A phase II study of trastuzumab-DM1, a first-in-class HER2 antibody-drug conjugate, in patients with HER2+ metastatic breast cancer.

Abstract Abstract #33 Background
 Trastuzumab-DM1 (T-DM1), an antibody drug conjugate (ADC) designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent anti-microtubule agent (DM1) to HER2-expressing cells, has demonstrated activity in a Phase I study. The maximally tolerated dose (MTD) for T-DM1 given every 3 wks was 3.6 mg/kg.
 Methods
 This is a multi-institutional, open-label, single-arm, Phase II study of T-DM1, 3.6 mg/kg administered by IV infusion every 3 wks, to pts with HER2+ MBC; 100 efficacy-evaluable pts who have progressed on prior T and chemotherapy given in the metastatic setting will be enrolled. The primary objective is to assess objective response rate (ORR) and safety and tolerability in this patient population. Key secondary objectives include measurement of duration of objective response and progression-free survival; to characterize the pharmacokinetics of this T-DM1 regimen; and to assess the formation of antibodies to T-DM1. A preplanned, protocol specified interim analysis of efficacy data was performed after the first 30 efficacy evaluable pts had completed 4 cycles (12 wks) of treatment. A final analysis will be conducted 26 wks after the last patient has been enrolled.
 Results
 As of June 6, 2008, 92/100 pts have been enrolled. Demographic data from the first 31 enrolled pts include: median age 57 (range 38-79); PS 0-1, 29; PS 2, 2; median number prior metastatic chemo agents 2 (range 1-9); median duration of prior T is 76.1 wks (range 12-379); 13 pts (42%) received prior lapatinib. Of the 31 pts, 30 were evaluable for efficacy per protocol. Based on investigator assessments, 12/30 (40%) pts have had a partial (11) or complete (1) response reported. The IRF has reported a partial response in 9/30 (30%) pts to date. To date, these 31 pts have received a median of 4 T-DM1cycles (range 1-11). Gr2 adverse events (AEs) include thrombocytopenia (10%), fatigue (13%), nausea/vomiting (10%), infusion reaction/fever/chills (10%). Gr3 thrombocytopenia occurred in 10% of pts and Gr4 AEs occurred in 2 (6%) pts (thrombocytopenia and transaminase elevation). Sixteen (52%) pts have discontinued therapy, 11 for progressive disease.
 Conclusions
 T-DM1 has shown single-agent clinical activity in pts who have progressed on prior HER2-directed therapy. The safety profile of T-DM1 appears tolerable at the recommended dose. To date, preliminary data show a 40% investigator-determined response rate and a 30% IRF-reported response rate. Updated results for the entire study population will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 33.