APPLICAZIONI CLINICHE DEI FARMACI ANTIANGIOGENETICI Giampaolo Tortora Cattedra di Oncologia Medica...

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

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