TBCRC 006: A multicenter phase II study of neoadjuvant lapatinib and trastuzumab in patients with HER2-overexpressing breast cancer.

505 Background: We reported that inhibition of the HER2 pathway with lapatinib (L) and trastuzumab (T) to block all homo- and hetero-dimer signaling leads to rapid eradication of HER2-amplified human xenografts in mice. In this clinical trial, we sought to translate these findings to patients (pts) using the L+T regimen without chemotherapy. Methods: Women with HER2+ breast cancers (>3cm or >2cm with palpable lymph nodes) were eligible. Pts received weekly T (4 mg/kg loading then 2mg/kg) and daily L 1,000 mg for 12 weeks. ER+ pts also received letrozole (plus goserelin if premenopausal), to block ER/HER crosstalk. Biopsies were obtained at baseline and weeks 2, 8, and 12 (surgery). This stratified study (ER+, ER−) was designed to detect an increase in pathologic response rate (pRR; defined as pathologic complete response in the breast (pCR) plus residual disease that is <1 cm (npCR)) from 10% with T alone to 35% in each stratum, using a Simon optimal two stage design, with one-sided alpha=5% and power=85%. Both strata met criteria to continue to full accrual (at least 21 per stratum). Results: We enrolled 66 eligible pts; 64 were evaluable for response (Table). Median tumor size was 6 cm (range 1.5-30 cm). Adverse events (AEs) were overall modest: mainly grade 1-2 (GI: 64%, skin: 45%). Grade 3 metabolic, GI, and liver (18%, 12 pts) and grade 4 liver toxicity (1 pt) were also observed. Two pts had treatment related serious AEs (GI, liver). Efficacy results below are for the first 57 pts who had surgery as of 1/4/2011. Results from all pts will be presented at the meeting. Overall pRR was 53% (ER+: 55%, ER−: 47%). More importantly, the overall pCR rate was 28% (ER+: 21%, ER−: 42%). Conclusions: L+T for 12 weeks led to a high pCR rate in pts with large HER2+ tumors without chemotherapy. Pts with npCR might be converted to pCR with longer therapy, a hypothesis to be tested in a follow up study. Our data strongly suggest that selected pts with HER2+ tumors may not need chemotherapy. N % Menopausal status Pre 32 48 Peri 4 6 Post 30 46 Age ≤50 35 53 >50 31 47 Race White 48 73 Black 14 21 Other 4 6 Ethnicity Hispanic 22 33 Not Hispanic 43 65 Tumor size ≤5 cm 24 39 >5 cm 38 61 Median 6 cm ER + 41 62 - 25 38