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PERFIL DE SEGURIDAD DE BEVACIZUMAB EN CÁNCER DE MAMA

Departamento de Oncología Hospital Vall d´Hebron Barcelona. España. PERFIL DE SEGURIDAD DE BEVACIZUMAB EN CÁNCER DE MAMA. Javier Cortés 23-11-2007. BEVACIZUMAB EN CANCER DE MAMA. Introducción

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PERFIL DE SEGURIDAD DE BEVACIZUMAB EN CÁNCER DE MAMA

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  1. Departamento de Oncología Hospital Vall d´Hebron Barcelona. España PERFIL DE SEGURIDAD DE BEVACIZUMAB EN CÁNCER DE MAMA Javier Cortés 23-11-2007

  2. BEVACIZUMAB EN CANCER DE MAMA • Introducción • Toxicidad del bevacizumab en cáncer de mama • Experiencia con bevacizumab en el Hospital Vall d´Hebron • Conclusiones

  3. BEVACIZUMAB EN CANCER DE MAMA • Introducción • Toxicidad del bevacizumab en cáncer de mama • Experiencia con bevacizumab en el Hospital Vall d´Hebron • Conclusiones

  4. Introducción Avastin, the first anti-angiogenic, is approved for first-line use in metastatic breast cancer Avastin Biological Hormonal agents Chemotherapy Radiotherapy Surgery 2007 3000 BC 1500’s 1800’s 1937 1950 1997

  5. Introducción 6.7 13.3 E2100: Avastin provided patients with clinical benefit due to improved progression-free survival 99% increase in median PFS Avastin + paclitaxel (n=368) Paclitaxel (n=354) 100 15 10 5 0 HR=0.48; p<0.0001 13,3 80 Median PFS (months) 60 6,7 Progression-free survival estimate 40 Paclitaxel Avastin +paclitaxel 20 0 0 10 20 30 40 Months PFS = progression-free survival; HR = hazard ratio; Avastin Summary of Product Characteristics (SmPC)

  6. Introducción Avastin breaks through the 12-month progression-free survival barrier Median PFS/TTP DocetaxelChan 1999 6,5 9 months 12 months DoxorubicinChan 1999 5,3 Monotherapy PaclitaxelSeidman 2004 6,0 VinorelbineMuhoz 2006 4,1 Doxorubicin + paclitaxelJassem 2001 8,3 Capecitabine + docetaxelO’Shaughnessy 2002 5,1 Gemcitabine + paclitaxelAlbain 2004 5,2 Combinationchemotherapy Fluorouracil + epirubicinZielinski 2005 9,0 Gemcitabine + vinorelbineMuñoz 2006 6,3 Epirubicin + taxanePacilio 2006 9,0 Anti-angiogenic therapy + chemotherapy Avastin + paclitaxelE2100 2005 13,3 PaclitaxelE2100 2005 6,7 0 2 4 6 8 10 12 14 Months PFS = progression-free survival; TTP = time to progression

  7. Introducción Multiple ongoing phase III trials are exploring the full potential of Avastin in 1st-line mBC Single-agenttaxane therapy Anthracycline-based chemotherapy Taxane-based chemotherapy RIBBON 1 AVADO MO19391 Taxane orcapecitabine RIBBON 1 Avastin AVEREL CALGB 40503 GEICAM 2006-11 Trastuzumab-containingregimens Hormonal therapy

  8. Introducción Avastin phase III studies in the neoadjuvant and adjuvant settings in breast cancer Neoadjuvant Adjuvant Triple-negative Multiple chemotherapy regimens Docetaxel + capecitabine orgemcitabine doxorubicin + cyclophosphamide BEATRICE HER2-negative NSABP B-40 Doxorubicin Cyclophosphamide Paclitaxel Avastin E5103 E2104 BETH HER2-positive Adjuvantchemotherapy + trastuzumab

  9. BEVACIZUMAB EN CANCER DE MAMA • Introducción • Toxicidad del bevacizumab en cáncer de mama • Experiencia con bevacizumab en el Hospital Vall d´Hebron • Conclusiones

  10. Toxicidad en CMM Evolución de los estudios clinicos del Avastin cáncer de mama metastasico Preclinicos Fase I Fase I/II Eficacia y seleccion de dosis en cáncer de mama Eficacia en modelos xenograficos de cáncer de mama Factibilidad de empleo clinica humana

