Neoadjuvant GW572016 to Treat Breast Cancer

The EGFR/HER family of transmembrane type I receptor tyrosine kinases are enzymes that play an important role in fundamental cell processes like cell proliferation, differentiation, and survival. These receptor tyrosine kinases, which include HER1 (epidermal growth factor receptor, EGFR), HER2 (HER2/neu, c-erbB2), HER3 and HER4 contain an extracellular domain and intracellular protein tyrosine kinase core. Aberrant HER1 and HER2 signaling has been causally associated with cancer cell proliferation and survival.

HER1 is expressed or over-expressed in many human solid tumors and plays an important role in progression to invasion and metastases.. The association between HER2 overexpression and poor prognosis in node-positive and advanced breast cancer has been shown by a number of studies. Based on this association between the members of HER1/HER2 family and worse clinical outcome, antibodies and small molecules that specifically target these receptor tyrosine kinases were developed for their therapeutic efficacy.

Trastuzumab (Herceptin) is a highly purified recombinant DNA-derived humanized monoclonal antibody that selectively binds with high affinity to the extracellular domain of the HER2 receptor. Pivotal multicenter efficacy trials in metastatic patients showed improved response rates and disease-free survival in patients who received trastuzumab in addition to chemotherapy. One of these studies was an open-labeled, multicenter, randomized phase III study evaluating the addition of trastuzumab to standard first-line chemotherapy in metastatic breast cancer. This study randomized 469 patients with metastatic disease to chemotherapy with or without trastuzumab. Results of this study showed survival in patients who received trastuzumab plus chemotherapy to be almost twice as long as chemotherapy alone (7.2 vs. 4.5 months, p<0.0001).

As dimerization is important in signal transduction, therapies that target more than one member of the HER family may have greater anti-tumor effect. Recently, data with trastuzumab plus IMC-C224 in human ovarian cancer cells showed greater growth inhibition compared to either monoclonal antibody alone. GW572016 is an orally active dual HER1/HER2 kinase inhibitor that blocks signal transduction pathways. This dual inhibition is an attractive therapeutic strategy for epithelial cancers, as ligand-induced HER1/HER2 dimerization triggers off potent proliferative and survival signals. In vitro studies with GW572016 have shown marked activity, leading to growth arrest and apoptosis in HER1 and HER2 overexpressing cell lines. GW572016 markedly reduced tyrosine phosphorylation of HER1 and HER2, and activation of MAP kinase and Akt, the downstream effectors of proliferation and survival, respectively. In vitro studies in HER-2 overexpressing cell lines have demonstrated synergistic activity when GW572016 is combined with taxanes. Phase I studies with GW572016 and taxanes have been completed, with results demonstrating that this small molecule inhibitor may be safely combined with chemotherapy with no unanticipated side effects.

The EGFR/HER family of transmembrane type I receptor tyrosine kinases are enzymes that play an important role in fundamental cell processes like cell proliferation, differentiation, and survival. These receptor tyrosine kinases, which include HER1 (epidermal growth factor receptor, EGFR), HER2 (HER2/neu, c-erbB2), HER3 and HER4 contain an extracellular domain and intracellular protein tyrosine kinase core. Aberrant HER1 and HER2 signaling has been causally associated with cancer cell proliferation and survival.

Trastuzumab (Herceptin) is a highly purified recombinant DNA-derived humanized monoclonal antibody that selectively binds with high affinity to the extracellular domain of the HER2 receptor. Results of this study showed survival in patients who received trastuzumab plus chemotherapy to be almost twice as long as chemotherapy alone (7.2 vs. 4.5 months, p<0.0001).

In vitro studies with GW572016 have shown marked activity, leading to growth arrest and apoptosis in HER1 and HER2 overexpressing cell lines. GW572016 markedly reduced tyrosine phosphorylation of HER1 and HER2, and activation of MAP kinase and Akt, the downstream effectors of proliferation and survival, respectively. In vitro studies in HER-2 overexpressing cell lines have demonstrated synergistic activity when GW572016 is combined with taxanes. Phase I studies with GW572016 and taxanes have been completed, with results demonstrating that this small molecule inhibitor may be safely combined with chemotherapy with no unanticipated side effects.

