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APPLICAZIONI CLINICHE DEI FARMACI
ANTIANGIOGENETICI
Giampaolo Tortora
Cattedra di Oncologia Medica
UOC e Laboratori di Terapia molecolare dei tumori
Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica
Università di Napoli Federico II
Strategies to inhibit VEGF signalling
Ferrara & Kerbel Nature 438: 967–974, 2005.
VEGF and VEGFR inhibitors under investigationVEGF and VEGFR inhibitors under investigation
Hicklin and Ellis, JCO 2005
BevacizumabBevacizumab
VEGF isoforms recognised by hypervariable murine
antibody fragment
Human IgG-1
93% human, 7% murine
Recognizes all isoforms of VEGF (Kd = 8x10–10
M)
Terminal half-life 17–21 days
No DLT as single agent
inhibits all functions of the VEGF ligand:• on vascular endothelial cells• on non-endothelial cells (dendritic cells,
monocytes)
Conseguenze della iperespressione e Conseguenze della iperespressione e ipersecrezione di VEGFipersecrezione di VEGF
Migrazione e proliferazione endoteliale
Distorsione dell’architettura vascolare
Aumento della permeabilità vascolare e della PIF
Modulazione della risposta immune
Riducela pressione del liquido interstiziale
e la densità microvascolare
Incrementail rilascio intratumorale dei farmaci
Modificato da Jain RK. Nat Med 2001; 7:987–9Willett CG. et al. Nat Med 2004; 10:145–7Tong R. et al. Cancer Res 2004; 64:3731–6$
NormalizzataNormale Anormale
Bevacizumab
Bevacizumab: effetti sulla vascolarizzazione tumorale
Willett CG, et al. Nat Med 2004;10:145–7
Evidenza diretta degli effetti di Bevacizumab sulla vascolatura tumorale umana: studio fase I
Avastin 5 mg/kgAvastin 5 mg/kg +
5-FU i.c. + Radioterapia
Patienti con ca rettale primario e non metastatico
(n=6)
Chirurgia
2 settimane 3 volte ogni 2 settimane
Sangue/urine TAC funzionale/PET Endoscopia Biopsia tumorale
perfusione sanguigna tumorale (40–44%, p<0.05) volume sanguigno tumorale (16–39%, p<0.05) densità microvascolare (25–59%, p<0.05) pressione interstiziale (da 15.0 ± 2.0 a 4.0 ± 2.2 mm Hg, p<0.01)
Ca colorettale 1a linea (NEJM 2004) Ca colorettale 2a linea (ASCO 2005)
Ca polmonare 1a linea (ASCO 2005) Ca mammario 1a linea (ASCO 2005)
Avastin aumenta la sopravvivenza in diversi tumori
Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)
E3200: progression-free survival
50% Incremento netto
Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)
E3200: overall survival
>11.000
Planned trials in adjuvant colon cancer
Studio n Tumore Stadio Trattamento
BO17920 (Avant)
3450 Colon II (alto rischio) III
FOLFOX4 vs FOLFOX4 + Avastin vs XELOX + Avastin
NSABP C -08 2700 Colon II (alto rischio) III
FOLFOX6 ± Avastin
E5205 3125 Colon II (alto rischio
FOLFOX6 ± Avastin
QUAS AR -2 1900 Colon III Xeloda ± Avastin
Binding del VEGF ai recettoriBinding del VEGF ai recettori
VEGFR-1/Flt-1 VEGFR-2/KDR
VEGFR-3/Flt-4
LYMPHANGIOGENESIS
ANGIOGENESIS
EGFRgefitinib (IRESSA™)erlotinib (Tarceva™)ZD6474AEE788
VEGFR ZD6474vatalanibAZD2171SU11248AEE788sorafenib
Bcr-Ablimatinib (Glivec™)
c-Kit AZD2171imatinibSU11248
PDGFRimatinibSU11248sorafenib
Key receptor tyrosine kinases and selective inhibitors
AZD2171
LY317615 (Enzastaurin)
CEP7055
GW786024
Agents affecting all VEGFRs
AZD2171
AZD2171 is an oral therapy with potential application in multiple tumor types
AZD2171 has activity against VEGF receptors 1, 2 & 3- No activity on EGFR
Phase I clinical studies in refractory solid tumors underway
Manageable toxicity in early phase I
AZD2171
VEGFR3 (Flt-4)
VEGFR1(Flt-1)
VEGFR2 (KDR)
Receptor
VEGF
DAG
IP3/Ca2+
PKC-
COX2
mRNA
• Tumor invasion• Angiogenesis
ENZASTAURIN
Activation
GSK3
AKT
Caspase 9
Apoptosis
Protein translationIL-6
IL-8
PKC- and the Proposed Action of Enzastaurin on Angiogenesis and Apoptosis
Acyclic indolylmaleimide competing with the ATP binding site
Combination of 2 selective Combination of 2 selective inhibitors approachinhibitors approach
Combination of 2 selective Combination of 2 selective inhibitors approachinhibitors approach
EGFR
VEGF
Endothelial cells
Cancer cells
Angiogenesis
Cell Proliferation
Tortora et al. 2004
ErlotinibCetuximab, etc
Bevacizumab etc.
