1 / 37

Bevacizumab: Antiangiogenic therapy for breast cancer: where do we stand

aya
Download Presentation

Bevacizumab: Antiangiogenic therapy for breast cancer: where do we stand

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

    1. Bevacizumab: Antiangiogenic therapy for breast cancer: where do we stand?

    2. VEGF as a key mediator of angiogenesis VEGF synthesis and expression can be upregulated by various factors, such as hypoxia, cyclooxygenase 2 (Cox-2) or by oncogenes. Counteracting agents can be Abs interacting with VEGF at the surface of the cell, or TKIs, which act within the cell to inhibit signal transduction. VEGF synthesis and expression can be upregulated by various factors, such as hypoxia, cyclooxygenase 2 (Cox-2) or by oncogenes. Counteracting agents can be Abs interacting with VEGF at the surface of the cell, or TKIs, which act within the cell to inhibit signal transduction.

    3. Rationale for anti-VEGF therapy in breast cancer VEGF expression is increased in many tumour types including breast cancer1 Positive correlation between VEGF levels and poor clinical outcome, including patient survival2 VEGF levels correlate with response to chemo/radiotherapy3 Anti-VEGF treatment inhibits growth of human breast tumour xenografts in animals4 VEGF expression is increased in many tumour types including breast cancer.1 In breast cancer, these increases are associated with poor clinical outcome, including decreased disease-free and overall survival.2,3 Furthermore, studies have demonstrated a correlation between VEGF levels and response to chemotherapy or radiotherapy.4 These observations suggest that inhibition of VEGF could be a rational therapeutic approach for the treatment of breast cancer. This view is further supported by animal studies, in which anti-VEGF treatment using A4.6.1, the parent antibody of Avastin, caused significant suppression of angiogenic activity in human breast tumour xenografts in nude mice.5 Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997;18:4–25. Gasparini G, Toi M, Gion M, et al. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst 1997;89:139–47. Linderholm B, Grankvist K, Wilking N, Johansson M, Tavelin B, Henriksson R. Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol 2000;18:1423–31. Gasparini G, Toi M, Miceli R, et al. Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy. Cancer J Sci Am 1999;5:101–11. Borgstrom P, Gold DP, Hillan KJ, Ferrara N. Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer Res 1999;19:4203–14.VEGF expression is increased in many tumour types including breast cancer.1 In breast cancer, these increases are associated with poor clinical outcome, including decreased disease-free and overall survival.2,3 Furthermore, studies have demonstrated a correlation between VEGF levels and response to chemotherapy or radiotherapy.4 These observations suggest that inhibition of VEGF could be a rational therapeutic approach for the treatment of breast cancer. This view is further supported by animal studies, in which anti-VEGF treatment using A4.6.1, the parent antibody of Avastin, caused significant suppression of angiogenic activity in human breast tumour xenografts in nude mice.5 Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997;18:4–25. Gasparini G, Toi M, Gion M, et al. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst 1997;89:139–47. Linderholm B, Grankvist K, Wilking N, Johansson M, Tavelin B, Henriksson R. Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol 2000;18:1423–31. Gasparini G, Toi M, Miceli R, et al. Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy. Cancer J Sci Am 1999;5:101–11. Borgstrom P, Gold DP, Hillan KJ, Ferrara N. Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer Res 1999;19:4203–14.

    4. Phase II trials of Bevacizumab plus chemotherapy in MBC

    5. Phase II trial of Bevacizumab plus vinorelbine in refractory breast cancer (AVF2324s) Two-stage design 19 patients recruited. ³6 responses required for a further 18 patients to be recruited Primary endpoint: response rate Secondary endpoints include time to progression and safety Treatment administration Bevacizumab 10mg/kg i.v. every 2 weeks vinorelbine 25mg/m2 i.v. weekly. Dose adjusted following ANC assessment A two-stage, phase II trial of Bevacizumab in combination with vinorelbine has been conducted in refractory breast cancer patients.1 Initially, 19 patients were enrolled and evaluated for a response. A further 18 patients were to be enrolled if ?6 patients had a response. Patients received Bevacizumab 10mg/kg every 2 weeks and vinorelbine 25mg/m2 i.v. each week. Vinorelbine dose was adjusted for ANC: full dose for ANC >1,250; 15mg/m2 for ANC 750–1,250; and no dose for ANC <750). Study endpoints included response rate (primary endpoint), and time to progression and safety (secondary endpoints). Due to initial activity, second stage accrual was expanded to achieve a total of 56 patients. With this design, there was an 8% chance that this regimen is worthy of further study if a response rate of 30% is achieved and an 80% chance if a response rate of 45% was achieved. Burstein HJ, Parker LM, Savoie J, et al. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. Breast Cancer Res Treat 2002;79:S115 (Abstract 446).A two-stage, phase II trial of Bevacizumab in combination with vinorelbine has been conducted in refractory breast cancer patients.1 Initially, 19 patients were enrolled and evaluated for a response. A further 18 patients were to be enrolled if ?6 patients had a response. Patients received Bevacizumab 10mg/kg every 2 weeks and vinorelbine 25mg/m2 i.v. each week. Vinorelbine dose was adjusted for ANC: full dose for ANC >1,250; 15mg/m2 for ANC 750–1,250; and no dose for ANC <750). Study endpoints included response rate (primary endpoint), and time to progression and safety (secondary endpoints). Due to initial activity, second stage accrual was expanded to achieve a total of 56 patients. With this design, there was an 8% chance that this regimen is worthy of further study if a response rate of 30% is achieved and an 80% chance if a response rate of 45% was achieved. Burstein HJ, Parker LM, Savoie J, et al. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. Breast Cancer Res Treat 2002;79:S115 (Abstract 446).