As the type I tyrosine kinases are involved in various aspects of cell growth and survival, a potent quinazoline and pyrido-[3,4-d]-pyrimidine small molecule (GW572016) against HER1 and HER2 was developed which showed potent in vitro inhibition of HER1 and HER2 in tumor cell lines. Mouse xenograft models of BT474 and HN5 cell lines also showed growth inhibition in a dose-responsive manner. In addition, GW572016 caused a reduction in HER1 and HER2 autophosphorylation, indicating interference of this signaling pathway. GW572016 not only inhibited baseline activation of HER1 and HER2, but also has been shown to interrupt downstream activation of Erk1/2 MAP kinases and Akt.

HER1 is expressed or over-expressed in many human solid tumors and plays an important role in progression to invasion and metastases.. The association between HER2 overexpression and poor prognosis in node-positive and advanced breast cancer has been shown by a number of studies. Based on this association between the members of HER1/HER2 family and worse clinical outcome, antibodies and small molecules that specifically target these receptor tyrosine kinases were developed for their therapeutic efficacy.

Trastuzumab (Herceptin) is a highly purified recombinant DNA-derived humanized monoclonal antibody that selectively binds with high affinity to the extracellular domain of the HER2 receptor. Pivotal multicenter efficacy trials in metastatic patients showed improved response rates and disease-free survival in patients who received trastuzumab in addition to chemotherapy. One of these studies was an open-labeled, multicenter, randomized phase III study evaluating the addition of trastuzumab to standard first-line chemotherapy in metastatic breast cancer. This study randomized 469 patients with metastatic disease to chemotherapy with or without trastuzumab. Results of this study showed survival in patients who received trastuzumab plus chemotherapy to be almost twice as long as chemotherapy alone (7.2 vs. 4.5 months, p<0.0001).

We have completed the first single-agent neoadjuvant trastuzumab study in human breast cancer. The specific aims of this study were to firstly, define the clinical efficacy of trastuzumab, and secondly, to determine its mechanism of action in human breast cancer specimens. From September 1999 to June 2003, 27 patients with HER2 overexpressing locally advanced breast cancer with or without gross metastatic disease, were considered for a phase II study with neoadjuvant trastuzumab. At presentation, the median tumor size was large at 8x8 cm2 (range 4x4 cm2 to 25x20 cm2). We did not expect measurable evidence of tumor regression with this short treatment duration. However, regression in the product of bidimensional tumor measurements with a median decrease of -20.0% (range 0, -60.4%, p=0.0001) was observed in primary tumors after only 3 weeks of single agent trastuzumab. Most surprisingly, partial response was observed in 26% (7/27). Minor response was seen in 44% (12/27), and stable disease in 30% (8/27). No tumors increased in size during this 3-week period.

This is the first neoadjuvant trastuzumab monotherapy study in treatment-naive patients with HER2 overexpressing breast cancers. The clinical efficacy with tumor reductions in some patients presenting with large initial tumors indicates that the monoclonal antibody can be safely administered as a single agent without fear of tumor progression. When the study was first started, the uncertainty of the clinical efficacy of neoadjuvant single agent trastuzumab limited its duration to 3 weeks. It seems likely that the true response rate would have been higher if therapy was continued for several months. Based on these data, longer treatment durations of HER2 targeted therapy, like with GW572016, given as a single agent should be investigated in clinical trials with careful monitoring of patients to assess its activity in this setting.

Aim 1: To demonstrate the clinical efficacy of GW572016 when given as neoadjuvant therapy as a single agent in patients with treatment-naive, locally advanced HER2 overexpressing breast cancer. We aim to discover the true response rate to inhibiting HER1/2 signal transduction with GW572016 in breast cancer patients.

Aim 2: To determine if GW572016 inhibits HER1 and HER2 signaling in situ.The mechanism of therapeutic action of GW572016 is not fully understood.