B Knebelmann

Service de Néphrologie et Inserm U845

Hôpital Necker,

Renal and Vascular Effects ofanti-vegf therapies

AN 2010

The target

1989: Ferrara et al, BBRC

Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells

VEGF

1989: Plouët et al, EMBO J

Isolation and characterization of a mewly identified endothelial cell mitogen produced by AtT-20 cells

Tumor angiogenesis: therapeutic implications.

1971: Folkman, NEJM

The man behind the concept

Tumor Cells produce angiogenic factors including VEGF(Vascular Endothelial Growth Factor)

VEGFVEGF

Robert J, L’angiogenèse, JL Eurotext, 2009

Kerbel S, NEJM, 2008

VEGFA 121VEGFA 145VEGFA 165VEGFA 189VEGFA 206

Tumor Cells produce angiogenic factors including VEGFs

5

small molecules,

tyrosine kinase (activity) inhibitors= TKI

X_mab

Monoclonal Ab

Therapeutic approaches to block vegf signaling

X_ib

Ferrara, N. & Kerbel, R.S. (2005). Angiogenesis as a therapeutic target. Nature, 438, 967-74.

Therapeutic approaches to block vegf signaling

Sunitinib

& Sorafenib Axitinib

Ferrara, N. & Kerbel, R.S. (2005). Angiogenesis as a therapeutic target. Nature, 438, 967-74.

Therapeutic approaches to block vegf signaling

Bevacizumab

Sunitinib

& Sorafenib Axitinib

Ferrara, N. & Kerbel, R.S. (2005). Angiogenesis as a therapeutic target. Nature, 438, 967-74.

Therapeutic approaches to block vegf signaling

BevacizumabVEGF trap

Sunitinib

& Sorafenib Axitinib

Ferrara, N. & Kerbel, R.S. (2005). Angiogenesis as a therapeutic target. Nature, 438, 967-74.

Therapeutic approaches to block vegf signaling

BevacizumabVEGF trap

Sunitinib

& Sorafenib Axitinib

²²

Nucleus

HIF‐2ERK

MEK

RAF

RAS

SORAFENIB

Apoptosis

MitochondriaMitochondria

EGF/HGFPDGFVEGFProliferationSurvival

EGF/HGF

Autocrine loop

AngiogenesisDifferentiationProliferationMigrationTubule formation

Nucleus

Apoptosis ERK

MEK

RAF

RAS

SORAFENIB

Tumour cell

Endothelial cell or pericyte

PDGF‐β

VEGF

PDGFR‐β

VEGFR‐2

Paracrine stimulation

TKI may have multiple TK targets and act directly on tumor cells

Cancers for which anti-vegf therapies are approved

• Kidney– Sunitinib, sorafenib, Bevacizumab– ( everolimus/temsirolimus)

• Colon, breast, liver, lung, Neuroendocrine tumors, GIST,…….

• # 120 000 novel cases /year

Anti-vegf induced High Blood Pressure

• One of the most frequent adverse event• Frequency depends on study design and

definitions used

Bevacizumab induced HBP:meta‐analysis of published series

RR: 3,0 (2,5-7,5 mg/kg/admin.), IC95%: 2,2-4,2

RR: 7,5 (10-15 mg/kg/admin.), IC95%: 4,2-13,4

RCP bevacizumab: 20-30% HBP (all grades)

Dose effect relationship: dose-intensity ? (2.5 mg/kg/wk vs. 5 mg/kg/wk)

Zhu et al, AJKD, 2007

TKI induced HBP

Sunitinib (Sutent r)

HBP : incidence : 20-26%RR 3.9 (2.6-5.9)

Sorafenib (Nexevar r)

HBP : incidence : 16-33%RR 6.1 (2.4-15.3)

Halimi et al Nephrol & Thérap, 2008

Limits of the NCI - CTCAE (v3.0) grading

Toxicité 0 1 2 3 4

HTAPA

normale

Asymptomatique,transitoire (< 24 h),augmentation > 20 mmHg pour la diastolique ou >150/100 mmHgpour un hypertendu antérieur