    6. Phase II trial of Bevacizumab plus vinorelbine in refractory breast cancer (AVF2324s): efficacy A total of 56 patients were recruited, of whom 54 were evaluable for response.1 There was one (2%) complete response and 16 (29%) partial responses. Twenty-five patients (45%) had stable disease and disease had progressed in 12 (21%) of patients. Burstein HJ, Parker LM, Savoie J, et al. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. Breast Cancer Res Treat 2002;79:S115 (Abstract 446).A total of 56 patients were recruited, of whom 54 were evaluable for response.1 There was one (2%) complete response and 16 (29%) partial responses. Twenty-five patients (45%) had stable disease and disease had progressed in 12 (21%) of patients. Burstein HJ, Parker LM, Savoie J, et al. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. Breast Cancer Res Treat 2002;79:S115 (Abstract 446).

    7. Phase II trial of Bevacizumab plus vinorelbine in refractory breast cancer (AVF2324s): safety Bevacizumab plus vinorelbine was well tolerated.1 The most common haematologic side effect was grade 3 neutropenia, seen in 26 patients. The most common grade 1, non-haematologic side effect was neurosensory toxicity, seen in 26 (47%) patients. Other common side effects included grade 1 vomiting (15 patients), hypertension (11 patients) and proteinuria. There were few grade 3/4 events, but the most common was vomiting in four (7%) patients. Burstein HJ, Parker LM, Savoie J, et al. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. Breast Cancer Res Treat 2002;79:S115 (Abstract 446).Bevacizumab plus vinorelbine was well tolerated.1 The most common haematologic side effect was grade 3 neutropenia, seen in 26 patients. The most common grade 1, non-haematologic side effect was neurosensory toxicity, seen in 26 (47%) patients. Other common side effects included grade 1 vomiting (15 patients), hypertension (11 patients) and proteinuria. There were few grade 3/4 events, but the most common was vomiting in four (7%) patients. Burstein HJ, Parker LM, Savoie J, et al. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. Breast Cancer Res Treat 2002;79:S115 (Abstract 446).

    8. Phase II trial of Bevacizumab plus vinorelbine in refractory breast cancer(AVF2324s): conclusions Bevacizumab plus vinorelbine has clinical activity 31% of patients had an objective response several patients had responses of >1 year, which is encouraging This combination was well tolerated side effects relating to Bevacizumab included hypertension and epistaxis Studies in less heavily pretreated patients may be warranted Bevacizumab combined with vinorelbine has activity in heavily pretreated patients with refractory breast cancer.1 A total of 31% of patients had an objective response, but this was significantly lower than the rate reported in the literature for vinorelbine alone. The investigators note, however, that time on study are interesting and may suggest that Bevacizumab improves the response to vinorelbine. The regimen is well tolerated with few grade 3/4 adverse events. Adverse events relating to Bevacizumab included grade 1 hypertension and epistaxis. Pending correlative studies may help to identify patients with breast cancer who may benefit from Avastin-based therapy. Trials of Bevacizumab in less refractory patients and with other chemotherapy agents are warranted based on preclinical and safety data. Burstein HJ, Parker LM, Savoie J, et al. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. Breast Cancer Res Treat 2002;79:S115 (Abstract 446).Bevacizumab combined with vinorelbine has activity in heavily pretreated patients with refractory breast cancer.1 A total of 31% of patients had an objective response, but this was significantly lower than the rate reported in the literature for vinorelbine alone. The investigators note, however, that time on study are interesting and may suggest that Bevacizumab improves the response to vinorelbine. The regimen is well tolerated with few grade 3/4 adverse events. Adverse events relating to Bevacizumab included grade 1 hypertension and epistaxis. Pending correlative studies may help to identify patients with breast cancer who may benefit from Avastin-based therapy. Trials of Bevacizumab in less refractory patients and with other chemotherapy agents are warranted based on preclinical and safety data. Burstein HJ, Parker LM, Savoie J, et al. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. Breast Cancer Res Treat 2002;79:S115 (Abstract 446).

    9. Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): study design A phase II trial of Bevacizumab in combination with docetaxel for the first-/second-line treatment of metastatic breast cancer has been performed.1 Twenty-one patients received 6 cycles of Bevacizumab 10mg/kg every 2 weeks and docetaxel 35mg/m2 i.v. weekly for 3 out of every 4 weeks. This was followed by Bevacizumab monotherapy until disease progression. The primary trial endpoints were response rate and toxicity. Other endpoints included progression-free survival and correlative studies to examine the relationship between various parameters (baseline plasma VEGF, soluble activated endothelial cell markers and adhesion molecules, microvessel density, tumour/endothelial cell apoptosis) and clinical outcomes. 1. Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9 A phase II trial of Bevacizumab in combination with docetaxel for the first-/second-line treatment of metastatic breast cancer has been performed.1 Twenty-one patients received 6 cycles of Bevacizumab 10mg/kg every 2 weeks and docetaxel 35mg/m2 i.v. weekly for 3 out of every 4 weeks. This was followed by Bevacizumab monotherapy until disease progression. The primary trial endpoints were response rate and toxicity. Other endpoints included progression-free survival and correlative studies to examine the relationship between various parameters (baseline plasma VEGF, soluble activated endothelial cell markers and adhesion molecules, microvessel density, tumour/endothelial cell apoptosis) and clinical outcomes. 1. Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9

