. Pertuzumab was administered intra-peritoneally once a week. Tumor growth inhibition (TGI) after 6 weeks of treatment was determined from tumor volume measurements. Apoptosis activity was measured with the activity of caspase 3/7. To measure ADCC activity, a real-time cell analyzer was used. Results: T-DM1 (1.25, 2.5, 5, 10, 20, 40 or 80 mg/kg) as monotherapy showed tumor growth inhibition dose-dependently in the NCI-N87 model. The maximum effective dose was 10 mg/kg and TGI on day 42 after treatment started was 113%. T-DM1 (5 mg/kg) in combination with pertuzumab (40 mg/kg) in the NCI-N87 model showed significantly potent anti-tumor activity with a TGI of 113%. Both T-DM1 and pertuzumab as monotherapies showed significant anti-tumor activity, their TGI were 79% and 47%, respectively. To examine the mechanism of action of the combination of T-DM1 and pertuzumab, we analyzed apoptosis of NCI-N87 cells after treatment with T-DM1, pertuzumab or both under stimulation of EGF or heregulin. 24 h after treatment, the combination group had significantly enhanced caspase 3/7 activity compared with the monotherapy groups. We also examined ADCC activity of these agents. Both T-DM1 and pertuzumab showed ADCC activity and that activity was enhanced by the combination. Conclusion: In this study, we showed that T-DM1 as monotherapy has significant anti-tumor activity in a mice model of HER2-positive gastric cancer. Furthermore, combining T-DM1 with pertuzumab significantly enhanced the anti-tumor activity compared with the efficacy of each agent used in monotherapy. The mechanism of this combination might be the potentiation of apoptosis induction and ADCC activity. The present study suggests that T-DM1 as monotherapy and in combination with pertuzumab would provide benefit for patients with HER2-positive gastric cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1761. doi:10.1158/1538-7445.AM2011-1761