Phase II dose escalation trial of Avastin™ (bevacizumab) in women with previously treated metastatic breast cancer

Breast cancer is known to produce vascular endothelial growth factor (VEGF), a key molecule in the regulation of angiogenesis. Increased VEGF protein and mRNA levels are associated with decreased overall and disease-free survival. It follows that inhibition of VEGF production may slow tumor growth and lead to longer survival. Therefore, a Phase II dose escalation trial of a recombinant humanized monoclonal antibody to VEGF (bevacizumab; rhuMAb VEGF) was undertaken. Methods: Seventy-five women with previously treated metastatic breast cancer were treated with Avastin at 3 mg/ kg (n=18), 10 mg/kg (n=41) or 20 mg/kg (n=16) IV every 2 weeks until progression. The endpoints of the trial were safety, best objective response rate and pharmacokinetics. Results: The median age of patients in this trial was 48 years and patients had received a median of two prior chemotherapy regimens for metastatic disease. The median duration of treatment was 10 weeks. Dose-limiting toxicity was headache (Grade 3 in 1; Grade 4 in 1) associated with nausea and vomiting which occurred in 4 patients treated at 20 mg/kg. Four patients discontinued study participation because of adverse events: 1 with hypertensive encephalopathy and nephrotic syndrome at 3 mg/kg, 1 with proteinuria at 10 mg/kg, 1 with nephrotic syndrome at 20 mg/kg and 1 with severe headache, nausea and vomiting at 20 mg/kg. 7 of 75 (9.3%) patients had an objective response including 1 CR in a supraclavicular node at 10 mg/kg that recurred 3 months after completing 1 year of therapy. PR occurred in 6 patients (2 unconfirmed) with disease in lymph nodes, skin, pleura, bone and liver. Median duration of confirmed response was 5.6 months. Responders had smaller tumor burden, lower ECOG status and higher albumin at baseline than the overall population. 12 of 75 (17%) patients had an ongoing response or stable disease at the last tumor assessment at 5 months. Three patients were treated for one year or longer without disease progression. Median survival was 10.2 months. Conclusions: Avastin monotherapy results in objective response or disease stabilization in a significant number of patients. Adverse events of significance included hypertension and proteinuria. A Phase III trial combining Avastin with capecitabine is currently underway.