Renal and Vascular Effects of anti-vegf...
Transcript of Renal and Vascular Effects of anti-vegf...
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