Letrozole (L) with bevacizumab (B) is feasible in patients (pts) with hormone receptor-positive metastatic breast cancer (MBC)

Abstract

3050 Background: Bevacizumab added to chemotherapy (CRx) prolongs PFS in pts with MBC. Data suggest that estrogen (E2) modulates VEGF-induced angiogenesis in physiologic and pathologic conditions. E2-induced VEGF expression may promote breast cancer growth therefore combination therapy with an aromatase inhibitor (AI) and an antibody to VEGF may be more effective than either agent alone. We performed a feasibility study testing B with L for the treatment (tx) of hormone receptor-positive MBC. Methods: Eligible pts have MBC and are candidates for AI therapy. Prior non-steroidal AI (NSAI) use without progression is permitted. Premenopausal pts undergo ovarian suppression/oophorectomy prior to tx. Therapy consists of L (2.5 mg daily) and B (15 mg/kg IV q3 weeks). The primary endpoint is frequency of Grade (Gr) 4 toxicity. Secondary endpoints include response rate, stable disease (SD) ≥ 6 mo and time to tumor progression. Using a two-stage design, 19 pts were accrued. Because <3 pts had Gr 4 toxicity, the 2nd stage is now enrolling an additional 23 pts. If <5 of the 42 pts have Gr 4 toxicity, the regimen will be considered feasible. Results: Thirty two pts are currently accrued and 28 are now evaluable. Medians: Age 49.5 yrs (32–77) and ECOG PS 0 (0–1). Sites of MBC: bone only 11/28, visceral 16/28, chest wall/soft tissue/lymph nodes 11/28. All are ER and/or PR (+); none are HER2 (+). Prior therapy: adjuvant CRx 20; adjuvant tamoxifen 14. Twenty five pts received an NSAI as first-line tx of MBC, starting a median of 23 wks (1–213) before B. Three pts received first-line tamoxifen; one pt had prior CRx for MBC. After a median of 8 cycles (1–20), tx-related toxicities: Gr 2: hypertension (HTN) 4, headache (HA) 4, proteinuria 3, fatigue 6, joint pain 5, hot flashes 1, epistaxis 1; Gr 3: HTN 5, HA 1, proteinuria 1. There has been no tx-related Gr 4/5 toxicity. Tx-related withdrawals: HTN 1 and headache 1. Twenty five pts are evaluable for response: PR 2, SD ≥ 6 mo 13, SD 4, progression 6. Conclusions: Combination L and B is well tolerated and will be studied in a randomized CALGB trial. Circulating endothelial and tumor cell data is reported separately. Supported in part by Genentech and Novartis. [Table: see text]

The economics of counterfeit Avastin: a geospatial and statistical analysis of demographic correlates to FDA warning letters

“…Avastin is an expensive medication in an injectable class of anti-cancer drugs called angiogenesis inhibitors, which is used in combination with chemotherapy. 11,12 When malignant tumors grow, so do their demand for oxygen and nutrients. To facilitate this increased demand, they release higher quantities of a protein called vascular endothelial growth factor, which stimulates the growth of new blood vessels.…”

Femara® and the future: tailoring treatment and combination therapies with Femara

“…Specifically, novel combination strategies may be developed to prevent or delay the development of endocrine therapy resistance [ 3 , 39 ], to restore sensitivity to endocrine therapy [ 53 ], and to treat hormone-resistant tumors [ 18 , 46 ]. Anti-vascular endothelial growth factor (VEGF) therapy with bevacizumab may be able to overcome resistance to endocrine therapy and improve efficacy in HR+ metastatic breast cancer [ 54 ], and preclinical models have shown that the estrogen-induced increase in VEGF expression may be counteracted by aromatase inhibition. Inhibition of growth factor signaling and angiogenesis pathways may be rationally combined with conventional endocrine strategies for breast cancer [ 4 , 35 , 50 , 55 , 56 ].…”

“…In a clinical trial [ 69 ] designed to test whether combination therapy with letrozole and bevacizumab was possible, patients with ER+ or progesterone receptor-positive (PR+) metastatic or locally advanced breast cancer were treated with letrozole (2.5 mg daily) and bevacizumab (15 mg/kg IV every 3 weeks) [ 54 ]. The majority of patients had received prior therapy with a nonsteroidal AI.…”

“…Median progression-free survival was reported to be 10 months, and this compares favorably with the published data on median time to progression with first-line letrozole (9.4 months) [ 70 ]. However, analysis of efficacy and biomarker data was confounded by the long duration of prestudy aromatase inhibition [ 54 , 71 ]. Nevertheless, when the data were corrected for duration of previous AI therapy, the study did determine that changes in circulating endothelial cell (CEC) levels may be a biomarker of response or progression on anti-angiogenic therapy [ 71 ].…”

The early days of letrozole

“…Since it is possible to block the estrogen receptor pathway almost completely with letrozole, the next step should be to target those growth pathways that may be up-regulated by complete blockade of the estrogen-dependent pathways. Thus, several studies investigating the efficacy of letrozole in combination with targeted therapies such as RAD001 [ 5 ], bevacizumab [ 6 ], or trastuzumab [ 7 ] are under way. Furthermore, emerging clinical data indicate that adjuvant letrozole therapy might be particularly effective in reducing the early risk of distant metastases, a well-recognized cause of breast cancer death [ 8 , 9 ].…”