  11. Toxicidad en CMM Estudios Fase I/II Escalada de dosis de Avastin agente único en Cáncer de Mama metastasico (MBC) Avastin 3mg/kg every 2 weeks (n=18) PD Previously treated MBC (n=75) Avastin 10mg/kgevery 2 weeks (n=41) Dosing cohorts PD Avastin 20mg/kgevery 2 weeks (n=16) PD • Primary endpoint: overall response rate • Avastin 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 PD = progression of disease Cobleigh MA, et al. Semin Oncol 2003

  12. Toxicidad en CMM Estudio Fase I/II: toxicidad grado 3/4 Adverse event 3mg/kg(n=18)n (%) 10mg/kg(n=41)n (%) 20mg/kg(n=16)n (%) Hypertension 4 (22) 7 (17) 3 (19) Proteinuria 1 (6) 1 (2) 1 (6) Thrombosis 0 2 (5) 0 Bleeding 0 0 0 CHF/cardiomyopathy 0 1 (2) 1 (6) Headache 0 0 3 (19) CHF = congestive heart failure Cobleigh MA, et al. Semin Oncol 2003

  13. Toxicidad en CMM In a phase I/II study, Avastin was generally well tolerated • Hypertension of all grades was reported in 23% of all patients • grade 3/4 in 18.7% • Proteinuria of all grades occurred in 24% of patients • grade 3/4 in 4.0% • Dose-limiting migraine-like headaches were reported in four patients at the 20mg/kg dose • not reported at the lower doses • developed 1–3 days after receiving Avastin • responded to treatment with dexamethasone • not caused by hypertension or the development of brain metastases Cobleigh MA, et al. Semin Oncol 2003

  14. Toxicidad en CMM Evolución de los estudios clinicos del Avastin cáncer de mama metastasico Preclinicos Fase I Fase I/II Fase III Eficacia y seleccion de dosis en cáncer de mama Eficacia en modelos xenograficos de cáncer de mama Factibilidad de empleo clinica humana Pretratadas: Avastin + capecitabina

  15. Toxicidad en CMM Estudio Fase III de Avastin + Capecitabina en Cáncer de Mama Capecitabine (n=230) PD* Previously treated MBC (n=462) Capecitabine + Avastin 15mg/kg every 3 weeks (n=232) PD • Primary endpoint: progression-free survival • Secondary endpoints: overall response rate, duration of response, overall survival • Treatment administration • Avastin 15mg/kg i.v. every 3 weeks • Capecitabine 2,500mg/m2 orally daily for 2 weeks of a 3-week cycle *No cross over was permitted Miller KD, et al. JCO 2005;

  16. Toxicidad en CMM Toxicidad en CMM Grade 3/4 Toxicities Capecitabine(n=332) Avastin + capecitabine(n=350) Grade 3 Grade 4 Grade 3 Grade 4 Hypertension (%) 0.5 0 17.9 0 Thromboembolic events (%) 2.3 2.8 3.9 3 Bleeding (%) 0.5 0 0.4 0 Proteinuria (%) 0 0 0.9 0 Hand and foot (%) 24.2 0 27.5 0 Headache (%) 0.5 0 1.7 0 Asthenia (%) 4.7 1.9 6.1 1.3 CHF/Cardiomyopathy (%) 0 1 2.6 0.4 CHF = congestive heart failure Miller, et al. JCO 2005

  17. Toxicidad en CMM Toxicidad en CMM Evolución de los estudios clinicos del Avastin cáncer de mama metastasico Preclinicos Fase I Fase I/II Fase III 1ª línea Avastin + paclitaxel Eficacia y seleccion de dosis en cáncer de mama Eficacia en modelos xenograficos de cáncer de mama Factibilidad de empleo clinica humana Pretratadas: Avastin + capecitabina

  18. Toxicidad en CMM Phase III MBC trial of first-line Avastin and Paclitaxel (E 2100) Paclitaxel (n=354) Treat to disease progression* Previously untreated locally recurrent or MBC (n=722) *No cross over permitted Paclitaxel + Bevacizumab 10mg/kg every2 weeks (n=368) Treat to disease progression Paclitaxel: 90mg/m2 qw for 3 weeks of a 4-week cycle • Primary endpoint: progression-free survival • Other endpoints: overall response rate, overall survival, quality of life Miller, et al. SABCS 2005

