Abstract P1-11-12: Phase II Trial of Presurgical Treatment with Trastuzumab (H) or Lapatinib (Ty) or the Combination of Trastuzumab and Lapatinib (H+Ty), Followed by Six Cycles of Docetaxel (T) and Carboplatin (C) with Trastuzumab (TCH) or Lapatinib (TCTy) or the Combination of Trastuzumab and Lapatinib (TCHTy) in Patients with HER2+ Breast Cancer
Authors: Callahan RD , Patel R , Chan D , Allison MA , DiCarlo B , Bosserman LD , Kennedy A , Zehngebot LM , Miller J , Giuliano AE , Spivack B , Lin L-s , Slamon DJ , Hurvitz SA. 
Published: April 2011

Abstract
BACKGROUND: Neoadjuvant trastuzumab (H) improves pathologic complete response (pCR) rates in HER2+ breast cancer (BC) vs. chemotherapy alone. Lapatinib (Ty) plus H exhibits synergy in vitro and efficacy in metastatic BC. This study evaluates the clinical and molecular effects as well as safety of neoadjuvant TC plus H and/or Ty in HER2+ BC.
METHODS: This is an open-label, randomized phase II study in which pts with Stg I-III BC are assigned to 1 of 3 arms: Arm 1: TCH, Arm 2: TCTy, and Arm 3: TCH-Ty. Planned accrual is 140 pts. To test the safety of TCH-Ty, the 1st 20 pts are all assigned to TCH-Ty. The next 120 pts are randomized (40:40:40) to 1 of the 3 arms. Data from the first 20 pts is being presented. These pts received a run-in cycle of Ty (1000 mg/d on days 1-21) + H (8 mg/kg iv), followed by 6 cycles of q3-wkly TCHTy (T: 75 mg/m2, C: AUC 5 or 6, H: 6 mg/kg, Ty: 1000 mg/d on d1-21). The 1st 6 pts were part of a dose escalation evaluation of C. Biopsies are taken at baseline, after the run-in cycle with H and/or Ty, and at the time of definitive BC surgery. The primary endpoint is pCR rate defined as the absence of viable tumor cells in the breast and axillary lymph nodes. Safety evaluation, molecular effects, clinical response, and cardiac events were secondary endpoints. RESULTS: The first 20 pts were assigned to TCH-Ty. No DLTs were observed in the dose escalation phase and pts 6-20 received carboplatin AUC 6. The median age was 50 years (range, 38-66 years). Nineteen pts had invasive ductal and 1 pt had invasive lobular carcinoma. Nine tumors (45%) were ER+/PR+, 3 (15%) were ER+/PR-, and 8 (40%) were ER-/PR-. At presentation, 8 pts had Stg IIA, 7 :IIB, 2: IIIA, and 3:IIIB disease. As of April 2010, 17 of the first 20 pts have completed the study (14 completed all protocol specified therapy and 3 discontinued due to adverse event). Six of these 14 pts (43%) achieved pCR. One additional pt who discontinued the study after 3 cycles of chemotherapy achieved pCR. No heart failure or decline in LVEF &gt;10% from baseline was observed. All pts experienced diarrhea (2 episodes of Grade 3 and no episodes of Grade 4). There were no deaths. The most common Grade 1/2 and all Grades 3/4 AEs are listed in the table below.
CONCLUSIONS: Preoperative combination therapy with TCH-Ty is an effective regimen with manageable toxicity in HER2+ non-metastatic BC. This is the first report of this 4-drug combination in early BC. Further study in a phase III trial is ongoing. Updated efficacy and toxicity data from the 1st 20 pts who received all 4 drugs will be presented.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-12.