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Anti-angiogenic therapy: a new approach to the treatment of metastatic breast cancer

Anti-angiogenic therapy: a new approach to the treatment of metastatic breast cancer. Kathy Miller Indiana University School of Medicine, USA. VEGF is a central mediator of angiogenesis, the formation of new blood vessels. Hemangioblast. SMC progenitor. Endothelial progenitors. SMC.

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Anti-angiogenic therapy: a new approach to the treatment of metastatic breast cancer

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  1. Anti-angiogenic therapy:a new approach to the treatmentof metastatic breast cancer Kathy Miller Indiana University School of Medicine, USA

  2. VEGF is a central mediator of angiogenesis, the formation of new blood vessels Hemangioblast SMC progenitor Endothelial progenitors SMC VEGF Artery VEGF Vein Mature vasculature Vasculogenesis Angiogenesis Adapted from Carmeliet P. Nat Med 2003;9:653–60 SMC = smooth muscle cell

  3. Angiogenesis is involved throughout tumor formation, growth and metastasis Premalignant stage Malignant tumor Tumorgrowth Vascularinvasion Dormantmicrometastasis Overtmetastasis (Avascular tumor) (Angiogenicswitch) (Vascularisedtumor) (Tumor cellintravasation) (Seeding indistant organs) (Secondary angiogenesis) Stages at which angiogenesis plays a role in tumor progression Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207–25

  4. VEGF: a candidate for anticancer therapy • Tumors rely on their existing vasculature for survival • VEGF is a powerful survival factor for the immature vessels that comprise tumor microvasculature1 • The abnormal structure and function of tumor vasculature inhibits the action of conventional therapies2 • inhibition of VEGF normalizes existing vasculature3 • Tumors require new vasculature for growth and metastasis4 • VEGF is a potent stimulator of new vessel growth • VEGF has a limited role in healthy adults,5 so anti-VEGF therapy should have minimal physiological effects 1Alon T, et al. Nat Med 1995;1:1024–8 2Netti PA, et al. Proc Natl Acad Sci USA 1999;96:3137–42 3Dvorak HF, et al. Am J Pathol 1995;146:1029–39 4Folkman J, N Engl J Med 1971;285:1182–6; 5Ferrara N, et al. Nat Med 2003;9:669–76

  5. Effects of VEGF inhibition:regression of microvasculature • Reduction in tumor blood flow after 1 day of anti-VEGF therapy • reduction in vessel patency and blood flow in RIP-Tag2 tumor vessels treated for 1 day with anti-VEGF therapy (B) and a vehicle control (A), as shown by lectin screening • over 7 days, this was followed by endothelial cell regression Inai T, et al. Am J Pathol 2004;165:35–52

  6. Effects of VEGF inhibition:modification of existing vasculature • Abnormal vasculature is ‘normalized’ following VEGF inhibition Inai T, et al. Am J Pathol 2004;165:35–52

  7. Effects of VEGF inhibition:inhibition of new vascular development Days after implantation Before implantation 1 6 9 Control Anti-VEGF therapy Neovascularization in a ‘vascular window’ mouse model following implantation of tumor cells and induction of ischaemia Osusky KL, et al. Angiogenesis 2004;7:225–33

  8. RhuMAb VEGF (bevacizumab) • Recombinant humanized monoclonal anti-VEGF antibody developed from murine anti-VEGF MAb A4.6.11 • 93% human, 7% murine • recognises all major isoforms of human VEGF, Kd = 8 x 10–10M. Affinity similar to that of the murine antibody • RhuMAb VEGF binding is restricted to human, non-human primate and rabbit VEGF • terminal half-life 17–21 days 1Presta LG, et al. Cancer Res 1997;57:4593–9 Rhu = recombinant human

  9. Bevacizumab mechanism of action: summary EARLY BENEFIT CONTINUED BENEFIT Regression of existing microvasculature Inhibition of vessel regrowth and neovascularisation Normalization of surviving microvasculature • Bevacizumab may act against tumors in three ways • regression of existing microvasculature • normalization of mature vasculature • inhibition of production of new vasculature

