NUEVAS DIANAS MOLECULARES Y PERSPECTIVAS FUTURAS DEL TRATAMIENTO DEL CANCER DE MAMA

RAFAEL TRUJILLO VILCHEZ Servicio de Oncologa Mdica Hospital Clnico Universitario de Malaga

1960 (MONOQT)

1980 (POLIQT)

2000 (BIO)

2007

???

CITOTXICOS: >RR alquilantes >TTP anlogos platinos antimetabolitos >SG inh.topoisomerasa BC antimucrotbulos avanzada
ANTIHORMONAS

Tendencias en el tratamiento
Nuevos frmacos Nuevas clases de frmacos Nuevas combinaciones Nuevas vas para frmacos antiguos

adyuvante neoadyuvante combinacin

RP y RC limitadas % pacientes Preocupacin: QoL, reduccin dosis suspensiones, duracin QT No respuesta: ToxInaceptable

Tratamiento Emprico

Marcadores moleculares para individualizar el tratamiento

Avances significativos en el tratamiento del cncer de mama en los ltimos 40 aos

ONCOFARMACOGENMICA

ONCOFARMACOGENTICA

Bases genticas (biologa molecular)

Variabilidad gentica (diversidad interpersonal) efecto de los frmacos Toxicidad Eficacia Metabolismo

Identificacin de posibles dianas teraputicas

Desarrollo de nuevos frmacos

Tratamiento individualizado

Patrones de expresin genmica del Cncer de Mama

RE RE +

Triple negativo

HER2+

Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.

Sorlie T, et al. Proc Natl Acad Sci U S A 2001

El Cncer de Mama es una Familia de Enfermedades

Convergencia de datos clnicos y genmicos No est claro cuntos miembros hay de esta familia Al menos: HER2+ Tipo basal o triple negativo RE+ (luminal A) RE+ (luminal B)

Tipos Moleculares y Evolucin

Repeated observation of breast tumor subtypes in independent gene expression data sets.

Sorlie T, Tibshirani R, Parker J, et al: Proc Natl Acad Sci U S A 100:8418-8423, 2003

Ensayo GEICAM 2006-03

SUBTIPO LUMINAL A R

ACx4Tx4 Exemestano

SUBTIPO HER-2 R

ACx4THx4
ACx4Tx4 +
Lapatinib

SUBTIPO TRIPLE NEGATIVO R

ACx4Tx4
ACx4Tx4 + CBDCAx4

Un cambio en el conocimiento

Cancer signalling pathways

Circa 1975

Visin simplificada (2004) Sistema inmune

angiognesis
Cel.Endotelial

Frmacos dirigidos a dianas especficas con potencial teraputico en cncer

Cetuximab

hu A33 Autologous vaccines

Mab VEGF

NUEVOS FRMACOS BASADOS EN LA INHIBICIN DE LAS SEALES DE TRANSDUCCIN

Clula Cancerosa Inhibidores de los receptores de los FC

Inhibidores seales de transduccin intracelular (PKA,ras,MAPK,PKC)

Anti-apoptsis (bcl2,AKT)

POTENCIALES VENTAJAS
Sinergismo con QT y RXT Diferente toxicidad (baja) Mayor Selectividad accin Deseable para ttos crnicos Administracin fcil (oral o iv)

Cel.Endotelial

Inhibidores Angiogenesis (VGFR)

HER2: Conceptos
El gen HER2/neu (C-erbB-2) est localizado en el cromosoma 17q El gen HER2/neu codifica una protena que es un receptor tirosina quinasa El receptor HER2 pertenece a la familia de receptores HER (tambin conocida como familia del EGFR) La familia HER est formada por cuatro receptores homlogos: EGFR (HER1) HER2, HER3 HER4

EGFR, HER3 y HER4 tienen ligandos conocidos mientras que HER2 es el nico receptor hurfano (sin ligando)
HER2 es el coordinador principal de esta familia de receptores gracias a su facilidad para heterodimerizar
Yarden. Oncology. 2001;61 Suppl 2:1-13. Review

La familia HER de receptores y frmacos anti-rHER

Trastuzumab Cetuximab
(Erbitux) (Herceptine)

Pertuzumab
(Omnitarg)

Dianas Extracelulares Anticuerpos monoclonales Anti-HER

Gefitinib
(Iressa)

Erlotinib OSI-774
(Tarceva)