    10. Metastatic disease measurable by RECIST 0–1 prior chemotherapy regimens for metastatic disease ECOG PS 0–2 At least 6 months since prior taxane therapy No brain metastases No major surgical procedure or significant traumatic injury within 28 days Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): eligibility criteria Eligible patients had breast cancer with at least one site of metastasis measurable by RECIST.1 Patients had received no more than one prior chemotherapy regimen for metastatic disease, and if prior therapy had included a taxane, at least 6 months must have elapsed since completion of this treatment. ECOG performance status of 0–2 was required, and eligible patients could not have brain metastases. Major surgery, open biopsy, non-healing wounds or significant traumatic injury were not permitted within 28 days prior to starting on the study. 1. Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9 Eligible patients had breast cancer with at least one site of metastasis measurable by RECIST.1 Patients had received no more than one prior chemotherapy regimen for metastatic disease, and if prior therapy had included a taxane, at least 6 months must have elapsed since completion of this treatment. ECOG performance status of 0–2 was required, and eligible patients could not have brain metastases. Major surgery, open biopsy, non-healing wounds or significant traumatic injury were not permitted within 28 days prior to starting on the study. 1. Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9

    11. Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): efficacy summary All patients were evaluable for response, but two withdrew during cycle 1 due to toxicity.1 In the remaining 25 patients, there were 14 (52%) partial responses and nine (33%) patients with stable disease. The median duration of response was 6.0 months. Median progression-free survival was 7.5 months. 1. Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9 All patients were evaluable for response, but two withdrew during cycle 1 due to toxicity.1 In the remaining 25 patients, there were 14 (52%) partial responses and nine (33%) patients with stable disease. The median duration of response was 6.0 months. Median progression-free survival was 7.5 months. 1. Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9

    12. Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): Avastin-related toxicity Grade 3 and 4 adverse events attributable to Bevacizumab were uncommon.1 Two patients (9.5%) experienced grade 4 pulmonary embolus and one patient (4%) had grade 3 hypertension. 1. Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9 Grade 3 and 4 adverse events attributable to Bevacizumab were uncommon.1 Two patients (9.5%) experienced grade 4 pulmonary embolus and one patient (4%) had grade 3 hypertension. 1. Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9

    13. Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): other toxicities Other toxicities reported in this trial were mainly attributable to the presence of docetaxel in the therapeutic regimen.1 The most common of these included grade 2 fatigue (70.3%), dyspnoea (66.7%) and eye tearing (55.6%), and grade 3 leukopenia (22.2%), neutropenia (14.8%) and fatigue (14.8%). The only grade 4 events were leukopenia, neutropenia and infection, each in only one patient. 1. Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9 Other toxicities reported in this trial were mainly attributable to the presence of docetaxel in the therapeutic regimen.1 The most common of these included grade 2 fatigue (70.3%), dyspnoea (66.7%) and eye tearing (55.6%), and grade 3 leukopenia (22.2%), neutropenia (14.8%) and fatigue (14.8%). The only grade 4 events were leukopenia, neutropenia and infection, each in only one patient. 1. Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9

    14. Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): summary Efficacy data from this first reported clinical trial of Avastin and docetaxel are encouraging the response rate of 52% shows that this is an active combination Toxicity was acceptable: the only grade 4 adverse event attributable to Avastin was venous thromboembolism in two patients most toxicity was consistent with the safety profile of weekly docetaxel This regimen is worthy of further investigation in a randomised phase III trial This single arm phase II trial investigated the combination of Avastin (10mg/kg every 2 weeks) with docetaxel (35mg/m2 weekly for 3 out of 4 weeks) in 27 patients with MBC. A response rate of 52% was achieved, with progression-free survival of 7.5 months and a response duration of 6.0 months. This regimen has an acceptable toxicity profile; there were few grade 4 adverse events and most observed toxicities can be attributed to weekly docetaxel. The most serious adverse event attributable to Avastin was grade 4 pulmonary embolus in two patients. This is the first trial to report on the combination of weekly docetaxel and Avastin, a regimen which is currently under investigation in the Roche AVADO phase III trial. 1. Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9 This single arm phase II trial investigated the combination of Avastin (10mg/kg every 2 weeks) with docetaxel (35mg/m2 weekly for 3 out of 4 weeks) in 27 patients with MBC. A response rate of 52% was achieved, with progression-free survival of 7.5 months and a response duration of 6.0 months. This regimen has an acceptable toxicity profile; there were few grade 4 adverse events and most observed toxicities can be attributed to weekly docetaxel. The most serious adverse event attributable to Avastin was grade 4 pulmonary embolus in two patients. This is the first trial to report on the combination of weekly docetaxel and Avastin, a regimen which is currently under investigation in the Roche AVADO phase III trial. 1. Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9

