Final Results of a Phase II Trial Evaluating Trastuzumab and Bevacizumab as First Line Treatment of HER2-Amplified Advanced Breast Cancer

Background: Overexpression of HER2/neu is associated with upregulation of VEGF in human breast cancer cells in vitro. In xenograft models, superior efficacy is observed when anti-HER2 antibody trastuzumab (T) is given in combination with anti-VEGF antibody bevacizumab (B). Results from a phase I study of T + B (Breast Cancer Res Treat. 88:S124, 2004) were sufficiently positive to proceed with phase II testing. The objectives of this phase II study were to more fully determine clinical efficacy and safety of T + B.Methods: Women with normal cardiac function and bidimensionally measurable, HER2-amplified (FISH), metastatic or locally recurrent unresectable breast cancer were eligible. Patients (pts) were excluded if they had received chemotherapy in the metastatic setting, had CNS metastases, proteinuria, >3 different organ sites of metastasis, >50% parenchymal liver metastasis, or symptomatic lung metastases. Prior adjuvant T was allowed if it was discontinued ≥ 1 year before study entry. B (10mg/kg q 2 weeks) + T (4mg/kg loading, then 2mg/kg weekly) IV was given, per the results of phase I testing (above).Results: From 12/2004 to 4/2007, 50 pts were enrolled at 19 US sites. Pt characteristics: median age 58, prior breast surgery-38 (76%), prior radiation-22 (44%), prior (neo)adjuvant chemotherapy-26 (52%), prior anthracyclines-25 (50%), prior taxanes-20 (40%), prior endocrine therapy–23 (46%), visceral metastasis-36 (72%). A median of 6.25 cycles (range 1-34) were administered to pts. Drug-related adverse events (AEs) (all Grade (Gr) 3/4 and any events reported in >10% of patients, NCI-CTC v.2) included hypertension (N= 30: 18 Gr 3/4, 12 Gr 1/2), fever/chills/infusion reaction (N=18: 2 Gr 3/4, 16 Gr 1/2), headache (N=17: 2 Gr 3/4, 15 Gr 1/2), epistaxis (N=17: all Gr 1/2), fatigue (N=15: 1 Gr 3, 14 Gr 1/2), proteinuria (N=12: 4 Gr 3/4, 8 Gr 1/2), AST /ALT increase (N=12, all Gr 1/2), diarrhea (N=10: 1 Gr 3, 9 Gr 1/2), edema (N=6, all Gr 1/2), nail changes (N=6, all Gr 1/2), dyspnea (N=5: 2 Gr 3/4, 3 Gr 1/2), leucopenia (N=5: Gr 3/4=2, Gr 1/2=3), inflammatory demyelination (N=1, Gr 3), hyperglycemia (N=1, Gr 3), hyponatremia (N=1, Gr 3) and irregular menses (N=1, Gr 3). One pt developed a perforated ulcer and 4 weeks later died of sepsis (Gr 5). One Gr 4 cardiac AE was reported at the end of cycle 2 in a pt who had previously received doxorubicin. In addition, there were 9 Gr 2 and 9 Gr 1 cardiac AEs (all asymptomatic). Objective clinical responses (WHO criteria) were documented in 24 pts (48%), including 2 CRs. 15 pts (30%) had stable disease, 6 of which lasted ≥ 6 mos (12%) for a clinical benefit rate of 60%. No pts remain on active study treatment. The median time to progression (TTP) was 9.2 mos (95% CI: 5.4-20.5). No difference in TTP was detected between hormone receptor negative and positive tumor types. Median overall survival was 43.8 months (95% CI: 40.6,NA).Conclusions: These are the final results for the first phase II trial of 2 humanized antibodies given in combination to human subjects. The results show that T + B is clinically feasible and very active despite the absence of chemotherapy in HER2+ advanced breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6094.