Récidivante persistante (> 24 h) ou symptomatique avec une augmentation > 20 mmHg de la diastolique ou > 150/100 mmHgpour un hypertendu antérieur avec nécessité d’introduire une monothérapie

Nécessité d’un traitement

médicamenteux supplémentaire

Mise en jeu du

pronostic vital

ProtéinurieNulle ou

< 0,15 g/24 h

1+ ou 0,15-1 g/24 h

2+ à 3+ ou1-3,5 g/24 h

4+ ou > 3,5 g/24 h

Syndrome néphrotiqu

e-> underestimates HBP frequency

# JNC7 or ESH classification

Ex: 130/85 145/100 = grade 0

Incidence depending on BP measurement

Veronese (JCO 2006)SorafenibMonitoring x 3 / week70% increase SBP > 10 mm Hg

Maitland (CCR 2009)SorafenibMAPA first 24hMedian increase in SBP : + 11 mm Hg

Azizi (NEJM 2007)Sunitinibteletransmitted home BPIncrease SBP > 10 mm Hg in 100% patients

Azizi M et al. N Engl J Med 2008W0 W4 W6 W10 W12

60

80

100

120

140

W0 W4 W6 W10 W1260

80

100

120

140

Offi

ce B

P (m

mH

g)Normotensive patients with advanced RCC receiving sunitinib 50

mg/dy have constant, early, reversible increase in BP

∆ HBP increase (mmHg)

W1 +13.6±8.4 / +10.9±4.7W4 +22.2±6.4 / +17.2±6.0W10 +27.9±9.2 /+20.1±5.3

teletransmitted home BPteletransmitted home BPteletransmitted home BP

Time to onset of HBP

Risk factors for anti-vegf induced HBP?Mir (JNCI 2007):

Cardiovascular RF

Scappaticci (JNCI 2008):CVRF, age > 65 yrs

Choi (ASCO 2008):previous HBP,

afro-americans > caucasiansOthers: mRCC with nephrectomy?

Additive toxicity of vegf antagonists

Phase 1 bevacizumab + sunitinib:

Feldman (JCO 2009):– n = 25 (mRCC)– 92% HBP (all grades)

Rini (CCR 2009):– n = 38 (6 mRCC)– 53% HBP grade 3

Phases 1 sorafenib + bevacizumab (ASCO 2009):increased incidence of HBP

Is HBP a marker of tumor response?

Dahlberg et al, JCO 2009Dahlberg et al, JCO 2009

HBP > 150/100 or + 20 mm Hg (DBP) after D21

Mir et al, Ann Oncol, 2009; The oncologist, in press

Scartozzi (bevacizumab): Scartozzi (bevacizumab):

56 dy, grade 2 NCI, n = 3956 dy, grade 2 NCI, n = 39

Maitland (sorafenib): Maitland (sorafenib):

24h, + 10 mm Hg, n = 5424h, + 10 mm Hg, n = 54

Mir/CERIA (bevacizumab): Mir/CERIA (bevacizumab):

42 dys, grade 1 ESH, n = 11942 dys, grade 1 ESH, n = 119

Early HBP may be an even better predictor of tumor response

HBP and tumor response

Dose escalation untill patients develop HBP?

Evaluate relationships betweenPK-PD / HBP / antitumor activity

How do we treat antivegf induced HBP?

• No controlled study• 5 main therapeutic classes can be used• Favor ACEI or ARBs if PU >1g/gr• Be aware of drug interactions:

– Vérapamil, Diltiazem = CYP3A4 inhibitors– Increase Sunitinib et Sorafenib activity

• Beta blokers:– ECG : PR / QT

• Target BP: ??