HER1 EGFR

HER2

HER3

HER4

Lapatinib
GW572016

Dianas intracelulares Inhibidores de TK

CI-1033

La Dimerizacin de los Receptores de la Familia HER es Imprescindible para su Activacin

Los receptores, en estado monomrico, son inactivos La dimerizacin (formacin de parejas) de los receptores resulta en la activacin del dominio tirosina quinasa y en la transduccin de seales La dimerizacin puede ocurrir entre dos receptores iguales (homodmeros; p.ej. HER2/HER2), o entre dos receptores distintos de la familia (heterodmeros; p.ej. EGFR/HER2 o HER2/HER3). Cada combinacin de homo- y heterodmeros resulta en efectos biolgicos potencialmente distintos

Mecanismos de Activacin de HER2

Homodimerizacin (HER2 3+) Requiere sobre-expresin de HER2 No precisa ligando Receptor sin ligando
K EGFR
pY KKK pY pY pY

Heterodimerizacin (HER2 1/2 +) No requiere sobre-expresin de HER2 Depende de ligando

TGF TGF

pY

K K pY

EGFR/HER2
heregulin

K K

KK
pY

K
heregulin

pY pY

HER2/HER2

HER2
X
HER3

pY

X K

pY

HER3/EGFR

Albanell J. et al. Adv Exp Med Biol. 2003;532:253-68.

Activacin de Receptores HER y Transduccin de Seales

R R
RAS RAF SOS K K PI3-K pY pY GRB2 MEK

PTEN

AKT
MAPK

Transcripcin gnica Progresin ciclo celular

G2 M

p27
S G1

Proliferacin

Supervivencia

Angiognesis Metstasis

Human Monoclonal Antibody Disruption of HER2 Signaling Pathway

Plasma membrane Growth factor Estrogen
P P P P P

IGFR HER2
P

Trastuzumab

Bevacizumab
PI3-K SOS RAS RAF MEK MAPK
P

Cell survival
ER

VEGF

Akt

p90RSK P

VEGFR

Cytoplasm
P P P P

ER

ER p160

CBP

Basal transcription machinery

Nucleus

ERE

ER-mediated gene transcription

Bases para considerar HER2 como Diana Teraputica en Cncer de Mama

ONCOGEN: La sobre-expressin de HER2 puede transformar a clulas normales en malignas EXPRESIN EN TUMORES HUMANOS: Un 20-30% de cnceres de mama humanos sobre-expresan HER2 PAPEL PATOGNICO: Los tumores de mama con sobre-expresin de HER2 tienen peor pronstico DIANA TERAPUTICA ESTABLECIDA: En modelos de laboratorio, anticuerpos anti-HER2 o inhibidores de la actividad quinasa de HER2, tienen un efecto antitumoral potente

Adaptado de Ross JR. et al. Oncologist. 2003;8(4):307-25

Terapias Anti-HER2 en la Prctica Clnica

Anticuerpos monoclonales (Trastuzumab [aprobado], pertuzumab ([fase I/II], MDX-210 [fase I])

Inhibidores tirosina quinasa HER2-especficos (TAK165 [fase I], CP724 [fase I])

= actividad tirosina quinasa

Transduccin de seal

Regiones de Unin de HER2 a Anticuerpos Monoclonales Teraputicos

Dominio extracelular

Pertuzumab
(aa 22-584)

Mecanismos generales Trastuzumab de accin:

(aa 529-625)

Dominio citoploasmtico Tirosina qiuasa

Interferir con la funcin de HER2 en cncer

Respuesta inmune
K

Adaptado de Fendly et al. Cancer Res 50;1550, 1990

La actividad de Trastuzumab en cncer de mama HER2+ depende estrictamente de la sobre-expresin de HER2 (homodmeros) pero en cambio el crecimiento de muchos cnceres de mama (y otros tumores) probablemente se debe a la activacin de HER2 mediada por ligandos/heterodmeros (Trastuzumab no impide los heterodmeros inducidos por ligando)

Heregulina TGF-alfa

Estimulacin autocrina

Estimulacin paracrina
Clula estroma

Clula maligna TUMOR CELL

Factores de crecimiento

Pertuzumab (2C4), pero no trastuzumab (o 4D5), impide los heterodmeros de HER2 e inhibe in vivo el crecimiento de cnceres de mama con expresin alta y baja de HER2
Agus et al. Cancer Cell 2002,2;127-37

HER2 alto

Ensayos fase I

HER2 bajo

Revisado en Albanell J. et al. Adv Exp Med Biol. 2003;532:253-68.

