CHER LOB Trial: Preoperative chemotherapy plus trastuzumab, lapatinib or both in HER2-positive operable breast cancer--Safety report as per Independent Data Monitoring Committee (IDMC) and preliminary activity data

Background: We conducted a phase IIb randomized trial of preoperative chemotherapy (CT) plus trastuzumab (T), lapatinib (L), or the combination of T+L in HER2+ operable breast cancer > 2cm . Primary endpoint is the % of pathologic complete response (pCR) in breast and axillary nodes. Secondary endpoints: breast objective response, % of breast conservative surgery, safety, molecular responses, gene expression related to pCR. Methods: Patients with HER2+ stage II-IIIA breast cancer are randomized to Arm A: CT+T; Arm B: CT+L; Arm C: CT+T+L. CT consists of paclitaxel (P) 80 mg/m2 weekly for 12 weeks followed by 4 cycles of FE75C q3weeks. T is administered at 2 mg/kg weekly in arms A and C; L is administered at 1,500 mg po daily in arm B, and at 1,000 mg po daily in arm C. Both T and L are administered throughout the duration of CT. Left ventricular ejection fraction (LVEF) is evaluated at baseline, before the start of FEC, and at the completion of treatment. The planned sample size, calculated with the two steps Simon's design, includes 120 patients. Safety analyses by the IDMC are planned at the following time-points: 1) after the first 15 patients treated for >3 months; 2) after the first 30 patients treated for >3 months. If no safety concerns, further analyses are planned for every 30 patients until study closure. Results: 28 patients have been randomized: 8 in Arm A, 9 in Arm B, 11 in Arm C. A total of 187 doses of weekly P+T, L or T+L, and 46 courses of FEC+T, L or T+L are evaluable. Hematologic toxicity: grade (G) 3-4 neutropenia in 9.6% of weekly P and in 52% of FEC cycles. Nonhematologic toxicity (excluding nausea and vomiting) reported for >5% of cycles were: diarrhea (G1-2: 26%; G3: 4%), G1-2 skin toxicity (23%), and G1 neurotoxicity (10%) during weekly P; G1-2 diarrhea (20%), G1-2 skin toxicity (28%) and G1 neurotoxicity (20%) during FEC therapy. The mean LVEF was 64% (range 54-74%) at baseline, 63% (60-71%) after 12 weeks, and 61% (60-63%) at the end of therapy. Conclusions: The preliminary safety data on the combination of T and L with an anthracycline-containing regimen seem encouraging. The first 2 evaluations as per IDMC and preliminary activity data will be presented at the Meeting.