    15. A phase II trial is investigating Avastin 15mg/kg plus docetaxel 75mg/m2 every 3 weeks in treatment-naïve MBC Primary endpoint: time to progression 43 of 75 patients have been enrolled 21 have had at least one assessment Response rate is 40% The most common grade 3/4 adverse events to date are neutropenia, febrile neutropenia and hypertension LVEF decline seen in one patient This regimen is well tolerated and appears active in this patient population Ongoing phase II trial of Bevacizumab plus docetaxel in MBC (AVF3110s) A single arm phase II trial of first-line Avastin (15mg/kg) with 3-weekly docetaxel (75mg/m2) is ongoing.1 A total of 75 patients will be enrolled; data are available for the first 43. The response rate is 40%, although no details regarding the extent of the responses have been published. Toxicity has been acceptable to date, with the most common grade 3/4 adverse events being neutropenia, febrile neutropenia and hypertension. Grade 3 LVEF decline was seen in one patient; the management of this patient and her outcome have not been presented. No treatment-related deaths occurred. Generally, the preliminary data from this trial are encouraging, with no unexpected toxicities. 1. Chan D, Allen H, Hu E, et al. Phase 2 study of docetaxel (D) plus bevacizumab (B) in Her/2 negative metastatic breast carcinoma (MBC). J Clin Oncol 2006;24(20 June suppl.):605s (Abstract 13047).A single arm phase II trial of first-line Avastin (15mg/kg) with 3-weekly docetaxel (75mg/m2) is ongoing.1 A total of 75 patients will be enrolled; data are available for the first 43. The response rate is 40%, although no details regarding the extent of the responses have been published. Toxicity has been acceptable to date, with the most common grade 3/4 adverse events being neutropenia, febrile neutropenia and hypertension. Grade 3 LVEF decline was seen in one patient; the management of this patient and her outcome have not been presented. No treatment-related deaths occurred. Generally, the preliminary data from this trial are encouraging, with no unexpected toxicities. 1. Chan D, Allen H, Hu E, et al. Phase 2 study of docetaxel (D) plus bevacizumab (B) in Her/2 negative metastatic breast carcinoma (MBC). J Clin Oncol 2006;24(20 June suppl.):605s (Abstract 13047).

    16. Phase III trials of Bevacizumab plus chemotherapy in MBC

    17. Phase III trial of Bevacizumab plus Xeloda® in MBC (AVF2119g) Primary endpoint: progression-free survival Secondary endpoints: overall response rate, duration of response and overall survival Treatment administration Bevacizumab 15mg/kg i.v. every 3 weeks Xeloda 2,500mg/m2 orally daily for 2 weeks of a 3-week cycle A phase III study of Bevacizumab (AVF2119g) in combination with chemotherapy was conducted.1 Four hundred and sixty-two women were randomised to either Xeloda (capecitabine) alone (2,500mg/m2 orally daily for 2 weeks of every 3-week cycle) (n=230) or Xeloda plus Bevacizumab (15mg/kg i.v. every 3 weeks) (n=232). Patients were treated until progression of disease, after which individuals in the Xeloda plus Bevacizumab arm were eligible to continue Bevacizumab therapy either alone or in combination with other therapies. No cross over was allowed in this study. The primary endpoint was progression-free survival and secondary endpoints were safety, objective response rate and overall survival. Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9.A phase III study of Bevacizumab (AVF2119g) in combination with chemotherapy was conducted.1 Four hundred and sixty-two women were randomised to either Xeloda (capecitabine) alone (2,500mg/m2 orally daily for 2 weeks of every 3-week cycle) (n=230) or Xeloda plus Bevacizumab (15mg/kg i.v. every 3 weeks) (n=232). Patients were treated until progression of disease, after which individuals in the Xeloda plus Bevacizumab arm were eligible to continue Bevacizumab therapy either alone or in combination with other therapies. No cross over was allowed in this study. The primary endpoint was progression-free survival and secondary endpoints were safety, objective response rate and overall survival. Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9.

    18. Phase III trial of Bevacizumab and chemotherapy in relapsed/refractory MBC (AVF2119g) Inclusion criteria prior anthracycline and taxane treatment one or two prior chemotherapy regimens for MBC or relapse within 12 months of completing anthracycline- and taxane-containing adjuvant therapy ECOG PS 0 or 1 Exclusion criteria antitumour therapy within 21 days anticoagulation therapy CNS metastases (head CT or MRI required) Patients recruited to this trial had been previously treated with one or two chemotherapy regimens for MBC or relapsed within 12 months of completing anthracycline- and taxane-based regimens.1 An ECOG PS of ?1 was also required. Patients were not eligible for this study if they had antitumour therapy within 21 days of the start of the trial, anticoagulation therapy and evidence of CNS metastases. Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9.Patients recruited to this trial had been previously treated with one or two chemotherapy regimens for MBC or relapsed within 12 months of completing anthracycline- and taxane-based regimens.1 An ECOG PS of ?1 was also required. Patients were not eligible for this study if they had antitumour therapy within 21 days of the start of the trial, anticoagulation therapy and evidence of CNS metastases. Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9.

    19. Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): patient characteristics The demographic and baseline data for patients are presented in this slide. Patients in both arms of this study were similar with respect to age, ECOG status, number of previous chemotherapies and the presence of visceral disease.1 The median age was 52 years and around 50% of the patients had an ECOG PS of 0. Due to their role and significance as prognostic indicators in breast cancer, HER2 and ER status in these patients were also determined. The percentage of patients positive for HER2 was slightly higher in the Xeloda plus Bevacizumab arm and there were fewer ER+ patients in the Xeloda plus Bevacizumab arm (41.8%) compared with the Xeloda-alone arm (51.7%); neither of these factors is favourable to the Bevacizumab arm. It can be seen from the table that this patient population was heavily pretreated: approximately 40% of patients in each arm were receiving study treatment in the third-line or greater. Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9.The demographic and baseline data for patients are presented in this slide. Patients in both arms of this study were similar with respect to age, ECOG status, number of previous chemotherapies and the presence of visceral disease.1 The median age was 52 years and around 50% of the patients had an ECOG PS of 0. Due to their role and significance as prognostic indicators in breast cancer, HER2 and ER status in these patients were also determined. The percentage of patients positive for HER2 was slightly higher in the Xeloda plus Bevacizumab arm and there were fewer ER+ patients in the Xeloda plus Bevacizumab arm (41.8%) compared with the Xeloda-alone arm (51.7%); neither of these factors is favourable to the Bevacizumab arm. It can be seen from the table that this patient population was heavily pretreated: approximately 40% of patients in each arm were receiving study treatment in the third-line or greater. Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9.