Clinical activity in a phase I trial of HER-2-targeted rhuMAb 2C4 (pertuzumab) in patients with advanced solid malignancies (AST)
N = 21 2C4 infusin cada 3 semanas Concentraciones biolgicamente activas Antes de alcanzar MTD 3 RP (14%): cncer de islotes pancreticos, prstata, ovario 5 estabilizaciones Efectos Adversos: Mayora grado 38% rash No cardiotoxicidad Vida media de aprox. 3 semanas Esquema fase II: 1050 mg cada 3 semanas
Desarrollo en cncer de mama y otros tumores (no precisa sobre-expresin HER2): Fase Ib: + Xeloda o + Docetaxel y otras combinaciones Fase II: monoterapia
D. Agus # 771, ASCO 2003

Inhibidores de Tirosina Quinasa del EGFR en Desarrollo Clnico

Factor de crecimiento (EGF, TGF alpha)
R R

ZD1839, OSI-774, EKB-569, PKI166, Lapatinib (DUAL), CI-1033 (Pan)

K
K

Actividad tirosina quinasa dependiente de ATP

Transduccin de seales (MAPK)

Marcadores de Respuesta al Agente Biolgico

Inhibidores del EGFR: Marcadores Farmacodinmicos
TGF

MAb

MAb cetuximab [nM]

200 0 20 0 0.2 2

TKI gefitinib [M]

1 0.0001 0.001 0.01 0.1 10

R R

TKI
PI3K

K
Shc Grb2 Sos

EGFR activado

Akt

MAPK

MAPK activada
Relative cell number (%) Relative cell number (%)

supervivencia

proliferacin N. cels

100 75 50 25 0

100 75 50 25 0

Los marcadores identificados en modelos preclnicos son luego estudiados en pacientes

Dosis biolgica ptima

Adaptado de Albanell & Gascon, Signal Junio 2003

Efectos Farmacodinmicos de Inhibidores TK de EGFR in vivo: Estudios en Biopsias de Piel

Pre-ZD1839 + ZD1839 A A Pre-ZD1839 + ZD1839

B B C

Activacin del EGFR

Activacin de MAPK
Albanell J et al. J Clin Oncol 2002; 20: 110-124.

EGFR Inhibitors in Clinical Development

Selective EGFR inhibitors gefitinib (reversible) erlotinib (reversible) EKB-569 (irreversible) Dual or pan-ErbB inhibitors LAPATINIB (EGFR/HER2 / reversible) CI-1033 (pan-ErbB / irreversible)

Adaptado de: Albanell, Muoz, Gascn. Rev Oncol, enero 2004

Lapatinib: mecanismo de accin

EGFR

HER2

Clula tumoral

Clula tumoral

Lapatinib
Cell survival, proliferation, migration

Lapatinib Blocks Signaling Through Multiple Receptor Combinations

Blocks signaling through ErbB1 and ErbB-2 homodimers and heterodimers Might also prevent signaling through heterodimers between these receptors and other ErbB family members Potentially blocks multiple ErbB signaling pathways more effectively than single-target inhibitors
Downstream signaling cascade Lapatinib 1+1 2+2 1+2

EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer

Refractory, progressive metastatic or locally advanced HER2+ breast cancer previously treated with anthracycline, taxane, or trastuzumab (N = 528 planned*)

Lapatinib 1250 mg daily + Capecitabine 2000 mg/m2 daily for Days 1-14, 3-week cycles (n = 160)

Capecitabine 2500 mg/m2 daily for Days 1-14, 3-week cycles (n = 161)

Follow-up: until progression or unacceptable toxicity

*Study enrollment terminated early by IDMC due to superiority of combination arm in primary endpoint.
Geyer CE, et al. ASCO 2006. Clinical Science Symposium.

Phase III Trial: EGF100151 Capecitabine Lapatinib in Women With Refractory Advanced or Metastatic Breast Cancer
O

Intestine Capecitabine

5-DFUR

Capecitabine
CE
N 5-DFCR N O O N F O

Liver

N N O

Rationale Capecitabine is converted to 5-FU by thymidine phosphorylase, which is expressed preferentially in tumor cells. ErbB-1 inhibition might upregulate thymidine phosphorylase and downregulate thymidine synthase, thereby enhancing the efficacy of capecitabine.