  19. Toxicidad en CMM The addition of Avastin was generally well tolerated with no unexpected safety findings Selected grade 3/4 adverse events* Paclitaxel(n=346) Avastin + Paclitaxel(n=362) Grade 3 Grade 4 Grade 3 Grade 4 Sensory neuropathy (%) 15.9 0.6 22.9 0.6 Fatigue (%) 4.6 0.3 8.8 0.3 Neutropenia (%) 1.2 0.3 2.8 0.3 Hypertension (%) 1.4 0 15.2 0.3 Arterial thromboembolic events† # (%) 0 0 1.1 1.4 Venous thromboembolic events (%) 1.4 1.7 2.5 0.3 Bleeding (%) 0 0 1.4 0.6 Proteinuria (%) 0 0 1.7 1.4 Left ventricular dysfunction† (%) 0 0 1.1 0.3 *Includes NCI AdEERS mandatory collection in the Avastin + paclitaxel arm only which does not allow a valid comparison between the two arms†Events were double counted where applicable #One additional patient died from myocardial infarction in the Avastin + paclitaxel arm Roche data on file submitted to regulatory authority in 2006 Miller, et al. SABCS 2005

  20. Toxicidad en CMM Avastin’s safety profile in combination with chemotherapy • Less frequently reported events • congestive heart failure (CHF)/cardiomyopathy • arterial thromboembolism (ATE) • venous thromboembolism (VTE) • wound-healing complications • gastrointestinal perforations • Commonly reported events • hypertension • proteinuria • bleeding/haemorrhage • Typical chemotherapy-associated side effects • neuropathy • neutropenia • fatigue

  21. Toxicidad en CMM CHF in Avastin-treated mBC patients • E2100 study: CHF reported in 1.4% of Avastin-treated patients • only patients with anthracycline pre-treatment developed CHF • AVF2119g: CHF reported in 3.5% of Avastin-treated patients • all patients had received previous anthracyclines • Most patients showed improvement of symptoms or left ventricularfunction following appropriate medical therapy • Possible risk factors • prior anthracycline exposure and/or prior radiation to the chest wall

  22. Toxicidad en CMM ATEs in Avastin-treated mBC patients • E2100: grade 3/4 ATEs reported in 2.5% of Avastin-treated patients • one grade 5 ATE was reported in the Avastin arm • AVF2119g: grade 3/4 ATEs reported in 0.4% of Avastin-treated patients, compared with 0.5% of patients in the control arm • Risk factors* • a prior history (stroke/heart attack) - ~5 fold • age > 65 years - ~3 fold • hypertension - ~2 fold • Recommendation • Avastin should be permanently discontinued in patients who develop ATEs ATEs= Arterial thromboembolic events

  23. Toxicidad en CMM Across all indications, it is unclear whether VTEs are due to cancer, chemotherapy, Avastin or other factors • E2100: grade 3/4 VTEs reported in 2.8% of Avastin-treated patients compared with 3.1% of patients in the control arm • AVF2119g: grade 3/4 VTEs were reported in 6.1% of Avastin- treated patients and 3.7% of patients in the control arm • Trial practice • in clinical trials, for grade 3/4 venous thrombosis interrupt Avastin for 3 weeks; continue Avastin once patient has stable anticoagulation parameters • Avastin should be discontinued in patients with symptomatic pulmonary embolism

  24. Toxicidad en CMM Wound-healing complications in Avastin-treated mBC patients • E2100: grade 3/4 wound infections (listed under the category wound-healing complications) were reported in 1.1% of Avastin-treated patients • AVF2119g: no wound-healing complications were reported • Recommendation • Avastin should • not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed • be withheld until the wound is fully healed • be withheld for elective surgery

  25. Toxicidad en CMM GI perforations in Avastin-treated mBC patients • E2100: grade 4 GI perforation was identified in 0.6% of Avastin-treated patients • associated with diverticulitis (n=1) and tumour erosion of the bowel (n=1) • 1 additional case of grade 4 rectal/anal fistula was reported • AVF2119g: no GI perforation reported • Recommendation • Avastin therapy should be permanently discontinued in patients who develop GI perforation

  26. Mechanisms by which anti-VEGF agents may cause hypertension Toxicidad en CMM • Anti-VEGF therapy • decreases endogenous nitric oxide, which causes hypertension • reduces vascular density leading to increased systemic vascular resistance • changes permeability resulting in increased intravascular volume

  27. Hypertension: NCI-CTCAE v3.0 definitions Toxicidad en CMM Hypertension (increase by >20mmHg diastolic or to >150/100 if previously normal) Grade 1: asymptomatic, transient increase; no treatment required Grade 2: recurrent, persistent or symptomatic increase; monotherapy may be required Grade 3: requiring more than one drug or more Intensive therapy than previously Grade 4: life-threatening (e.g. hypertensive crisis)

