Abstract P5-18-16: A Multicenter Phase 2 Study (JO22997) Evaluating the Efficacy and Safety of Trastuzumab Emtansine in Japanese Patients With Heavily Pretreated HER2-Positive Metastatic Breast Cancer
Authors: Masuda N , Ito Y , Takao S , Doihara H , Rai Y , Horiguchi J , Kohno N , Fujiwara Y , Tokuda Y , Watanabe J , Iwata H , Ishiguro H , Miyoshi Y , Matsubara M , Kashiwaba M 
Published: August 2014

Abstract
Background: Trastuzumab emtansine (T-DM1) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate in development for the treatment of HER2-positive recurrent, locally advanced or metastatic breast cancer (MBC). T-DM1 comprises trastuzumab, DM1—a microtubule inhibitory cytotoxic agent derived from maytansine—and the stable linker ([N-maleimidomethyl] cyclohexane-1-carboxylate) that conjugates DM1 and trastuzumab. A phase 1 study in Japanese patients determined a maximum tolerated dose for T-DM1 of 3.6 mg/kg every 3 weeks (q3w), which was identical to that reported in Western populations (TDM3569g). Single-agent T-DM1 has demonstrated robust clinical efficacy in Western phase 2 and phase 3 clinical studies (TDM4258g, TDM4374g and EMILIA). Since the efficacy of T-DM1 in Japanese patients has not previously been investigated, this study examined the efficacy and safety of T-DM1 in Japanese patients with pretreated HER2-positive MBC.
Methods: JO22997 is a phase 2, multicenter, single arm clinical study assessing the efficacy and safety of single-agent T-DM1 given at 3.6 mg/kg q3w to patients with HER2-positive MBC. Key eligibility criteria were prior treatment with trastuzumab and at least 1 chemotherapy, ECOG performance status (PS) of ≤2, and adequate organ function. Patients were required to have target lesions according to the guidelines of the Response Evaluation Criteria In Solid Tumors, v1.1. The primary objective of the study was to assess the objective response rate (ORR) by independent review committee (IRC); secondary objectives were progression-free survival (PFS), safety, and to obtain pharmacokinetic data in Japanese patients.
Results: 73 patients received T-DM1. Median age was 58 years (range, 36–82 years); 61 (83.6%), 10 (13.7%), and 2 (2.7%) patients had ECOG PS of 0, 1, and 2, respectively; 39 (53.4%) patients had tumors that were estrogen receptor– and/or progesterone receptor–positive. The median number of prior chemotherapy regimens for MBC was 3 (range, 1–8) including lapatinib in 43 (58.9%) patients. Median duration of treatment with T-DM1 was 23.1 weeks (range, 0.1–63.3 weeks). The ORR by IRC was 38.4% (90% confidence interval [CI], 28.8%–48.6%; partial response only), and clinical benefit rate (partial response + stable disease ≥24 weeks) was 45.2% (95% CI, 33.5%–57.3%). Median PFS by IRC was 5.6 months (95% CI, 4.6–8.2 months). The most frequently observed grade ≥3 adverse events were thrombocytopenia (21.9%), increased aspartate aminotransferase (13.7%), increased alanine aminotransferase (8.2%) and vomiting (5.5%). One patient (1.4%) discontinued treatment due to thrombocytopenia. No patient received platelet transfusion. Grade 3/4 hemorrhage was observed in one patient (1.4%). PK parameters for T-DM1 and its metabolites were consistent with previous phase I results.
Conclusion: Single-agent T-DM1 has promising activity in Japanese patients with previously treated HER2-positive MBC and was well tolerated. Although the incidence of grade 3/4 thrombocytopenia tends to be higher than in Western studies, this was not associated with clinically important manifestations. (JapicCTI-101277)
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-16.