CyD

N 5-DFCR N O O O N F O 5-DFUR N O N F

CyD

O
O F O

O 5-FU N

Thymidine Phosphorylase (TP)

Tumor >> healthy tissue

5DFCR = 5deoxy-g fluorocytidine; 5DFUR = 5deoxy-5-fluorouridine;

CyD = cytidine deaminase; CE = carboxylesterase

EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer (contd)

100 80

Severity
Gr 1 Gr 2

Gr 3

Gr 4

Patients (%)

60 40 20 26 19

Diarrhea

PPES

Rash and/or Skin Reaction

28 12 13 15

20
11 0 9

19

0
L+C

6
0 L+C C Alone

13 3 0

12 11 7 0

5
0

C Alone

L+C

C Alone

Geyer CE, et al. ASCO 2006. Clinical Science Symposium.

Progression-Free Survival (PFS) Based on Independent Review

Cumulative Progression-Free Survival

1.0 0.8 0.6 0.4 0.2 0.0 0

10

Capecitabine No. of pts 163 161 Progressed or died 49 (30%) 76 (47%) Median PFS, wk 36.7 (8.4 mo) 17.9 (4.1 mo) Hazard ratio (95% CI) 0.47 (0.33, 0.67) P-value (log-rank, 1-sided) 0.00001

Lapatinib + Capecitabine

20

30

40

50

60

70

Time (weeks)

Study EGF100151: A Preliminary Biomarker Analysis

HER2 receptor proteolytic processing produces soluble 105 kDa ECD and a retained 95 kDa fragment Presence of 95 kDa fragment has increased transforming potential and linked to poor prognosis and metastasis Increased serum levels of 105 kDa ECD potentially linked to chemotherapy resistance Increased circulating 105-kDa HER2 ECD, found in many patients with HER2positve breast cancer, correlates with worse prognosis Current analysis designed to Correlate biomarker analyses with clinical endpoints of TTP and PFS Define biomarkers, such as ECD levels, that might predict clinical benefit from lapatinib

105 kDa ECD

HER2 (p185erb-2) protein kinase domain

Cameron D, et al. SABCS 2006. Abstract 2.

Lapatinib: inhibits HER2

Study EGF100151: PFS Associated With Levels of HER2 ECD and Therapy
High ECD L+C 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 Weeks
Cameron D, et al. SABCS 2006. Abstract 2.

Low ECD C L+C C

Hazard ratio 95%CI

0.271 (P = 0.0013) 0.122-0.621

0.483 (P = .0018) 0.306-0.763

Proportion With PFS

40

50

60

Cardiotoxicity and Lapatinib

Prospective evaluation of cardiotoxicity in lapatinibtreated patients
18 phase I-III trials (N = 3127) 10 lapatinib monotherapy 8 lapatinib combination Cardiotoxicity defined as NCI CTC grade 3 or 4 20% asymptomatic in LVEF from baseline
LVEF in LapatinibTreated Patients Breast cancer patients (n = 1674) n (%)

22 (1.3)

Symptomatic
Asymptomatic All patients* (N = 3127) Symptomatic

2 (0.1)
20 (1.2) 41 (1.3) 4 (0.1)

Incidence of LVEF: 1.3%

Symptomatic cases: 0.1%
Perez EA, et al. ASCO 2006. Abstract 583.

Asymptomatic

37 (1.2)

*Breast and nonbreast cancer patients treated with lapatinib.

Targeting HER2 via HSP-90

Heat shock protein-90 (HSP-90) is a chaperone protein for a variety of oncogenic proteins, including HER2, ER/PR, AKT, MET, and Raf kinase 17-AAG 17-AAG (KOS-953), an inhibitor of HSP-90, suppresses tumor growth in mouse xenograft models of HER2+ human breast cancers

PIP2
H E R 2 H E p85 R p110 3

PTEN PIP3 PDK AKT 17-AAG

Cyclin D

BAD, Caspase 9, FKHD, etc

Modi S, et al. ASCO 2006. Abstract 501.

17-AAG + Trastuzumab
Data from phase I trial of 17-AAG + trastuzumab reported
Weekly 17-AAG (various doses) + standard weekly trastuzumab

Partial response: 1
59% in lung metastasis

Tumor regression: 4
All HER2+ MBC who progressed on trastuzumab Decreases in lung, nodal, breast metastases noted

25 patients with various solid tumor types evaluated

Largest proportion had HER2+ overexpressing breast cancer

Maximum 450 mg/m2 dose well tolerated

1 grade 2 thrombocytopenia

Stable disease: 4 ( 4 months) Phase II trial of 17-AAG (450 mg/m2) + trastuzumab in HER2+ metastatic breast cancer ongoing
Modi S, et al. ASCO 2006. Abstract 501.