Halimi et al, Neph & Ther, 2008

Severe HBP leading to TRT interruption

• malignant HBP

• Severe refractory HBP

• PRES (Glusker P, NEJM, 2006; 354:980)

• HBP + TMA

• HTA + cardiac Insufficancy– direct cardiac toxicity (Chu TF,Lancet 2007; 370:2011 )

– QT long (Strevel EL, J Clin Oncol 2007; 25: 3362)

HBP: Mecanisms involved

• No classical blood marker correlates with sorafenib induced HBP:– Plasma Vegf – Rénine/Aldosterone– Catécholamines,– Endothéline 1,

• No correlation with Pulse wave Velocity

Veronese ML et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol. 2006

²

Ca2+

PI3

C‐Scr

VEGFVEGFR‐2

NO

eNOS

L‐arginine

L‐citrulline

PLC‐γ

PKC

MAPK

PGI2

PI3K

AKT cPLA2

Membrane phospholipids

Arachidonic acid

PGH2

PGI2synthase

COX‐1

Vegf induces NO and PGI2 production

Tsurumi et al, Nature Med, 1997 Horowitz et al, Arterioscler Thromb Vasc Biol, 1997

VEGF induces vasodilatation And NO dependent BP decrease

Role of salt retention in vegf inhibitors induced HBP

Facemire CS, Hypertension, 2009

Role of salt retention in vegf inhibitors induced HBP

Facemire CS, Hypertension, 2009 Granger J, Hypertension, 2009

VEGF antagonists

Endothelial dysfunction

NO Prostacyclin

Endothelin

Hypertension

Capillary rarefaction

Total Peripheral resistance Decrease Renal Pressure Natriuresis

Protéinurie Nulle ou < 0,15 g/24 h

1+ ou 0,15-1 g/24 h

2+ à 3+ ou1- 3,5 g /24 h

4+ ou > 3,5 g/24 h

Syndrome néphrotiqu

e

Toxicité 0 1 2 3 4

Anti-vegf induced Proteinuria: classification NCT - CTC (v3.0)

Anti‐vegf induced Proteinuria

• Which drugs?– Probably all!

Zhu X, Am J Kidney Dis 2007;49:186

Anti‐vegf induced Proteinuria

• Which drugs?– Probably all!

Zhu X, Am J Kidney Dis 2007;49:186

•Which Frequency ? –Less studied/ different methods used–21‐64% with Bevacizumab–RRI: 1.2 à 4…

Anti‐vegf induced Proteinuria

• Which drugs?– Probably all!

Zhu X, Am J Kidney Dis 2007;49:186

•Which Frequency ? –Less studied/ different methods used–21‐64% with Bevacizumab–RRI: 1.2 à 4…

•Dose relationship seems to exist– dose dépendent (bevacizumab)

– Low Dose : RR 1.4 (1.1‐1.7) – High Dose : RR 2.2 (1.6‐2.9)

• Time to onset of Proteinuria?– variable – From a few days to several months

• How abundant is Proteinuria?– « mild » most often:

– grade 1/2: but…. up to 3, 5g/24h!

– Grade 3 (>3,5 g/dy ) in 1 à 7%

Anti‐vegf induced Proteinuria

Zhu X, Am J Kidney Dis 2007;49:186

• Follow up– Generally Réversible

Anti‐vegf induced Proteinuria

• Follow up– Generally Réversible

Anti‐vegf induced Proteinuria

•Predisposing Factors?–age?–HBP or kidney disease–Not Nephrectomie (RCC)

• Follow up– Generally Réversible

Anti‐vegf induced Proteinuria

•Predisposing Factors?–age?–HBP or kidney disease–Not Nephrectomie (RCC)

•Consequences–Often treatment can be pursued–Dose reduction can be necessary if proteinuria > X g/dy ?– Balance risk/benefit- Start RAS blocker

Une « faible » protéinurie n’est pas toujours « bénigne »….

