[301] Phase II combined biological therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor using trastuzumab (T) and bevacizumab (B) as first line treatment of HER2-amplified breast cancer.

Pegram M, Chan D, Dichmann RA, Tan-Chiu E, Yeon C, Durna L, Lin LS, Slamon D.. UCLA/Jonsson Comprehensive Cancer Center, Los Angeles, CA

Background: Overexpression of HER2 is associated with up-regulation of VEGF in breast cancer cells, and there is strong association between HER2 and VEGF, which predicts clinical outcome, in primary breast tumors (Konecny, et al., Clin Cancer Res 10: 1706-16, 2004). In xenograft models, superior efficacy is observed when T is given in combination with B. In a phase I study of T + B, we reported a recommended phase II dose of B 10mg/kg q 2 weeks plus T 4mg/kg loading dose, then 2mg/kg weekly (Pegram, et al. Breast Cancer Res Treat. 88:S124, 2004). Co-administration of T + B did not alter pharmacokinetics of either agent. Clinical responses were observed in 5 of 9 patients in phase I, including one patient with prior disease progression on T. The objectives of this phase II study are: to determine clinical efficacy of T + B combination, and to evaluate the safety of T + B.
Methods: Key eligibility: females (age 18-75), HER2-amplified (FISH) metastatic or locally-relapsed, surgically-unresectable breast cancer (BC), normal left ventricular function, bidimensionally measurable disease, and signed informed consent. Key exclusions: prior chemotherapy in the metastatic setting, newly-diagnosed, untreated stage IIIB BC, CNS metastastasis, significant cardiovascular disease, proteinuria, coagulopathy, or anticoagulation, >3 different organ sites of metastasis, >50% parenchymal liver metastasis, or symptomatic pulmonary metastases.
Results: 30 of 50 planned patients have been dosed. Patient characteristics: prior mastectomy - 15 (50%), prior radiation - 14 (47%), prior adjuvant/neoadjuvant chemotherapy - 17 (57%), prior anthracyclines - 17 (57%), prior endocrine therapy - 13 (43%), visceral metastasis - 20 (67%). Grade III/IV drug-related adverse events (N=28, treated with a total of 115 monthly cycles): dyspnea (N=1), left ventricular dysfunction (N=1), HTN (N=5), and proteinuria (N=1). Most common grade I/II adverse events: fever/chills/headache/infusion reaction (N=14), fatigue (N=6), epistaxis (N=6), HTN (N=6), and AST /ALT increase (N=10). Stringent cardiac safety surveillance has been followed. Six cardiac adverse events (NCI-CTC version 2) have been reported, one of which was symptomatic: 2 grade 1, 3 grade 2, and 1 grade 4. Investigator reported, objective clinical responses (WHO criteria) have been documented in 13 of 28 (46%) evaluable patients; all partial responses. An additional 9/28 patients had stable disease at week 8. Eleven of 30 patients remain on active treatment.
Discussion: This is the first phase II trial of two humanized antibodies given in combination to human subjects. T + B is clinically feasible and active in HER2-amplified recurrent or metastatic BC. These data support the use of combination therapies directed against HER2 and VEGF for treatment of BC with HER2 alteration.

Friday, December 15, 2006 5:00 PM

Poster Discussion Session III: HER2 and Family (5:00 PM-7:00 PM)