  28. Toxicidad en CMM Hypertension in phase III trials of Avastin in mBC Paclitaxel (n=346) Paclitaxel + Avastin* (n=362) Capecitabine (n=215) Capecitabine + Avastin† (n=229) 40 30 20 10 0 Percentage 23,5 17,9 15,2 2,4 1,4 0,3 0,5 0 NR 0 0 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 *Avastin given every 2 weeks; †Avastin given every 3 weeks

  29. Toxicidad en CMM Blood pressure should be managed actively • Pre-existing hypertension should be appropriately controlled before starting Avastin • During treatment, blood pressure should be monitored regularly • Hypertension can generally be well-controlled with oral antihypertensive medications • In patients with severe (grade 3) hypertension • temporary interruption of Avastin is recommended until adequate control is achieved • if hypertension cannot be controlled, Avastin should be permanently discontinued • Discontinuation of Avastin is rarely required • Avastin should be discontinued in patients who develop hypertensive crisis or hypertensive encephalopathy

  30. Mechanism by which anti-VEGF agents may cause proteinuria Toxicidad en CMM • VEGF maintains the glomerular and peritubular capillary network in the kidney • anti-VEGF therapy may affect the glomerular and peritubular capillary network

  31. Proteinuria: NCI-CTCAE v3.0 definitions Toxicidad en CMM Dipstick Urine protein level Grade 1 transient 1+ 0.15–1.0g/24 hours Grade 2 persistent moderate 2+ - 3+ >1.0–3.5g/24 hours Grade 3 severe 4+ >3.5g/24 hours Grade 4 nephrotic syndrome As above but with hypoalbuminaemia and peripheral oedema

  32. Proteinuria in phase III trials of Avastin in mBC Toxicidad en CMM 40 30 20 10 0 Paclitaxel (n=346) Paclitaxel + Avastin* (n=362) Capecitabine (n=215) Capecitabine + Avastin† (n=229) 22,3 Percentage 7,4 1,7 1,4 0,9 0 0 0 0 NR 0 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 *Avastin given every 3 weeks; †Avastin given every 2 weeks Most reported proteinuria was grade 1 Patients with a history of hypertension may be at increased risk of proteinuria when treated with Avastin

  33. Monitoring for proteinuria is recommended before and during Avastin therapy Toxicidad en CMM • Proteinuria was not associated with renal dysfunction • Dipstick urinalysis is recommended prior to and during therapy • 24-hour urine collection should be used if dipstick reading is 2+ or greater (3+ on second and subsequent occurrences) • Trial practice • interrupt Avastin if urine protein levels (UPL) 2g/24h, restart once UPL <1g/24h • currently planned adjuvant trials allow Avastin treatment up to UPL 3.5g/24h • Discontinuation of Avastin is rarely required • Avastin should be discontinued in patients who develop nephrotic syndrome

  34. Mechanisms of anti-VEGF agents may cause bleeding Toxicidad en CMM • Antagonising VEGF, the major endothelial mitogen, may • decrease the renewal capacity of the endothelial cell in response to trauma • cause endothelial dysfunction and defects in the internal vascular lining

  35. Bleeding/haemorrhage: NCI-CTCAE v3.0 definitions Toxicidad en CMM Grade 1: mild, intervention not indicated Grade 2: symptomatic, medical intervention indicated Grade 3: transfusion indicated Grade 4: life-threatening consequences, major urgent intervention indicated

  36. The most common bleeding event for Avastin is mild (grade 1) nose bleed Toxicidad en CMM Bleeding events in phase III Avastin mBC trials 40 30 20 10 0 Capecitabine (n=215) Capecitabine + Avastin† (n=229) Paclitaxel (n=346) Paclitaxel + Avastin* (n=362) 28,8 Percentage 11,2 1,1 0,3 0,4 0,5 0 0 0 0 NR All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 *Avastin given every 2 weeks; †Avastin given every 3 weeks

  37. The majority of bleeding events were minor – severe events are infrequently reported Toxicidad en CMM • The majority of bleeding events were minor and mucocutaneous and did not require medical intervention • The risk of CNS haemorrhage in patients with CNS metastases receiving Avastin has not been fully evaluated • these patients were excluded from clinical trials • Avastin should be permanently discontinued in patients who experience grade 3/4 bleeding