Phase II Study of Patient Response to Tanespimycin + Trastuzumab

Inhibition of Hsp90 chaperone function by tanespimycin (KOS-953) induces proteasomal degradation of client proteins including HER2 receptor Rapid degradation of HER2 Loss of pAKT and cyclin D2 Tumor growth inhibition Current study evaluated efficacy of tanespimycin plus trastuzumab in women with HER2-positive MBC and disease progression previously treated with trastuzumab

Modi S, et al. SABCS 2006. Abstract 1102.

Phase II Study of Tanespimycin + Trastuzumab: Clinical Outcomes

Overall favorable clinical response: 63%
Outcome, n Best response Partial Stable disease 2 3 Evaluable Patients (n = 8)

Overall incidence of adverse events

Fatigue: 80% Diarrhea: 60% Dizziness: 50% Muscle cramps: 40% Headache: 30% Nausea: 30% Vomiting: 20%

Modi S, et al. SABCS 2006. Abstract 1102.

Phase II Study of Tanespimycin + Trastuzumab: Conclusions

Heat-shock protein 90 (Hsp90) inhibitor tanespimycin plus trastuzumab showed activity in 63% of women with HER2-positive metastatic breast cancer with disease progression after prior trastuzumab therapy Clinical proof of activity in this patient population suggests further investigation of Hsp90 inhibitors are justified Clinical trials initiated, which evaluate the use of a next-generation Hsp90 inhibitor, alvespimycin
Modi S, et al. SABCS 2006. Abstract 1102.

Normal Expression of Tumor Suppressor Genes

Tumor suppressor gene

A

A
Histones acetylated: tumor suppressor gene expressed

A
Histone

A = Acetyl group (CH3COO)

HDAC Action Negatively Regulates Tumor Suppressor Gene Expression

HDAC

Tumor suppressor gene

Deacetylation Deacetylated histones: tumor suppressor gene repressed

Histone

A = Acetyl group (CH3COO)

Vorinostat Targets HDAC and May Result in Tumor Suppression

HDAC

Tumor suppressor gene

Vorinostat A

A
Histones acetylated: tumor suppressor gene expressed

A
Histone

A = Acetyl group (CH3COO)

California Cancer Consortium Analysis of Vorinostat Treatment of MBC

Novel agents needed for the treatment of hormone receptor and HER2negative relapsed or refractory breast cancer Vorinostat (suberoylanilide hydroxamic acid): small molecule inhibitor of histone deacetylase (HDAC) Phase II study evaluated efficacy and safety of single-agent vorinostat as salvage therapy in patients with metastatic breast cancer Vorinostat 200 mg twice daily orally for 14 days 21-day cycle Entry criteria Metastatic breast cancer (confirmed by histologic analysis) with measurable disease 2 prior chemotherapy regimens for metastatic breast cancer ECOG PS 0-2

Luu T, et al. SABCS 2006. Abstract 1109.

MBC Patient Response to Vorinostat Monotherapy

Stable disease observed in more than 30% of patients treated with vorinostat
Evaluable Patients (n = 12) 0 0

Patient Best Response, n Complete response Partial response

Stable disease
Disease progression

4
8

Vorinostat-associated toxicity reported in 12 patients Grade 4 toxicity: lymphopenia (n = 1) Grade 2/3 toxicity: lymphopenia (n = 6); diarrhea (n = 3); vomiting (n = 3) nausea (n = 2); mucositis (n = 1); fatigue: n = 1 2 early withdrawals prior to response evaluation due to nausea and fatigue

Luu T, et al. SABCS 2006. Abstract 1109.

Vorinostat Single Agent Treatment of MBC: Study Conclusions

Vorinostat monotherapy produced stable disease in 4 of 12 MBC patients with a manageable toxicity profile
Median duration 7.8 months No objective responses reported

Results support further evaluation of vorinostat in combination with other agents

Luu T, et al. SABCS 2006. Abstract 1109.

