CHER-LOB: PREOPERATIVE CHEMOTHERAPY PLUS TRASTUZUMAB, LAPATINIB OR BOTH IN HER2-POSITIVE OPERABLE BREAST CANCER – PRELIMINARY SAFETY REPORT WITH FOCUS ON CARDIAC TOLERABILITY

Introduction and aims: This is a phase IIb randomized trial evaluating activity and safety of chemotherapy (CT) plus trastuzumab (T), lapatinib (L), or the combination of T+L as preoperative therapy for HER2+ operable breast cancer (BC). Primary endpoint: %of pCR. Secondary aims: breast objective response, breast conservative surgery, safety, molecular responses, gene expression related to pCR. Patients and methods: patients with HER2+ stage II-IIIA BC are randomized to: Arm A: CT+T; Arm B: CT+L; Arm C: CT+T+L. CT consists in: paclitaxel (P) 80 mg/m2 wkly for 12 wks, followed by 4 courses of FEC (5FU 600 mg/m2 + Epirubicin 75 mg/m2 + Cyclophosphamide 600 mg/m2 iv) q3wks. T is administered at 2 mg/kg wkly in arms A and C; L is administered at 1500 mg po daily in arm B, and at 1000 mg po daily in arm C. T and L are administered throughout the duration of CT (26wks). Sample size: assuming a 50% increase in the pCR rate for the CT+T+L arm vs CT+T or CT+L, in the first stage 52 patients will be enrolled; in case we observe 16 pCR, additional 68 patients will be enrolled, for a total of 120 patients (Simon’s design). Left ventricular ejection fraction (LVEF) is evaluated at baseline, prior to start FEC, and at the completion of treatment. The first IDMC evaluation of the protocol cardiac safety is pre-planned after the first 15 evaluable pts. Results 13 patients have been randomized: 4 in Arm A, 4 in Arm B, and 5 in Arm C. A total of 101 doses of wkly P +T, L or T+L, and 19 courses of FEC+T, L or T+L are evaluable. No G2-4 hematologic toxicity has been reported during P+ T, L or T+L; G3-4 neutropenia occurred in 42% of FEC+T, L or T+L cycles. Non-hematologic toxicity reported in >5% of the P+ T, L or T+L cycles were: G1 diarrhea (19%), G2 rash (6%), and G1 neurotoxicity (9%). Non-hematologic toxicity reported in >5% of the FEC + T, L or T+L cycles were: G1/2 nausea/vomiting (53%), G1 diarrhea (5%), G1 stomatitis (5%). The mean LVEF was 62.7% (range 54-74%) at baseline, and 62.2% (60-71%) after 12 wks of P + T, L or T+L. Conclusions These very preliminary data are encouraging regarding the safety of these combinations. Updated results will be presented at the Meeting. Supported by GlaxoSmithKline