  38. Impact of Avastin on typical chemotherapy-associated side effects Toxicidad en CMM Grade 3/4 adverse event (%) Capecitabine(n=215) Avastin + Capecitabine(n=229) Paclitaxel* (n=346) Avastin + paclitaxel* (n=362) Neutropenia 2.8† 2.6† 1.5 3.1 Fatigue 8.6 9.1 4.9 9.1 Diarrhoea 10.7 11.8 1.4 3.6 Neuropathy 0.9 0 16.5 23.5 †Leukopenia • Since patients were receiving concomitant chemotherapy, it is not clear to what extent Avastin contributed to these events • in E2100, the substantial improvement in PFS was associated with longer treatment duration of paclitaxel in the Avastin arm • likely accounts for the increase in neuropathy, fatigue and other chemotherapy related events • in contrast, in the Avastin + capecitabine trial, treatment duration did not differ, and no meaningful differences in chemotherapy-related side effects were observed

  39. Toxicidad en CMM 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 11 3 0 0 Hypertension Pericardial effusion 0 0 1 0 11 2 1 0 Proteinuria 0 1 1 0 Thrombosis Haemorrhage 3 0 0 0 10 0 1 0 Epistaxis 15 3 4 0 Vomiting Neurosensory 26 1 1 0 Data from 55 evaluable patients Burstein HJ, et al. SABCS 2002

  40. Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): Avastin-related toxicity • Bevacizumab plus docetaxel • (n=27) • Grade 2 • Grade 3 • Grade 4 • Hypertension, n (%) 4 (14.8) 1 (3.7) 0 • Proteinuria, n (%) 11 (40.7) 0 0 • Epistaxis, n (%) 1 (3.7) 0 0 • Thromboembolic events, n (%) 0 0 2 (7.4) Ramaswamy B, et al. Clin Cancer Res 2006

  41. 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

  42. BEVACIZUMAB EN CANCER DE MAMA • Introducción • Toxicidad del bevacizumab en cáncer de mama • Experiencia con bevacizumab en el Hospital Vall d´Hebron • Conclusiones

  43. Vall d´Hebron Valoración retrospectiva de los pacientes tratados en el Hospital Vall d´Hebron con Avastin N (28 pts) (%) Característica basales de las pacientes Mujeres (Med edad: 47 años) 28 (100) Edad, límites 30 a 71 Receptores hormonales + 17 (61) HER2 + 5 (18) Triple negativas 8 (29) Tratamiento hormonal (RH +) 17 (100% de RH+) Trastuzumab previo (HER2 +) 5 (100% de hER 2 +)

  44. Vall d´Hebron Valoración retrospectiva de los pacientes tratados en el Hospital Vall d´Hebron con Avastin N (28 pts) (%) Característica basales de las pacientes Más de 4 QT previas 10 (36) 3-4 líneas previas 11 (39) Taxanos y antraciclinas previos 28 (100)

  45. Vall d´Hebron Valoración retrospectiva de los pacientes tratados en el Hospital Vall d´Hebron con bevacizumab Esquemas de tratamiento N (%) RP NC P Capecitabina + bevacizumab 2 (7) 0 2 0 Docetaxel + bevacizumab 1 (4) 0 0 1 Paclitaxel + bevacizumab 20 (71) 9 3 6 2 pts no valorados Paclitaxel + bevacizumab + trastuzumab 4 (14) 2 1 1 CDDP + Gemcitabina + bevacizumab 1 (4) 1 0 0

  46. Vall d´Hebron Toxicidad • Bevacizumab + quimioterapia (n=28) • Grade 2 • Grade 3 • Grade 4 • HTA (%) • 2 (7) • 0 • 0 • Proteinuria (%) • 1 (4) • 0 • 0 • Fatigue (%) • 3 (12) • 0 • 0 • Neurotoxicidad (%) • 1 (4) • 3 (12) • 0 • Edemas (%) • 1 (4) • 0 • 0 • Hemorragias (%) • 0 • 0 • 1 (4)* • ATEs(%) • 0 • 0 • 0 • VTEs (%) • 0 • 1 (4)** • 1 (4%) *Hemorragias digestivas secundarias a hepatopatía metastásica. Tras TIPS: RC **TEP

  47. BEVACIZUMAB EN CANCER DE MAMA • Introducción • Toxicidad del bevacizumab en cáncer de mama • Experiencia con bevacizumab en el Hospital Vall d´Hebron • Conclusiones

  48. Conclusiones Bevacizumab se tolera bien en cáncer de mama metastásico • El perfil de seguridad del bevacizumab es aceptable y consistente en todos los estudios. • Los pacientes deben monitorizarse para la HTA y la proteinuria. • Los efectos secundarios no característicos del bevacizumab pueden deberse al incremento del tiempo libre de progresión y, por lo tanto, a una mayor exposición a la quimioterapia. • En nuestra experiencia, el bevacizumab, además de aportar actividad, se maneja con relativa facilidad.

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