  10. Phase I/II dose-escalation trial of bevacizumab in MBC: study design Bevacizumab 3mg/kg every 2 weeks (n=18) PD Bevacizumab 10mg/kg every 2 weeks (n=41) PD Bevacizumab 20mg/kg every 2 weeks (n=16) PD • Primary endpoint: overall response rate • Bevacizumab administered i.v. every 2 weeks until PD or maximum of 13 treatments • Response assessment on days 70 and 154 • patients with stable disease or better were eligible for extension study Previously treated MBC (n=75) Dosing cohorts PD = progression of disease i.v. = intravenous Cobleigh MA, et al. Semin Oncol 2003;30(5 Suppl. 16):117–24

  11. Phase I/II trial of bevacizumab monotherapy in MBC: efficacy The efficacy data for this trial compare favorably with those for other agents as monotherapy in similar patient populations Cobleigh MA, et al. Semin Oncol 2003;30(5 Suppl. 16):117–24

  12. Phase I/II trial of bevacizumab monotherapy in MBC: summary • Headache with nausea and vomiting occurred in 4 patients at 20mg/kg and was dose limiting • Otherwise bevacizumab was well tolerated, with the now typical events associated with this agent • hypertension (23% of patients) • minor bleeding (epistaxis, 25.3%) • venous thromboembolism (4%) • proteinuria (24%) • A bevacizumab dose of 10mg/kg every 2 weeks produced the best therapeutic ratio in this population of heavily pretreated patients Cobleigh MA, et al. Semin Oncol 2003;30(5 Suppl. 16):117–24

  13. Phase I/II clinical trials of bevacizumab in breast cancer: summary • Bevacizumab has been combined with several other therapeutic agents in phase I/II trials in locally advanced/recurrent or MBC • vinorelbine1 • docetaxel2 • erlotinib3 • trastuzumab4 • letrozole5 • Efficacy and safety data from these trials suggest that these combinations are worthy of further investigation 1Burstein HJ, et al. Breast Cancer Res Treat 2002;76:Abstract 446 2Ramaswamy B, et al. Breast Cancer Res Treat 2003;81:Abstract 224 3Dickler M, et al. J Clin Oncol 2004;22(15 July Suppl.):Abstract 2001 4Pegram M, et al. Breast Cancer Res Treat 2004;88:Abstract 3039 5Traina TA, et al. Breast Cancer Res Treat 2005 94: Abstract 2030

  14. Phase III trial of bevacizumab plus capecitabine in MBC (AVF2119g) Primary endpoint: progression-free survival Secondary endpoints: overall response rate, duration of response, overall survival Treatment administration bevacizumab 15mg/kg i.v. every 3 weeks capecitabine 2,500mg/m2 orally daily for 2 weeks of a 3-week cycle Capecitabine (n=230) PD* Previously treated MBC (n=462) Capecitabine + bevacizumab 15mg/kg every 3 weeks (n=232) PD *No cross over was permitted Miller KD, et al. J Clin Oncol 2005;23:792–9

  15. Phase III MBC trial of bevacizumab and capecitabine: efficacy summary Inv = investigator IRF = independent review facility Miller KD, et al. J Clin Oncol 2005;23:792–9

  16. Phase III MBC trial of bevacizumab and capecitabine: grade 3/4 adverse events *No grade 4 Miller KD, et al. J Clin Oncol 2005;23:792–9

  17. Progression of angiogenic activity in human tumors Breast cancer tumor growth VEGF VEGF bFGF TGF-1 VEGF bFGF TGF-1 PlGF VEGF bFGF TGF-1 PlGF PD-ECGF VEGF bFGF TGF-1 PlGF PD-ECGF Pleiotrophin bFGF = basic fibroblast growth factor TGF-1 = transforming growth factor beta-1 PlGF = placental growth factor PD-ECGF = platelet-derived endothelial cell growth factor Adapted from Relf M, et al. Cancer Res 1997;57:963–9