Targeting Bone Resorption Mediator RANK Ligand

RANK ligand (RANKL) key mediator for osteoclast formation, function, survival
Potential target for treating bone metastasis
RANKL RANK

Cancer Cells in Bone

Denosumab novel human monoclonal RANKL antibody

Does not bind TNF-, TNF-, TRAIL, or CD40L Administered subcutaneously

RANKL

Cytokines and Growth Factors (IL-6, IL-8, IL-1, PGE-2, TNF-, CSF-1. PTHrP)

Direct effects on tumor?

Growth Factors (TGF-, IGFs, FGFs, PDGFs, BMPs)

Osteoclast Bone Resorption

Osteoblast Lineage

Bone

Lipton A, et al. ASCO 2006. Abstract 512.

Randomized, Dose-Ranging Trial of RANKL Inhibitor Denosumab

Interim data from 255 breast cancer patients with 1 bone metastasis randomized to
Denosumab (30, 120, or 180 mg q 4 wk or 60 or 180 mg q 12 wk) IV bisphosphonates q 4 wk (open label)

Denosumab effectively suppressed bone resorption

Median reduction in uNTx at Week 13 of treatment: 63% to 82% ~ 75% achieved > 65% reduction in uNTx by Week 13

Further study warranted

Denosumab 120 mg every 4 weeks selected for phase III study in metastatic breast and prostate cancer
Lipton A, et al. ASCO 2006. Abstract 512.

VEGF AND RECEPTORS

Extracellular

VEGF-A VEGF-B

VEGF-A VEGF-C VEGF-D VEGF-E

VEGF-C VEGF-D

VEGFR-1/Flt-1

VEGFR-2/KDR

VEGFR-3/Flt-4

Angiogenesis

Angiogenesis

Lymphangiogenesis Tumor metastasis

Dvorak HF. J Clin Oncol. 2002;20:4368-4380. Luttun A, et al. Ann NY Acad Sci. 2002;979:80-93.

Agents targeting the VEGF pathway

Antibodies inhibiting VEGF receptors
Antibodies inhibiting VEGF (e.g. bevacizumab) Permeability

Soluble VEGF receptors (VEGF-TRAP)

VEGF VEGF receptor-2

Cation channel

P P

P P

Small-molecules inhibiting VEGF receptors (TKIs) (e.g. PTK-787)

P P

P P P P P P

Migration, permeability, DNA synthesis, survival

Ribozymes (Angiozyme)

Angiogenesis

Lymphangiogenesis

Investigational VEGF/VEGF Receptor Inhibitors

Courtesy of Dan Hicklin, adapted from Hicklin, DJ & Ellis LM. J Clin Oncol. 2005;23:1011-1027. Agent
Bevacizumab IMC-1121B CDP-791 2C3 VEGF-trap

Class
MAB MAB Pegylated DiFab MAB Soluble receptor

Target
VEGF-A VEGFR-2 VEGFR-2 VEGF-A VEGF-A, PlGF

Company
Genentech ImClone Systems Celltech Peregrine Aventis/Regeneron

PTK-787
AEE788 ZD6474 AZD2171 SU11248

TKI
TKI TKI TKI TKI

VEGFR-1, 2
VEGFR-1, 2, 3, EGFR VEGFR-1, 2 VEGFR-1, 2, PDGFR

Novartis
AstraZeneca AstraZeneca Pfizer

VEGFR-2, EGFR/HER2 Novartis

AG13925
AG013736 CEP-7055 CP-547,632 GW786024

TKI
TKI TKI TKI TKI

VEGFR-1, 2
VEGFR-1, 2 VEGFR-1, 2, 3 VEGFR-1, 2 VEGFR-1, -2, -3

Pfizer
Pfizer Cephalon Pfizer GlaxoSmithKline

Bay 93-4006
AMG706

TKI
TKI

VEGFR-1, -2, PDGFR

VEGFR-1, -2, -3

Bayer/Onyx
Amgen

Phase III Trial of Capecitabine vs. Capecitabine + Bevacizumab

Eligibility Prior anthracycline and taxane (and trastuzumab if HER2+)
R A N D O M I Z E

ECOG PS 0-1 No CNS involvement <2 prior chemo for MBC

Optional continuation of bevacizumab

Capecitabine + bevacizumab

Capecitabine N=462

Miller. JCO. 2005; 792:23.

