Abstract OT1-1-06: A phase 3, randomized, open-label trial comparing trastuzumab emtansine and trastuzumab as adjuvant therapy for HER2-positive primary breast cancer with residual invasive tumor in the breast or axillary lymph nodes following preoperative therapy (KATHERINE)
Authors: Geyer CE , Loibl S , Mamounas EP , Untch M , Wolmark N , Huang C-S , Mano M , Zheng M , Smitt M , von Minckwitz G 
Published: August 2014

Abstract
Background: HER2-positive patients (pts) who do not achieve pathologic complete response with preoperative chemotherapy and HER2 directed therapy (PST) are at increased risk of recurrence and mortality despite further anti-HER2-targeted and endocrine treatment. The antibody–drug conjugate trastuzumab emtansine (T-DM1) combines the antitumor activities of trastuzumab (H) with intracellular delivery of the cytotoxic agent DM1 via a stable linker. T-DM1 prolonged progression-free survival (PFS) and overall survival (OS) in a phase 3 study in pts with previously treated HER2-positive metastatic breast cancer (MBC) compared with capecitabine and lapatinib. It also prolonged PFS compared with H and docetaxel in a phase 2 study in pts with previously untreated HER2-positive MBC.
Trial design: KATHERINE (NCT01772472) is a phase 3, 2-arm, open-label trial in pts with HER2-positive primary breast cancer (BC) who have received PST, including H, and have residual invasive disease after surgery. Pts are randomly assigned 1:1 to adjuvant T-DM1 3.6 mg/kg IV q3w or H 6 mg/kg IV q3w for 14 cycles. Pts can receive concomitant radiotherapy and/or hormonal therapy if clinically indicated.
Eligibility criteria: HER2-positive BC (centrally determined IHC 3+ and/or ISH ratio ≥2); clinical stage T1–4, N0–3, M0 (T1a/bN0 ineligible) prior to PST; ECOG PS 0 or 1; adequate surgical excision; ≥6 cycles of preoperative treatment (≥16 weeks total; ≥9 weeks of H and ≥9 weeks of taxane-based chemotherapy); residual invasive breast or axillary lymph node disease after preoperative therapy; ≤12 weeks from surgery to random assignment. Pts with anthracycline exposure equivalent to doxorubicin &gt;240 mg/m2 or significant cardiopulmonary dysfunction are excluded.
Specific aims: The primary efficacy endpoint is invasive disease-free survival (IDFS). Secondary endpoints include disease-free survival, OS, distant recurrence-free interval, quality of life, and pharmacokinetics. Safety assessments include all adverse events, abnormal laboratory values, cardiac events, and LVEF.
Statistical methods: The log-rank test (stratified by clinical stage, hormone receptor status, preoperative HER2-directed therapy, and pathologic nodal status after preoperative therapy) will be used to compare IDFS between arms. The hazard ratio (HR) and its 95% confidence interval (CI) will be estimated using Cox proportional hazards model (also stratified). The Kaplan-Meier approach will be used to estimate 3-year IDFS rates and 95% CIs for each arm. The final IDFS analysis, which provides 80% power to detect a HR of 0.75 (a 6.5% improvement in 3-year IDFS from 70% in the control arm to 76.5% in the T-DM1 arm) at a 2-sided alpha level of 5%, will be performed after ∼384 IDFS events have occurred. The final OS analysis will be performed at the end of 10 years of follow-up. Interim analyses of IDFS and OS are planned.
Current and target accrual: Enrollment to 342 sites in 28 countries began in April 2013, and target accrual is 1484 pts.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-06.