  18. Phase III MBC trial of bevacizumab and capecitabine: summary • The combination of bevacizumab and capecitabine was well tolerated, with no increase in capecitabine-related toxicities • Addition of bevacizumab to capecitabine produced a significant increase in response rate, but did not result in longer progression-free survival, the primary trial endpoint • As a tumor progresses, the angiogenic pathways involved become more numerous and redundant; the optimal timing for use of bevacizumab is likely to be at an earlier stage

  19. Phase III trial of first-line bevacizumab in MBC (E2100): study design • Stratify: • disease-free interval (DFI) ≤24 months vs >24 months • <3 vs ≥3 metastatic sites • adjuvant chemotherapy yes vs no • estrogen receptor (ER)-positive vs -negative vs status unknown RANDOMIZE Paclitaxel + bevacizumab 28-day cycle: Paclitaxel 90 mg/m2 days 1, 8 and 15 Bevacizumab 10 mg/kg days 1 and 15 Paclitaxel Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)

  20. Phase III trial of first-line bevacizumab in MBC (E2100): key eligibility criteria • Locally recurrent or metastatic breast cancer • HER2+ only if prior treatment with trastuzumab • No prior chemotherapy regimens for MBC • Adjuvant taxane allowed if DFI >12 months • ECOG PS 0 or 1 • No antitumor therapy within 21 days • No CNS metastases (head CT or MR required) • No significant proteinuria (>500 mg/24 hr) • No therapeutic anticoagulation Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)

  21. Phase III trial of first-line bevacizumab in MBC (E2100): statistical design • Primary endpoint: progression-free survival (PFS) • 85% power for a 33% improvement • 6 vs 8 months • One-sided type I error ≈ 2.5% required 650 eligible patients • Final analysis after 546 PFS events • Interim analyses after 270 and 425 events • Asymmetric boundaries to stop early either for demonstrated benefit or for lack of benefit • Safety analyses • Grade 4 hemorrhage or hypertension (1% acceptable) • Grade 3/4 thrombosis or embolism (5% acceptable) Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)

  22. Phase III trial of first-line bevacizumab in MBC (E2100): current analysis • Study activated December 21, 2001 • Closed March 24, 2004 • 680 eligible patients • Most common reasons for ineligibility: Baseline evaluation >4 weeks from entry (11) Hormonal therapy within 3 weeks (10) • Data cut-off September 27, 2005 • 484 events • Progression – 426 • Death without documented progression – 58 Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)

  23. Phase III trial of first-line bevacizumab in MBC (E2100): patient characteristics Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)

  24. Phase III trial of first-line bevacizumab in MBC (E2100): response p<0.0001 p<0.0001 37.7% 16% 262 236 Measurable disease Pac + bev Paclitaxel 40 30 20 10 0 29.9% Overall response rate 13.8% 339 341 All patients Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)

  25. Phase III trial of first-line bevacizumab in MBC (E2100): progression-free survival Pac + bev 11.4 months Paclitaxel 6.11 months 1.0 0.8 0.6 0.4 0.2 0.0 HR = 0.51 (0.43–0.62) Log rank test p<0.0001 PFS probability 0 6 12 18 24 30 Months Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3) 484 events reported

  26. Phase III trial of first-line bevacizumab in MBC (E2100): progression-free survival Group Ratio 95% CI ER+, PR+ 0.39 (0.29, 0.53) ER+, PR- 0.86 (0.52, 1.43) ER–, PR– 0.47 (0.35, 0.63) No adj chemo 0.60 (0.44, 0.82) Non-taxane 0.51 (0.39, 0.67) Taxane 0.38 (0.25, 0.59) Age 27–49 0.45 (0.32, 0.63) Age 50–64 0.44 (0.33, 0.58) Age 65–85 0.79 (0.53, 1.17) DFI 0–24 months 0.57 (0.43, 0.75) DFI >24 months 0.47 (0.37, 0.60) <3 sites 0.48 (0.37, 0.61) ≥3 sites 0.54 (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