Progression Free Survival

Cap
Months HR (stratified) 4.17

Cap + AVF
4.86 0.98 (NS)

E2100: Study Design

Stratify:

R A N D O M I Z E

DFI < 24 mos. vs. > 24 mos. < 3 vs. > 3 metastatic sites Adjuvant chemotherapy yes vs. no ER+ vs. ER- vs. ER unknown Paclitaxel + Bevacizumab
28-Day Cycle:

Paclitaxel

Paclitaxel 90 mg/m2 D1, 8 and 15 Bevacizumab 10 mg/kg D1 and 15

Current Analysis
Study activated Dec 21, 2001 Closed March 24, 2004 680 eligible patients
Most common reasons for ineligibility:
Baseline evaluation > 4 wks from entry (11) Hormonal therapy within 3 wks (10)

Data cutoff September 27, 2005 484 events

Progression 426 Death without documented progression - 58

Response
P<0.0001

Paclitaxel Pac + Bev

Overall Response Rate

40 30 20
13.8%

29.9%

10
339 341

All Patients

Progression-Free Survival
1.0

Pac. + Bev. 11.4 months Paclitaxel 6.11 months

0.8

PFS Probability

0.6

HR=0.51 (0.43-0.62)
0.4

Log Rank Test P<0.0001

0.2

0.0 0 6 12

484 events reported

Months

18

24

30

Bevacizumab Toxicity NCI-CTC Grades 3 and 4

Paclitaxel (N=330)

Pac. + Bev. (N=342)

HTN* Thromboemboli c Bleeding

Grade Grade Grade Grade 3 4 3 4 0% 0% 13% 0.3%

0.3%
0%

0.9%
0% 0%

1.2%
0.6% 0.9%

0%
0.3% 1.5%

0% Proteinuria** NCI-CTC v3.0, worst per patient *P<0.0001; **P=0.0004

DF/PCC Breast Cancer SPORE Randomized Phase II Trial of Metronomic Chemotherapy Bevacizumab

Eligibility Highlights
Advanced Breast Cancer Measurable Disease 0-1 Prior Chemo Regimens

"Metronomic" Cyclo+ MTX

"Metronomic" Cyclo+ MTX + Bevacizumab

PD Off study [option: add B]

PD Off study

Measurable disease PS 0-1 Good organ fxn 0-1 prior regimens b/c nonstandard chemo Prior trastuzumab if HER2+ Prior anthracyclines if visceral metastases

MCF-7/HER2 Xenografts: Chemotherapy + Trastuzumab + Bevacizumab Pre-Clinical Synergy

3000

Tumor Volume (mm3)

2000

Control Paclitaxel Paclitaxel + bevacizumab Paclitaxel + trastuzumab Paclitaxel + bevacizumab + trastuzumab

1000

20

40

Days

60

80

100

120

Epstein. Breast Cancer Res Treat. 2002;76:S143. Abstract S70.

Bevacizumab + Trastuzumab: Phase II Study Design

HER2+ metastatic breast cancer patients (N = 37) received Bevacizumab 10 mg/kg on Day 7 and then every 2 weeks thereafter Trastuzumab 4 mg/kg loading dose followed by 2 mg/kg every week Primary objectives Assess clinical efficacy of bevacizumab/trastuzumab combination Assess safety of bevacizumab/trastuzumab combination
Pegram M, et al. SABCS 2006. Abstract 301.

Bevacizumab + Trastuzumab: Baseline Demographics

Median age: 56 years (range: 38-73) ECOG PS 0: 26 (70%) Prior breast cancer treatment Mastectomy: 31 (84%) Radiation: 18 (49%) Adjuvant/neoadjuvant chemotherapy: 20 (54%) Endocrine therapy: 18 (49%) Visceral metastasis: 23 (62%) Estrogen and/or progesterone receptor positive: 23 (62%)
Pegram M, et al. SABCS 2006. Abstract 301.

Patient Responses to Bevacizumab + Trastuzumab Therapy

More than one half of patients had objective response to treatment
Objective Clinical Response, n (%) Patients (N = 37)

Overall
Complete* Partial* Stable disease Progressive disease
*1 complete response and 13 partial responses confirmed by pathology.

20 (54.1)
1 (2.7) 19 (51.4) 11 (29.7) 6 (16.2)

Pegram M, et al. SABCS 2006. Abstract 301.

Bevacizumab + Trastuzumab: Associated Toxicity

Total of 113 grade 1-4 drug-related adverse events reported in 37 patients 9 grade 3 events reported Hypertension: 7 events Dyspnea: 1 event Proteinuria: 1 event 1 grade 4 event reported Left ventricular dysfunction Cardiac adverse events generally mild/moderate in nature and typically observed within first 16 weeks of treatment 1 patient experienced grade 4 event
Pegram M, et al. SABCS 2006. Abstract 301.

