responding to lapatinib and to the combination of the two. I believe that it is important to see these trials completed, to collect the tissue and to find out whether there are fundamental differences among these women that can be identified before we begin therapy. Then we can choose the correct drug from day one. That is why I believe the neoadjuvant studies are of particular importance here — to provide us with that kind of information. 3.5
A Phase III Trial of Neoadjuvant Therapy for Patients with Palpable and Operable HER2-Positive Breast Cancer
Protocol ID: NSABP-B-41 Target Accrual: 522
Start Date: July 2007
Eligibility HER2-positive, invasive breast cancer diagnosed with core needle biopsy with palpable breast mass ≥ 2.0 centimeters
R
AC
paclitaxel qwk + trastuzumab
AC
paclitaxel qwk + lapatinib 1,500 mg
AC paclitaxel qwk + trastuzumab + lapatinib 1,000 mg Postoperative therapy for all patients: Trastuzumab 6 mg/kg q3wk to one year after the first dose of preoperative trastuzumab or lapatinib
Rationale for Lapatinib in NSABP-B-41: Mechanisms of Action and Resistance “Since resistance to trastuzumab eventually results in progressive disease in the metastatic setting and contributes to recurrence following adjuvant trastuzumab-based therapy, it is important to develop agents other than trastuzumab that target HER2 signaling through different mechanisms of action. Lapatinib, an oral, small molecule, dual tyrosine kinase inhibitor of HER2 and EGFR, has demonstrated non-cross resistance with trastuzumab in preclinical studies and activity in women with HER2-positive, metastatic breast cancer progressing on trastuzumab. Trastuzumab blocks the downstream signaling of HER2 by binding to the extracellular domain of the receptor. Potential mechanisms of resistance to HER2 include: cleavage of the extracellular domain of HER2 which results in a potent oncogenic receptor (p95HER2) that is less responsive to trastuzumab; abnormal PTEN function; and heterodimerization with EGFR, with continued activation through the heterodimer by EGFR activation in spite of interruption of HER2 signaling. Lapatinib binds to the intracellular domains of HER2 and EGFR at the ATP-binding sites and prevents phosphorylation and activation of downstream signaling pathways. Because of this different mechanism of action, lapatinib may be effective in trastuzumab-resistant disease.” SOURCES: www.nsabp.pitt.edu/B-41.asp; www.clinicaltrials.gov; NSABP-B-41 Protocol
Document, version June 12, 2007. 30