Combined blockade of EGFR and VEGF
RCC (59 pts.): 47% Responses (including MR) and 39% SD; 76% 1 year Overall survival (Hainsworth et al., ASCO 2004; Spigel et al., ASCO 2005).
NSCLC: 85% Disease control (including 20% PR); 52% 1 year Overall survival and 7 mo. PFS (Sandler et al., ASCO 2005).
Breast Cancer: 33% Disease control (including PR) in heavily pretreated patients. Early data (Rugo et al., ASCO 2005).
3 Phase II studies of Bevacizumab and Erlotinib in Patients 3 Phase II studies of Bevacizumab and Erlotinib in Patients with Renal Carcinoma (RCC), Breast cancer and NSCLCwith Renal Carcinoma (RCC), Breast cancer and NSCLC
Hainsworth JD, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 4502Sandler AB, et al. J Clin Oncol 2004;22(July 15 Suppl.) Abstract 2000
Rugo H et al., J Clin Oncol 2004;22(July 15 Suppl.)
Indirect Comparison of the Efficacy Results in BOND-1 and BOND-2
BOND-1BOND-1C225C225
BOND-2BOND-2C225 + C225 +
BEVBEVBOND-1BOND-1
C225 + CPTC225 + CPT
BOND-2BOND-2C225 + CPT C225 + CPT
+ BEV+ BEV
No. patients 111 35 218 39
Prev oxal (%) 64 89 62 87
RR (%) 11 23 23 38
TTP (months) 1.5 6.9 4.1 8.5
Median OS (months)
6.9 -- 8.6 --
Modified from Saltz et al., ASCO 2005
Multitargeted agents Multitargeted agents approachapproach
Multitargeted agents Multitargeted agents approachapproach
ZD6474 (VEGF-R2 + EGFR + RET)
AE778 (VEGF-R2 + EGFR)
SU11248 (VEGFRs + PDGF-Rs+ c-Kit)
Sorafenib (VEGFRs + PDGF-Rs + MAPK + Erk + c-Kit)
PTK787 (VEGFRs + PDGF-Rs)
Multitargeted agents affecting VEGF-Rs and EGFR, PDGF-Rs etc.
EGFR
VEGF
Endothelial cells
Cancer cells
TGF
KDR
Angiogenesis
Cell Proliferation
ZD6474ZD6474
Tortora & Ciardiello 2003Carlomagno et al, Cancer Res. 2002Ciardiello et al., Clin Cancer Res. 2003Ciardiello et al., Clin Cancer Res. 2005Damiano et al., Clin Cancer Res 2005
ZD6474 inhibits KDR and EGFR
RET
1.00
0.75
0.50
0.25
0
Progression-free survival (days)
0 50 100 150 200 250 300 350 400
Pro
bab
ilit
y o
f re
ma
inin
g p
rog
ress
ion
-fre
e Median progression-free survival:
Placebo + docetaxel = 12.0 weeksZD6474 100 mg + docetaxel = 18.7 weeks ZD6474 300 mg + docetaxel = 17.0 weeks
DATI ANCORA IMMATURI PER OS
Objective responses
Placebo+D = 12%ZD 100 +D = 26%ZD 300 +D = 18%
Randomized Phase II trial of ZD6474 plus docetaxel in patients Randomized Phase II trial of ZD6474 plus docetaxel in patients with NSCLC. Primary endpoint : PFSwith NSCLC. Primary endpoint : PFS
Targeting VEGF and EGFR: AEE788Phase I trial
•dose-dependent inhibition of EGFR signalling in skin and tumour observed
•most common adverse events were diarrhea (67%), fatigue/asthenia (51%), anorexia (49%), rash (43%), nausea (42%) and vomiting (28%)
•DLT (diarrhea) dose levels defined at 500 and 550 mg
2Baselga J, et al. J Clin Oncol 2005;23(June 1 Suppl.):198s (Abstract 3028)3Martinelli E, et al. J Clin Oncol 2005;23(June 1 Suppl.):201s (Abstract 3039)
The endothelial cell-pericyte network of signals