  27. Phase III trial of first-line bevacizumab in MBC (E2100): overall survival Pac + bev 28.4 months Paclitaxel 25.2 months 1.0 0.8 0.6 0.4 0.2 0.0 Survival probability HR = 0.84 (0.64–1.05) Log rank test p=0.12 0 6 12 18 24 30 36 Months Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3) 275 events reported

  28. Phase III trial of first-line bevacizumab in MBC (E2100): bevacizumab toxicity NCI-CTC v3.0, worst per patient *p<0.0001; **p=0.02; ***p=0.002 Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)

  29. Phase III trial of first-line bevacizumab in MBC (E2100): other grade 3/4 toxicities NCI-CTC v3.0, worst per patient ↓LVEF = decreased left ventricular ejection fraction *p=0.05 Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)

  30. Phase III trial of first-line bevacizumab in MBC (E2100): FACT-B 110 Pac + bev Paclitaxel 105 FACT-B total 100 95 Baseline 17 weeks 33 weeks 310 252 198 301 220 167 Mean and 95% CI Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)

  31. Phase III trial of first-line bevacizumab in MBC (E2100): FACT-G 85 Pac + bev Paclitaxel FACT-G total 80 75 Baseline 17 weeks 33 weeks 311 254 200 303 223 168 Mean and 95% CI Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)

  32. Phase III trial of first-line bevacizumab in MBC (E2100): ongoing correlative studies • Circulating markers • Serum VCAM-1 • Urine VEGF • Analysis of primary tumor samples • VEGF expression • VEGF polymorphisms Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)

  33. Phase III trial of first-line bevacizumab in MBC (E2100): conclusions and future directions • Addition of bevacizumab to paclitaxel • Significantly prolongs progression-free survival • Increases objective response rate • Longer follow-up required to assess impact on overall survival • Further studies should • Explore the role of bevacizumab in the adjuvant setting • Develop methods to identify patients who are most likely to benefit from VEGF-targeted therapies Miller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)

  34. E2104 Adjuvant Pilot Trial Arm A: ddBAC >BT >B R E G I S T E R Doxorubicin 60 mg/m2 plus Cyclophosphamide 600 mg/m2 Bevacizumab 10 mg/kg every 14 days x 4 Paclitaxel 175 mg/m2Bevacizumab 10 mg/kg every 14 days x 4 Bevacizumab 10 mg/kg every 14 days x 18 Doxorubicin 60 mg/m2 plus Cyclophosphamide 600 mg/m2 every 14 days x 4 Paclitaxel 175 mg/m2Bevacizumab 10 mg/kg every 14 days x 4 Bevacizumab 10 mg/kg every 14 days x 22 Arm B: ddAC >BT >B *Hormone therapy and radiation per standard care

  35. Planned phase III trial of bevacizumab plus docetaxel in MBC (AVADO): study design PD PD PD Docetaxel + placebo Docetaxel + bevacizumab 7.5mg/kg every3 weeks Previously untreated MBC (n=705) Docetaxel + bevacizumab 15mg/kg every3 weeks Docetaxel – 100mg/m2 every three weeks 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 to commence late March 2006

  36. Conclusions • Bevacizumab is the first anti-angiogenic agent with proven clinical benefit in breast cancer • Bevacizumab is well tolerated in patients with breast cancer, with side effects that are easily managed • Combination of bevacizumab with other agents does not increase the frequency or severity of chemotherapy-related toxicities • Bevacizumab significantly improves progression-free survival and response rate in patients with locally advanced or MBC when used first line in combination with paclitaxel

  37. Acknowledgements ECOG Operations Christine Sceppa Pam Cogliano Michelle Parent ECOG Statistical Office Robert Gray Molin Wang Mark Powell CTEP Jeff Abrams Helen Chen Genentech Robert Mass Ginny Langmuir Amy Sing IU Anita Rush-Taylor Robin Zon George Sledge Investigators Patients

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