Researchers conducted a phase IIb randomized trial of preoperative chemotherapy ( CT ) plus Trastuzumab ( T ), Lapatinib ( L ), or the combination of Trastuzumab plus Lapatinib in HER2+ operable breast cancer more than 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.
Patients with HER2+ stage II-IIIA breast cancer are randomized to Arm A: preoperative chemotherapy plus T; Arm B: preoperative chemotherapy plus Lapatinib; Arm C: preoperative chemotherapy plus Trastuzumab plus Lapatinib.
CT consists of Paclitaxel ( P ) 80 mg/m2 weekly for 12 weeks followed by 4 cycles of FE75C q3weeks.
Trastuzumab is administered at 2 mg/kg weekly in arms A and C; Lapatinib is administered at 1,500 mg po daily in arm B, and at 1,000 mg po daily in arm C. Both Trastuzumab and Lapatinib are administered throughout the duration of preoperative chemotherapy.
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 ( Independent Data Monitoring Committee ) are planned at the following time-points: 1) after the first 15 patients treated for greater than or equal to 3 months; 2) after the first 30 patients treated for greater than or equal to 3 months.
If no safety concerns, further analyses are planned for every 30 patients until study closure.
28 patients have been randomized: 8 in Arm A, 9 in Arm B, 11 in Arm C. A total of 187 doses of weekly Paclitaxel plus Trastuzumab, Lapatinib or Trastuzumab plus Lapatinib, and 46 courses of FEC plus Trastuzumab, Lapatinib or Trastuzumab plus Lapatinib 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 greater than or equal to 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.
In conclusion, the preliminary safety data on the combination of Trastuzumab and Lapatinib with an anthracycline-containing regimen seem encouraging. ( Xagena )
Guarneri V et al J Clin Oncol, 2008; 26, 15S ( 20 Supplement): 580