Nature Review Cancer
• Pericytes protect endothelial cells from apoptosis and overexpress PDGF-R• PDGF-R is overexpressed in many tumors• PDGF-R and VEGF cooperate
SU11248 is an Oral, Multi-targeted, RTK Inhibitor With Selective Activity against PDGFR, VEGFR, KIT, and FLT3
Split Kinase Domain RTKs
FLT1FLK1/KDRFLT4
FGFR1FGFR2FGFR3FGFR4
PDGFR
CSF1RKITFLT3/FLK2
PDGFR
Potent Activity vs. Class III, Class V RTKs:Biochemical Ki values <10nMCellular IC50 values 5-50nM
Weak Activity vs. Class IV RTKs:Biochemical Ki values 1000 nMCellular IC50 values 6000 nM
Highly selective for Class III, Class V RTKs, versus other tyrosine kinases and serine/threonine kinases evaluated
Class III Class V Class IV
• Direct anti-tumor activity via inhibition of target RTKs
- VEGFR in Melanoma, PDGFR in Glioma, KIT in GIST, FLT3 in AML
• Indirect inhibition of tumor growth via inhibition of angiogenesis
- VEGFR and PDGFR
SU11248 is active in different tumors
- Activity observed in leukemia
- Active in sarcomas
- Active in GIST (including those resistant to imatinib)
*Escudier et al. J Clin Oncol. 1999;17:2039-2043; †Yang et al. N Engl J Med. 2003;349:427-434;‡Motzer et al. J Clin Oncol. 2004; 22:454-463.
No. ORR, % TTP, mo
SU11248 63 33 8.3
Interleukin-2* 65 5 NA
Interferon-* 48 2 NA
Avastin (high dose)† 39 10 4.8
Placebo† 40 0 2.5
Multiple agents in
phase II trials‡137 3 2.9
SU11248 in mRCCActivity Versus Other Second-Line Agents
Phase II study of SU11248 in MBC
Miller et al., ASCO 2005
6 weeks cycle (50 mg/day for 28 d. and 2 weeks rest).
64 pts enrolled (80% HER-2 negative/unknown). The majority with multiple visceral sites. Heavily pretreated (several previous CT regimens, also in adjuvant setting).
Asthenia and diarrhea major grade 2 toxicities. 40% grade 3 neutropenia.
51 evaluable for responses. PR: 7 (14%); SD > 6 mo: 1 (2%). Study is ongoing.
No obvious correlation between response and ER or HER-2 status.
• Complete inhibitor of the VEGF receptor tyrosine kinases VEGFR1(FLT-1), VEGFR2 (KDR) and VEGFR3 (FLT-4). It also inhibits PDGF-R.
• Well tolerated up to 1250 mg/day (phase III dose, used up to 15 mo)
• Rapidly absorbed (1 to 2.5 hours), T1/2: 3-6 hrs
• Renal metabolism
PTK787/ZK 222584PTK787/ZK 222584(Vatalanib)(Vatalanib)
Formula: C24H21N4Cl MW = 346.82
PTK787/ZK 222584PTK787/ZK 222584(Vatalanib)(Vatalanib)
Formula: C24H21N4Cl MW = 346.82
PTK/ZK: A multi-VEGF receptor tyrosine kinase inhibitor
ONGOING AND PLANNED PHASE IIICONFIRM STUDIES
Over 700 pts treated up to date
in combination with CT
Chemonaive CRCFOLFOX + PTK
CPT-11/FU resistant CRCFOLFOX + PTK
BAY 43-9006 (Sorafenib)
Bisaryl urea, multiple targeted inhibitor.
Inhibits B-Raf-1 kinase (including the mutated form) with IC50 of 6 nM, MAPK, ERK.
Inhibits also endothelial cells and VEGFR2, VEGFR-3, FLT-3, PDGFR, c-Kit.
Raf is probably important in endothelial cells and double targeting (Raf and VEGFR-2) may be critical.
Cl
F3C NH NH
OO
N
NHCH3
O