    20. Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): progression-free survival The Kaplan-Meier curve shows there was no significant difference in progression-free survival between the two arms.1 The proportion of progression-free patients at 6 months was 33.8% for the Xeloda alone arm and 33.0% for the Xeloda plus Bevacizumab arm. Median progression-free survival was 4.17 and 4.86 months, respectively (HR=0.98, p=0.857). Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9. The Kaplan-Meier curve shows there was no significant difference in progression-free survival between the two arms.1 The proportion of progression-free patients at 6 months was 33.8% for the Xeloda alone arm and 33.0% for the Xeloda plus Bevacizumab arm. Median progression-free survival was 4.17 and 4.86 months, respectively (HR=0.98, p=0.857). Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9.

    21. Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): duration of survival The Kaplan-Meier curve shows overall survival data for the Xeloda-alone arm (14.5 months) compared with the Xeloda plus Bevacizumab arm (15.1 months).1 There was no significant difference between the two arms. Overall, 62% of patients were alive at the time of analysis. Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9.The Kaplan-Meier curve shows overall survival data for the Xeloda-alone arm (14.5 months) compared with the Xeloda plus Bevacizumab arm (15.1 months).1 There was no significant difference between the two arms. Overall, 62% of patients were alive at the time of analysis. Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9.

    22. Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): efficacy summary This slide summarises the efficacy data for this trial. Although the addition of Bevacizumab to Xeloda did not improve progression-free survival, there was an absolute increase of ~11% in overall response rate compared with Xeloda alone (19.8% vs 9.1%, p=0.001 as assessed by an IRF).1 The magnitude of the difference for overall response rate between the two arms was comparable when assessed by the IRF and the investigators. Similarly to progression-free survival, the overall survival for both arms was comparable. Data from this trial show that Bevacizumab has antitumour activity, but this did not translate into an improvement in either progression-free survival or overall survival in this population. This could be related to the decreasing influence of VEGF later in MBC.2 Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9. Relf M, LeJeune S, Scott PA, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 1997;57:963–9.This slide summarises the efficacy data for this trial. Although the addition of Bevacizumab to Xeloda did not improve progression-free survival, there was an absolute increase of ~11% in overall response rate compared with Xeloda alone (19.8% vs 9.1%, p=0.001 as assessed by an IRF).1 The magnitude of the difference for overall response rate between the two arms was comparable when assessed by the IRF and the investigators. Similarly to progression-free survival, the overall survival for both arms was comparable. Data from this trial show that Bevacizumab has antitumour activity, but this did not translate into an improvement in either progression-free survival or overall survival in this population. This could be related to the decreasing influence of VEGF later in MBC.2 Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9. Relf M, LeJeune S, Scott PA, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 1997;57:963–9.

    23. Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): grade 3/4 adverse events Grade 3/4 adverse events seen in this trial were consistent with those reported in other trials of Bevacizumab. Increases in the incidence of hypertension, proteinuria and epistaxis were seen in the Bevacizumab arm, with hypertension being the most common side effect (17.9% [Bevacizumab plus Xeloda] vs 0.5% [Xeloda alone]).1 The addition of Bevacizumab to Xeloda did not increase any chemotherapy-associated side effects (e.g. hand-foot syndrome).2 These data indicate that Bevacizumab has a non-overlapping toxicity profile and does not increase side effects associated with Xeloda. Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9. Blum JL, Jones SE, Buzdar AU, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999;17:485–93.Grade 3/4 adverse events seen in this trial were consistent with those reported in other trials of Bevacizumab. Increases in the incidence of hypertension, proteinuria and epistaxis were seen in the Bevacizumab arm, with hypertension being the most common side effect (17.9% [Bevacizumab plus Xeloda] vs 0.5% [Xeloda alone]).1 The addition of Bevacizumab to Xeloda did not increase any chemotherapy-associated side effects (e.g. hand-foot syndrome).2 These data indicate that Bevacizumab has a non-overlapping toxicity profile and does not increase side effects associated with Xeloda. Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9. Blum JL, Jones SE, Buzdar AU, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999;17:485–93.

    24. Phase III trial of Bevacizumab in first-line MBC (E2100) This trial focuses on a less heavily pretreated population than AVF2119g Primary endpoint: progression-free survival (PFS) Other endpoints: overall response rate, overall survival, quality of life, correlative studies E2100 is an ongoing open-label, phase III trial in which Bevacizumab is being evaluated in combination with weekly paclitaxel as first-line therapy for MBC.1 Patients recruited to this trial are less heavily pretreated than patients in AVF2119g. A total of 722 patients have been randomised to one of two arms: paclitaxel 90mg/m2 alone every week for 3 weeks followed by 1 week without treatment or paclitaxel plus Bevacizumab 10mg/kg every 2 weeks. No cross over is permitted in this trial. Objectives are to compare progression-free survival (PFS), overall response rate and overall survival (OS) between the arms. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3). E2100 is an ongoing open-label, phase III trial in which Bevacizumab is being evaluated in combination with weekly paclitaxel as first-line therapy for MBC.1 Patients recruited to this trial are less heavily pretreated than patients in AVF2119g. A total of 722 patients have been randomised to one of two arms: paclitaxel 90mg/m2 alone every week for 3 weeks followed by 1 week without treatment or paclitaxel plus Bevacizumab 10mg/kg every 2 weeks. No cross over is permitted in this trial. Objectives are to compare progression-free survival (PFS), overall response rate and overall survival (OS) between the arms. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3).