• Mme B, 46 ans,• Hydradénome malin métastasé du cuir chevelu en

échec de radio + chimiothérapie conventionnelle• Sunitinib 37.5 mg/j : 4 Semaines/6• So: PA 125/72 mmHg; BU négative• S3 PA 152/92 ‐> Amlodipine 10mg/j• S15: OMI‐> Diltiazem puis + HTZ• S16: PU 1+ 1.1g/24h• Réponse tumorale + , mais dissociée• S18: avis néphrologique

Case

• HTA modérée

• PU modérée # 1 à 1.5 g/j

• Pas d’ IR (créat 75 umol/L)

• Pas de stigmates hématologiques de MAT– Plaquettes, Hb, Haptoglobine, LDH: Nx

*Endothéliose

mésangiolyse Doubles contours

VegfNl ME

Bollée et al, NDT, 2008

Renal Biopsy : TMA !

IFqq dépots

Evolution

• Arret du sunitinib

• Mise sous ARA2 (Irbesartan 300)

• Normalisation PA 126/74 mmHg

• Disparition PU (0.40g/j)

• Reprise du sunitinib apres 4S pendant 3 m

• Maintien – PA <130/80, PU 0,50g/j, créat Nle

• Echappement et DC après qq mois

TMA under anti‐vegf therapy

• HBP+/‐ PU +/‐ HU +/‐ ARF

• +/‐Tpenia, anemia

• Rare (# 15 cases) (underestimation?)

• Bevacizumab/ vegf trap > sunitinib

• Is TRT interruption mandatory (?)

• RAS inhibitors and strict BP control (<130/80mmHg)

• Could be associated with a better tumor response

VEGF highlyExpressed by Podocytes (Dvorak, 1997)

VEGF‐R1/2 expressed in vivoBy glomerular ECPeritubular capillaries

+/‐ podocytes, mesangial cells, tubular cells

Eremina, Curr Opin Neph, 2004

Glomerular Toxicity of anti-vegf

Eremina JCI, 2003

Genetic evidence:Podocyte specific Inactivation of one VEGF allele disrupts glomerular cp fenestrated endothelium /induces proteinuria and RF

anti-VEGF antibody in mice

ProteinuriaGlomerular Endothéliosis

NO foot process effacement

Kalluri R, JBC, 2003; JASN 2006

Dose‐dependent proteinuria and loss of capillaries fenestrations after 7 day‐administration of a RTKI

Albustix ≥ 2+ (% )

Kamba T. et al. Br J Cancer 2007;96:1788

Preeclampsia:a « natural model » of anti‐vegf induced renal and vascular effects

Identification of sFlt1, a soluble VEGF Receptor inplacentas and serum from PE patients

A Karumanchi

Hypertension

Glomerular

endothelial damage

sFlt1

VEGF antagonists

Endothelial dysfunction

NO Prostacyclin

Endothelin

Hypertension

Capillary rarefaction

Total Peripheral resistance Decrease Renal Pressure Natriuresis

glomerular endothelial cells

Endothelial dysfonction/TMA

Proteinuria Renal Failure

Genetic Predisposition to anti‐vegf induced renal toxicity?

• Past preeclampsia?• Endothelial dysfunction/TMA

– Vegf polymorphisms?vegf A, ratios isoforms, ,Vegf B, Vegf R1, Vegf R2, sFlt1….

– Role of vegf C?– Other angiogenic and antiangiogenic factors

bFGF, TGF-b/endoglin, angiopoétines, Tie1/2…

– Complement(Facteurs H, I, MCP, C3,)

• Podocyte Gene Polymorphisms? néphrine, podocine (R229Q), CD2AP, TRPC6, alpha actinin4

…

Acknowledgements

Service de Néphrologie Necker

G BolleeA Servais

Service d’AnatomopathologieLH Noël

Service d’Oncologie Cochin

B BillemontO MirB BlacherF Godvasseur

Beth Israel Deaconess Medical CenterHarvard Medical School

Ananth Karumanchi