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Bevacizumab: Antiangiogenic therapy for breast cancer: where do we stand? Fortunato Ciardiello Division of Medical Oncology, Department of Clinical and Experimental Medicine, Second University of Naples, Italy VEGF as a key mediator of angiogenesis TGFa IL-6 bFGF Antibodies Hypoxia COX-2 NO Oncogenes IGF-1 Upstream activators of VEGF synthesis PDGF H2O2 Release VEGF Binding and activation of VEGF receptor VEGF Endothelial cell Tyrosine kinase inhibitors Survival Migration Proliferation ANGIOGENESIS Downstream signaling pathways 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 1Brown LF, et al. Hum Pathol 1995;26:86–91 B, et al. J Clin Oncol 2000;18:1423–31 3Gasparini G, et al. Cancer J Sci Am 1999;5:101–11 4Borgstrom P, et al. Anticancer Res 1999;19:4203–14 2Linderholm VEGF = vascular endothelial growth factor Phase II trials of Bevacizumab plus chemotherapy in MBC Phase II trial of Bevacizumab plus vinorelbine in refractory breast cancer (AVF2324s) Refractory breast cancer Bevacizumab (10mg/kg every 2 weeks) + vinorelbine PD Two-stage design • 19 patients recruited. 6 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 ANC = absolute neutrophil count Burstein HJ, et al. Breast Cancer Res Treat 2002;79: S115 (Abstract 446) Phase II trial of Bevacizumab plus vinorelbine in refractory breast cancer (AVF2324s): efficacy Number of patients (%) Complete response 1 (2) Partial response 16 (29) Stable disease 25 (45) Progressive disease 12 (21) Data from 54 evaluable patients Burstein HJ, et al. Breast Cancer Res Treat 2002;79: S115 (Abstract 446) Phase II trial of Bevacizumab plus vinorelbine in refractory breast cancer (AVF2324s): safety Grade (number of patients) 1 2 3 4 Haematologic 10 5 27 15 Non-haematologic Hypertension Pericardial effusion Proteinuria Thrombosis Haemorrhage Epistaxis Vomiting Neurosensory 11 0 11 0 3 10 15 26 3 0 2 1 0 0 3 1 0 1 1 1 0 1 4 1 0 0 0 0 0 0 0 0 Data from 55 evaluable patients Burstein HJ, et al. Breast Cancer Res Treat 2002;79: S115 (Abstract 446) 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 Burstein HJ, et al. Breast Cancer Res Treat 2002;79: S115 (Abstract 446) Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): study design Metastatic breast cancer (n=27) Bevacizumab (10mg/kg every 2 weeks) + docetaxel X 6 Bevacizumab alone PD Primary endpoints: response rate, overall survival and toxicity Secondary endpoints: correlative studies • baseline plasma VEGF • soluble activated endothelial cell markers and adhesion molecules • microvessel density by CD31 immunohistochemistry • tumour and endothelial cell apoptosis by TUNEL assay Docetaxel 35mg/m2 weekly for 3 weeks of a 4-week cycle Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9 Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): eligibility criteria • 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 Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9 Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): efficacy summary Response n (%) Complete response 0 (0) Partial response 14 (52) Stable disease 9 (33) Overall response 14 (52) Withdrawn due to toxicity prior to 2 cycles 2 (7) Median progression-free survival (months) [95% CI] 7.5 [6.2–8.3] Median duration of response (months) [95% CI] 6.0 [4.6–6.5] Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9 Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): Avastin-related toxicity Bevacizumab plus docetaxel (n=27) Grade 2 Hypertension, n (%) Proteinuria, n (%) Epistaxis, n (%) Thromboembolic events, n (%) 4 (14.8) Grade 3 Grade 4 1 (3.7) 0 11 (40.7) 0 0 1 (3.7) 0 0 0 0 2 (7.4) Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9 Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): other toxicities Bevacizumab plus docetaxel (n=27) Grade 2 Grade 3 Grade 4 Dyspnoea, n (%) 18 (66.7) 1 (3.7) 0 Eye tearing, n (%) 15 (55.6) 0 0 Fatigue, n (%) 19 (70.3) 4 (14.8) 0 Leukopenia, n (%) 3 (11.1) 6 (22.2) 1 (3.7) Neutropenia, n (%) 2 (7.4) 4 (14.8) 1 (3.7) Infection, n (%) 4 (14.8) 0 1 (3.7) Neuropathy, n (%) 3 (11.1) 2 (7.4) 0 Stomatitis, n (%) 9 (33.3) 2 (7.4) 0 Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9 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 Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9 Ongoing phase II trial of Bevacizumab plus docetaxel in MBC (AVF3110s) 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 Chan D, et al. J Clin Oncol 2006;24(20 June suppl.):605s (Abstract 13047) Phase III trials of Bevacizumab plus chemotherapy in MBC Phase III trial of Bevacizumab ® plus Xeloda in MBC (AVF2119g) Xeloda (n=230) PD* Previously treated MBC (n=462) Xeloda + Avastin 15mg/kg every 3 weeks (n=232) PD 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 *No cross over was permitted Miller KD, et al. J Clin Oncol 2005;23:792–9 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 taxanecontaining adjuvant therapy • ECOG PS 0 or 1 Exclusion criteria • antitumour therapy within 21 days • anticoagulation therapy • CNS metastases (head CT or MRI required) Miller KD, et al. J Clin Oncol 2005;23:792–9 Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): patient characteristics Xeloda (n=230) Xeloda + Avastin (n=232) 52 (30–77) 51 (29–78) Visceral disease (%) 80.0 77.6 ER+ (%) 51.7 41.8 HER2+ (%) 20.4 26.3 Treatment setting First-line (%) Second-line (%) Third-line + (%) 16.1 42.6 41.3 15.1 46.1 38.8 Median age, years (range) Miller KD, et al. J Clin Oncol 2005;23:792–9 Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): progression-free survival Proportion progression-free 1.0 0.8 Xeloda alone (n=230) (median progression-free survival = 4.17 months) 0.6 Xeloda + Bevacizumab (n=232) (median progression-free survival = 4.86 months) HR=0.98; p=0.857 0.4 0.2 0 4.17 0 1 2 3 4.86 4 5 6 7 8 9 10 11 12 13 14 15 16 Progression-free survival (months)* *Determined by independent review facility where available Miller KD, et al. J Clin Oncol 2005;23:792–9 Proportion surviving Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): duration of survival 1.0 Xeloda alone (n=230) (median survival = 14.5 months) 0.8 Xeloda + Bevacizumab (n=232) (median survival = 15.1 months) 0.6 0.4 0.2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Duration of survival (months) Miller KD, et al. J Clin Oncol 2005;23:792–9 Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): efficacy summary Xeloda alone (n=230) Overall response rate (%) Inv IRF Progression-free survival (months) Overall survival (months) 19.1 9.1 4.17 14.5 Xeloda + Avastin (n=232) 30.2 19.8 4.86 15.1 p-value 0.006 0.001 0.857 – Inv = determined by investigators IRF = determined by independent review facility Miller KD, et al. J Clin Oncol 2005;23:792–9 Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): grade 3/4 adverse events Incidence (%) Adverse event Xeloda (n=215) Xeloda + Avastin (n=229) Hypertension* 0.5 17.9 Proteinuria* 0 0.9 Thrombosis 3.7 5.6 24.2 27.5 Bleeding* 0.5 0.4 CHF/cardiomyopathy 1 3 Nausea* 1.9 2.6 Hand-foot syndrome* *No grade 4 Miller KD, et al. J Clin Oncol 2005;23:792–9 Phase III trial of Bevacizumab in first-line MBC (E2100) Previously untreated MBC (n=722) Paclitaxel (n=354) PD* Paclitaxel + Bevacizumab 10mg/kg every 2 weeks (n=368) PD 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 *No cross over will be permitted Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3) 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 HER = human epidermal growth factor receptor CT = computed tomography MRI = magnetic resonance imaging Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3) Phase III trial of Bevacizumab in first-line MBC (E2100): patient characteristics 55 (27-85) Paclitaxel + Bevacizumab (n=341) 56 (29-84) <24 months (%) 42 42 >3 sites (%) 43 43 Adjuvant chemotherapy (%) 64 65 Taxane (%) 18 18 ER+ (%) 64 59 HER2+ (%) 4 5 Paclitaxel (n=339) Median age, range (years) Disease-free interval ER = oestrogen receptor Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3) Phase III trial of Bevacizumab in first-line MBC (E2100): progression-free survival Bevacizumab + paclitaxel: 11.4 months Paclitaxel: 6.11 months Progression-free survival proportion 1.0 0.8 HR = 0.51 (0.43-0.62) 0.6 Log rank test p<0.0001 0.4 0.2 6.11 0.0 0 HR = hazard ratio 484 events reported (89% of required events) 11.4 6 12 Months 18 24 30 Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3) Phase III trial of Bevacizumab in first-line MBC (E2100): progression-free survival Group Ratio 95% CI ER+, PR+ ER+, PRER–, PR– 0.39 0.86 0.47 (0.29, 0.53) (0.52, 1.43) (0.35, 0.63) No adj chemo Non-taxane Taxane 0.60 0.51 0.38 (0.44, 0.82) (0.39, 0.67) (0.25, 0.59) Age 27–49 Age 50–64 Age 65–85 0.45 0.44 0.79 (0.32, 0.63) (0.33, 0.58) (0.53, 1.17) DFI 0–24 months DFI >24 months 0.57 0.47 (0.43, 0.75) (0.37, 0.60) <3 sites ≥3 sites 0.48 0.54 (0.37, 0.61) (0.41, 0.71) Overall 0.51 (0.43, 0.62) Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3) 0.0 0.5 1.0 1.5 Phase III trial of Bevacizumab in first-line MBC (E2100): overall response rate Paclitaxel p<0.0001 Bevacizumab + paclitaxel p<0.0001 Overall response rate (%) 40 29.9 30 20 37.7 16.0 13.8 10 339 341 262 236 0 All patients Measurable disease Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3) Phase III trial of Bevacizumab in first-line MBC (E2100): overall survival Bevacizumab + paclitaxel: 28.4 months Overall survival proportion 1.0 Paclitaxel: 25.2 months 0.8 0.6 0.4 HR = 0.84 (0.64, 1.05) Log rank test: p=0.12 0.2 0.0 0 6 275 events reported (57% of required events) 12 18 24 30 36 Months Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3) Phase III trial of Bevacizumab in first-line MBC (E2100): NCI-CTC grade 3 and 4 toxicities Paclitaxel + Bevacizumab (n=350) Paclitaxel (n=332) Grade 3 Grade 4 Grade 3 Grade 4 Hypertension* (%) 2 0 15 <1 Thromboembolic events (%) 2 2 2 0 Bleeding† (%) 0 0 2 <1 Proteinuria§ (%) 0 0 1 1 NCI-CTC v3.0, worst per patient *p<0.0001; †p=0.02; §p=0.002 NCI-CTC = National Cancer Institute common toxicity criteria Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3) 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 Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3) Ongoing and future trials of Bevacizumab in MBC Planned phase III trial of Bevacizumab plus docetaxel in MBC (AVADO): study design Docetaxel + placebo PD Previously untreated MBC (n=705) Docetaxel + Bevacizumab 7.5mg/kg every 3 weeks PD Docetaxel – 100mg/m2 every three weeks Docetaxel + Bevacizumab 15mg/kg every 3 weeks PD Randomised, double-blind, placebo-controlled, multicentre, phase III trial Primary endpoint: progression-free survival Secondary endpoints: overall response rate, duration of response, time to treatment failure, overall survival, safety, quality of life Recruitment commenced March 2006 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 Ongoing trials of Bevacizumab in breast cancer: RIBBON 1 (AVF3694g) Randomise 2:1 2 Previously untreated MBC (n=950) 1 Taxane-based or anthracycline-based or Xeloda + Avastin 15mg/kg every 3 weeks PD* Taxane-based or anthracycline-based or Xeloda + placebo PD* Primary endpoint: progression-free survival Chemotherapy regimen is determined by investigator prior to randomisation Trial already open in USA and will be opening in other countries during 2006 *Continuation or cross over to Avastin after confirmation of PD is allowed at the discretion of the investigator Planned trial of docetaxel and Herceptin with or without Bevacizumab (AVEREL) Docetaxel + Herceptin PD* Docetaxel + Herceptin + Avastin 15mg/kg every 3 weeks PD Previously untreated HER2+ MBC (n=320) Primary endpoint: progression-free survival Secondary endpoints: response rate, duration of response, overall survival, safety Start date: Q3 2006 * No cross-over permitted 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