    25. Phase III trial of Bevacizumab in first-line MBC (E2100): eligibility criteria Locally recurrent or MBC HER2+ only if prior treatment with Herceptin (trastuzumab) or contraindication No prior chemotherapy regimens for MBC adjuvant taxane allowed if disease-free interval >12 months ECOG PS 0 or 1 No antitumour therapy within 21 days No CNS metastases (head CT or MRI required) No significant proteinuria (>500mg/24 hours) No therapeutic anticoagulation To be eligible for this trial patients must have locally or recurrent MBC.1 HER2-positive patients were permitted only if previously treated with Herceptin or if Herceptin was contra-indicated. Additionally, they must not have received prior chemotherapy, although adjuvant taxane was allowed if the disease-free interval was >12 months. Patients must also have had ECOG PS of 0 or 1, and no antitumour therapy within 21 days. Patients with brain metastases, significant proteinuria (>500mg/24 hours) or those taking anticoagulation therapy were not be eligible for this trial. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3). To be eligible for this trial patients must have locally or recurrent MBC.1 HER2-positive patients were permitted only if previously treated with Herceptin or if Herceptin was contra-indicated. Additionally, they must not have received prior chemotherapy, although adjuvant taxane was allowed if the disease-free interval was >12 months. Patients must also have had ECOG PS of 0 or 1, and no antitumour therapy within 21 days. Patients with brain metastases, significant proteinuria (>500mg/24 hours) or those taking anticoagulation therapy were not be eligible for this trial. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3).

    26. Phase III trial of Bevacizumab in first-line MBC (E2100): patient characteristics From December 2001 to March 2004, 715 patients were enrolled onto the study; of which 680 were eligible for analysis.1 339 and 341 patients were analysed for paclitaxel and Bevacizumab plus paclitaxel, respectively. The characteristics of each group were similar with respect to age, disease-free interval ?24 months, metastatic sites ?3, adjuvant chemotherapy, taxane therapy, ER+ and HER2+ status. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3). From December 2001 to March 2004, 715 patients were enrolled onto the study; of which 680 were eligible for analysis.1 339 and 341 patients were analysed for paclitaxel and Bevacizumab plus paclitaxel, respectively. The characteristics of each group were similar with respect to age, disease-free interval ?24 months, metastatic sites ?3, adjuvant chemotherapy, taxane therapy, ER+ and HER2+ status. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3).

    27. Phase III trial of Bevacizumab in first-line MBC (E2100): progression-free survival The Kaplan-Meier curve shown here demonstrates the effect of Bevacizumab plus paclitaxel on PFS.1 A significant increase in median PFS was observed in patients receiving Bevacizumab plus paclitaxel compared with paclitaxel alone (11.4 months vs 6.11 months, respectively). The hazard ratio (HR) for progression was 0.51 (p<0.0001), which corresponds to a two-fold chance of being progression free. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3). The Kaplan-Meier curve shown here demonstrates the effect of Bevacizumab plus paclitaxel on PFS.1 A significant increase in median PFS was observed in patients receiving Bevacizumab plus paclitaxel compared with paclitaxel alone (11.4 months vs 6.11 months, respectively). The hazard ratio (HR) for progression was 0.51 (p<0.0001), which corresponds to a two-fold chance of being progression free. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3).

    28. Phase III trial of Bevacizumab in first-line MBC (E2100): progression-free survival Patients with ER+/PR+, ER-/PR-, prior taxane treatment, aged ?64 years, a disease-free interval (DFI) of >24 months, and <3 tumour sites all have a greater than 50% reduction in the risk of death with Bevacizumab plus paclitaxel treatment.1 Groups which have the lowest reduction in the risk of death include patients with ER+/PR- disease and patients aged ?65 years. Overall there is a two-fold chance of being progression free (HR 0.51; 95% CI 0.43, 0.62). 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3). Patients with ER+/PR+, ER-/PR-, prior taxane treatment, aged ?64 years, a disease-free interval (DFI) of >24 months, and <3 tumour sites all have a greater than 50% reduction in the risk of death with Bevacizumab plus paclitaxel treatment.1 Groups which have the lowest reduction in the risk of death include patients with ER+/PR- disease and patients aged ?65 years. Overall there is a two-fold chance of being progression free (HR 0.51; 95% CI 0.43, 0.62). 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3).

    29. Phase III trial of Bevacizumab in first-line MBC (E2100): overall response rate A significant, more than two-fold increase in overall response rate (complete response plus partial response) was observed in all patients receiving Bevacizumab plus paclitaxel compared with paclitaxel alone (29.9% vs 13.8%, p<0.0001).1 A significant increase in response rate was also seen in patients with measurable disease receiving Bevacizumab plus paclitaxel compared with those receiving paclitaxel alone (37.7% vs 16.0%, p<0.0001). 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3). A significant, more than two-fold increase in overall response rate (complete response plus partial response) was observed in all patients receiving Bevacizumab plus paclitaxel compared with paclitaxel alone (29.9% vs 13.8%, p<0.0001).1 A significant increase in response rate was also seen in patients with measurable disease receiving Bevacizumab plus paclitaxel compared with those receiving paclitaxel alone (37.7% vs 16.0%, p<0.0001). 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3).

