A Phase II Study of Trastuzumab-DM1 (T-DM1), a Novel HER2 Antibody–Drug Conjugate, in HER2+ Metastatic Breast Cancer (MBC) Patients Previously Treated with Conventional Chemotherapy, Lapatinib and Trastuzumab.
Authors: Krop I. , LoRusso P. , Miller K. , Modi S. , Yardley D. , Rodriguez G. , Agresta S. , Zheng M. , Amler L. , Rugo H. 
Published: December 2010

Abstract
ABSTRACT WITHDRAWN: This abstract was withdrawn by the authors prior to the start of the Symposium. It was rescheduled to a Poster Discussion session and renumbered as Abstract 710.
Background: T-DM1 combines the HER2-inhibiting properties of trastuzumab with targeted delivery of the anti-microtubule agent DM1. In a prior phase II study, single agent T-DM1 was well tolerated and had significant activity (objective response rate [ORR] of 26% by independent review [IRF]) in 112 patients (pts) with pre-treated HER2+ MBC (Vogel CL, et al.J Clin Oncol 27:15s, 2009 (suppl; abstr 1017). To confirm and extend these findings, we conducted a phase II study that enrolled a more homogenous population of HER2+ MBC pts who had all received prior anthracycline, taxane, capecitabine, trastuzumab and lapatinib therapy and progressed on the last regimen received (at least 2 HER2-directed regimens had to be given for metastatic disease).MethodsThis is an open-label, single-arm study of T-DM1 given at 3.6 mg/kg IV q3w. Primary objectives are to assess ORR by IRF and evaluate the safety of T-DM1. Key secondary objectives assess the clinical benefit rate (CBR = ORR + stable disease (SD) at 6 months), duration of response (DoR) and progression-free survival (PFS). Pts remain on study until disease progression or unmanageable toxicity. Key exploratory objectives were the assessment of ORR and clinical benefit rate (CBR) by IRF in retrospectively tested, centrally confirmed HER2 positive patients.Results: The study completed enrollment of 110 patients. This analysis has a median follow-up of 8.3 months (range 0.7-13.1). Median age was 52.5 yr (range 34–77). Pts received a median of 7 agents for metastatic disease (range 1–15). Median durations of prior trastuzumab and lapatinib treatment in metastatic setting were 19.4 and 6.9 months respectively. The ORR was 32.7% and the CBR was 44.5% by IRF. Median DoR and PFS have not reached maturity. In retrospectively tested, centrally confirmed HER2 positive patients, the ORR was 39.5% and the CBR was 52.6% by IRF. T-DM1 was well tolerated, with no dose-limiting cardiotoxicity. One pt with pre-existing non-alcoholic fatty liver disease died with hepatic dysfunction. The most common adverse events were fatigue (59.1% of pts), nausea (37.3%), and thrombocytopenia (29.1%); 41.8% of pts experienced at least one grade 3 or above adverse event.Conclusions: In this study, single agent T-DM1 demonstrates a 32.7% ORR with an acceptable safety profile in a well defined, homogeneous, and extensively pretreated population that has not been previously studied. Centrally confirmed HER2 positivity strongly correlated with objective response. These results confirm the activity of T-DM1 in treatment resistant HER2+ MBC. An ongoing global randomized phase III study is evaluating T-DM1 compared with lapatinib plus capecitabine in pts with advanced HER2+ who have been previously treated with a taxane and trastuzumab.