    30. Phase III trial of Bevacizumab in first-line MBC (E2100): overall survival The Kaplan-Meier curve shown here demonstrates the effect of Bevacizumab plus paclitaxel on OS.1 An increase in median OS was observed in patients receiving Bevacizumab plus paclitaxel compared with paclitaxel alone. The HR for death was 0.84 (p=0.12). At the time of this interim analysis, overall survival data was immature, only 57% of required events were included. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3). The Kaplan-Meier curve shown here demonstrates the effect of Bevacizumab plus paclitaxel on OS.1 An increase in median OS was observed in patients receiving Bevacizumab plus paclitaxel compared with paclitaxel alone. The HR for death was 0.84 (p=0.12). At the time of this interim analysis, overall survival data was immature, only 57% of required events were included. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3).

    31. Phase III trial of Bevacizumab in first-line MBC (E2100): NCI-CTC grade 3 and 4 toxicities Treatment-related side effects were graded by the NCI-CTC. Increases in the incidence of hypertension, bleeding and proteinuria were seen in the Bevacizumab plus paclitaxel treatment arm.1 Hypertension was the one of the most common side effects, observed in >15% of patients receiving Bevacizumab plus paclitaxel. These Avastin-related side effects are consistent with those observed in other trials of Bevacizumab in both breast cancer and other tumour types. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3). Treatment-related side effects were graded by the NCI-CTC. Increases in the incidence of hypertension, bleeding and proteinuria were seen in the Bevacizumab plus paclitaxel treatment arm.1 Hypertension was the one of the most common side effects, observed in >15% of patients receiving Bevacizumab plus paclitaxel. These Avastin-related side effects are consistent with those observed in other trials of Bevacizumab in both breast cancer and other tumour types. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3).

    32. Phase III trial of first-line Bevacizumab in MBC (E2100): summary Addition of Bevacizumab to paclitaxel significantly increased progression-free survival, the primary endpoint of the trial Addition of Bevacizumab to paclitaxel significantly increased overall response rate in all patients and in patients with measurable disease Overall survival data are preliminary, after only 57% of required events The combination of Bevacizumab and paclitaxel was well tolerated, with no unexpected side effects reported This phase III trial of Bevacizumab in combination with paclitaxel in previously untreated metastatic breast cancer successfully met its primary endpoint of progression-free survival.1 Addition of Bevacizumab to paclitaxel significantly increased PFS from 6.11 to 11.4 months (p<0.0001). This is after 89% of required PFS events, so is unlikely to change in the final analysis. Subgroup analysis revealed that this PFS benefit occurred across all patient subgroups analysed. The addition of Bevacizumab to paclitaxel also significantly increased the response rate. The increase was from 13.8 to 29.9% (p<0.0001) in all patients and from 16.0 to 37.7% (p<0.0001) in patients with measurable disease. At this stage, no significant increase in overall survival can be attributed to Bevacizumab. The analysis shows a slight increase from 25.2 to 28.4 months (p=0.12) when Bevacizumab is added to paclitaxel; however this is after only 57% of required OS events, therefore may be very different once analysis of the required OS events has taken place. The combination of Bevacizumab and paclitaxel was well tolerated. Adverse events were consistent with the usual side effects profiles of the two therapeutic agents. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3). This phase III trial of Bevacizumab in combination with paclitaxel in previously untreated metastatic breast cancer successfully met its primary endpoint of progression-free survival.1 Addition of Bevacizumab to paclitaxel significantly increased PFS from 6.11 to 11.4 months (p<0.0001). This is after 89% of required PFS events, so is unlikely to change in the final analysis. Subgroup analysis revealed that this PFS benefit occurred across all patient subgroups analysed. The addition of Bevacizumab to paclitaxel also significantly increased the response rate. The increase was from 13.8 to 29.9% (p<0.0001) in all patients and from 16.0 to 37.7% (p<0.0001) in patients with measurable disease. At this stage, no significant increase in overall survival can be attributed to Bevacizumab. The analysis shows a slight increase from 25.2 to 28.4 months (p=0.12) when Bevacizumab is added to paclitaxel; however this is after only 57% of required OS events, therefore may be very different once analysis of the required OS events has taken place. The combination of Bevacizumab and paclitaxel was well tolerated. Adverse events were consistent with the usual side effects profiles of the two therapeutic agents. 1. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract 3).

    33. Ongoing and future trials of Bevacizumab in MBC

    34. Planned phase III trial of Bevacizumab plus docetaxel in MBC (AVADO): study design A randomised, double-blind, placebo-controlled, multicentre phase III trial commenced recruitment in late March 2006. A planned total of 705 patients will receive docetaxel at a dose of 100mg/m2 every three weeks with either placebo, Bevacizumab 7.5mg/kg or Bevacizumab 15mg/kg. The primary trial endpoint will be progression-free survival. Secondary endpoints will include overall response rate, duration of response, time to treatment failure, overall survival, safety and quality of life.A randomised, double-blind, placebo-controlled, multicentre phase III trial commenced recruitment in late March 2006. A planned total of 705 patients will receive docetaxel at a dose of 100mg/m2 every three weeks with either placebo, Bevacizumab 7.5mg/kg or Bevacizumab 15mg/kg. The primary trial endpoint will be progression-free survival. Secondary endpoints will include overall response rate, duration of response, time to treatment failure, overall survival, safety and quality of life.

    35. AVADO: key eligibility criteria Chemonaïve locally recurrent or metastatic breast cancer Aged =18 years, female ECOG performance status 0–1 HER2-negative; documented oestrogen/progesterone receptor status Prior adjuvant chemotherapy permitted if relapse =6 months since last dose (=12 months if taxane based) No uncontrolled hypertension To be eligible for enrolment in the AVADO trial, patients must have previously untreated locally recurrent or metastatic breast cancer. Prior adjuvant therapy is permitted if relapse occurred =6 months after the last dose (=12 months if this therapy was taxane based). Female patients aged at least 18 years may enrol, and menopausal status is unimportant. Eligible patients must be HER2 negative, with a documented hormone receptor status. Uncontrolled hypertension was not permitted.To be eligible for enrolment in the AVADO trial, patients must have previously untreated locally recurrent or metastatic breast cancer. Prior adjuvant therapy is permitted if relapse occurred =6 months after the last dose (=12 months if this therapy was taxane based). Female patients aged at least 18 years may enrol, and menopausal status is unimportant. Eligible patients must be HER2 negative, with a documented hormone receptor status. Uncontrolled hypertension was not permitted.

    36. Ongoing trials of Bevacizumab in breast cancer: RIBBON 1 (AVF3694g) Further development of Bevacizumab in breast cancer is planned following the positive results of the US E2100 study. This phase III trial, to be conducted in countries worldwide, will investigate further combinations of Avastin and chemotherapy. The primary trial endpoint is progression-free survival. Investigators assign patients to a chemotherapy regimen, including specified regimens of anthracycline-based combination chemotherapy, taxane (docetaxel or Abraxane™) every 3 weeks, or Xeloda. Patients are then randomised to receive Avastin (15mg/kg every 2 weeks) or placebo (2:1 Avastin:placebo). Upon disease progression, patients may either continue on or cross over to Avastin plus chemotherapy at the investigator’s discretion. Further development of Bevacizumab in breast cancer is planned following the positive results of the US E2100 study. This phase III trial, to be conducted in countries worldwide, will investigate further combinations of Avastin and chemotherapy. The primary trial endpoint is progression-free survival. Investigators assign patients to a chemotherapy regimen, including specified regimens of anthracycline-based combination chemotherapy, taxane (docetaxel or Abraxane™) every 3 weeks, or Xeloda. Patients are then randomised to receive Avastin (15mg/kg every 2 weeks) or placebo (2:1 Avastin:placebo). Upon disease progression, patients may either continue on or cross over to Avastin plus chemotherapy at the investigator’s discretion.

    37. Planned trial of docetaxel and Herceptin with or without Bevacizumab (AVEREL) Primary endpoint: progression-free survival Secondary endpoints: response rate, duration of response, overall survival, safety Start date: Q3 2006 Roche are currently planning a trial of Avastin, docetaxel and Herceptin in patients with previously untreated, HER2-positive metastatic breast cancer. 320 patients will be randomised to receive either docetaxel and Herceptin or docetaxel, Herceptin and Avastin until disease progression. Patients from the control arm will not be permitted to cross over to receive Avastin upon progression. The primary trial endpoint is progression-free survival. Other endpoints include response rate, duration of response, overall survival and safety.Roche are currently planning a trial of Avastin, docetaxel and Herceptin in patients with previously untreated, HER2-positive metastatic breast cancer. 320 patients will be randomised to receive either docetaxel and Herceptin or docetaxel, Herceptin and Avastin until disease progression. Patients from the control arm will not be permitted to cross over to receive Avastin upon progression. The primary trial endpoint is progression-free survival. Other endpoints include response rate, duration of response, overall survival and safety.

    38. Bevacizumab in MBC: summary Bevacizumab monotherapy has activity in patients with MBC Bevacizumab plus paclitaxel significantly prolongs progression-free survival, and significantly improves response rate Ongoing trials are evaluating Bevacizumab with other chemotherapy agents and in other settings, including the adjuvant and neoadjuvant settings Bevacizumab monotherapy has demonstrated activity in patients with pretreated MBC, which has stimulated trials of Bevacizumab in combination with chemotherapy. As in other indications, hypertension and minor bleeding events were the most common side effects seen in patients treated with Bevacizumab monotherapy. Based on the results of the monotherapy trial, a dose intensity of 5mg/kg every week, i.e. 10mg/kg every 2 weeks or 15mg/kg every 3 weeks, was selected for future trials. First-line Bevacizumab /paclitaxel significantly prolonged progression-free survival, and improved response rate in patients with locally recurrent breast cancer or MBC, compared with paclitaxel alone. The efficacy and safety of adding Bevacizumab to chemotherapy for the treatment of MBC is currently being investigated. Phase II data with docetaxel, vinorelbine and erlotinib in pretreated patients are encouraging. The relative decrease in the influence of VEGF on tumour angiogenesis later in disease has stimulated the design of adjuvant and neoadjuvant trials of Bevacizumab breast cancer. Bevacizumab monotherapy has demonstrated activity in patients with pretreated MBC, which has stimulated trials of Bevacizumab in combination with chemotherapy. As in other indications, hypertension and minor bleeding events were the most common side effects seen in patients treated with Bevacizumab monotherapy. Based on the results of the monotherapy trial, a dose intensity of 5mg/kg every week, i.e. 10mg/kg every 2 weeks or 15mg/kg every 3 weeks, was selected for future trials. First-line Bevacizumab /paclitaxel significantly prolonged progression-free survival, and improved response rate in patients with locally recurrent breast cancer or MBC, compared with paclitaxel alone. The efficacy and safety of adding Bevacizumab to chemotherapy for the treatment of MBC is currently being investigated. Phase II data with docetaxel, vinorelbine and erlotinib in pretreated patients are encouraging. The relative decrease in the influence of VEGF on tumour angiogenesis later in disease has stimulated the design of adjuvant and neoadjuvant trials of Bevacizumab breast cancer.

More Related