Conclusions From Phase II Bevacizumab + Trastuzumab Study

Feasible to combine bevacizumab with trastuzumab in HER2-positive recurrent/metastatic breast cancer patients Data support the strategy of testing combination therapy directed against both HER2 and VEGF in FISH-amplified HER2 breast cancer

Pegram M, et al. SABCS 2006. Abstract 301.

E5103 Schema
Patients eligible for initiation of Trastuzumab plus chemotherapy as first-line therapy for HER2 + MBC
Previous neo-adjuvant or adjuvant Taxane therapy Yes No Previous adjuvant Trastuzumab therapy Yes No Disease-Free Interval <=24 months >24 months

Randomize

Group A Trastuzumab 2 mg/kg IV weekly (after loading dose of 4 mg/kg) Paclitaxel 80 mg/m2 IV weekly x 3 followed by 1 week rest Carboplatin AUC 2 IV weekly x 3 followed by 1 week rest Total number of cycles = 6 (one cycle = 4 weeks) Group B Trastuzumab 2 mg/kg IV weekly (after loading dose of 4 mg/kg) Bevacizumab 10 mg/kg IV every 2 weeks Paclitaxel 80 mg/m2 IV weekly x 3 followed by 1 week rest Carboplatin AUC 2 IV weekly x 3 followed by 1 week rest Total number of cycles = 6 (one cycle = 4 weeks)

Trastuzumab 4 mg/kg IV every 2 weeks

Trastuzumab 4 mg/kg IV every 2 weeks Bevacizumab 10 mg/kg IV every 2 weeks

Adjuvant Bevacizumab
Most successful use of anti-VEGF therapy predicted to be in adjuvant setting
Breast cancer growth

VEGF

VEGF bFGF TGF-1

VEGF bFGF TGF-1 PlGF

Relf. 1997.

VEGF bFGF TGF-1 PlGF PD-ECGF

VEGF bFGF TGF-1 PlGF PD-ECGF Pleiotrophin

Pilot Adjuvant Bevacizumab: E2104 Schema

Arm A: ddBAC >BT >B

R E G I S T E R
Doxorubicin 60 mg/m2 plus Cyclophosphamide 600 mg/m2 Bevacizumab 10 mg/kg every 14 days x 4 Paclitaxel 175 mg/m2 Bevacizumab 10 mg/kg every 14 days x 4 Bevacizumab 10 mg/kg every 14 days x 18

Doxorubicin 60 mg/m2 plus Cyclophosphamide 600 mg/m2 every 14 days x 4

Paclitaxel 175 mg/m2 Bevacizumab 10 mg/kg every 14 days x 4

Bevacizumab 10 mg/kg every 14 days x 22

Arm B: ddAC >BT >B

*Hormone therapy and radiation per standard care.

Sunitinib Mechanism of Action in RCC

Loss of VHL Protein Function VEGF
VEGFR
VEGF

PDGF
PDGF

PDGFR

Vascular Endothelial Cell

Pericyte/Fibroblast/ Vascular Smooth Muscle

Sunitinib
Vascular permeability Cell survival, proliferation, migration Vascular formation, maturation

Inhibition of RCC pathogenesis and progression

SU11248
O H3C N H N CH
3

CH
3

Indolinone Oral dosing

O

N H

CH3

N H

Selective inhibitor of: PDGFR VEGFR2 (KDR) KIT FLT3

Efficacy of SU11248
N=51 Partial Response* 7 (14%)

Stable Disease > 6 months 1 (2%)

Overall Clinical Benefit

8 (16%)

*One PR not yet confirmed. 13 patients too early for response assessment.

KD Miller, ASCO 2005.

CONCLUSIONES I
HER2 representa un modelo de diana molecular para el desarrollo de terapias biolgicas a la carta Trastuzumab es el primer anticuerpo aprobado para el tratamiento de una alteracin gentica somtica de las clulas malignas (la sobre-expresin de HER2)

La combinacin de trastuzumab + QT aumenta la supervivencia global y SLE de las mujeres con cncer de mama avanzado y localizado HER2+

Otros anticuerpos anti-HER2 (p.ej. Pertuzumab) podran ser tiles en tumores (mama y otros tipos) con expresin baja o moderada de HER2 Inhibidores TK de HER2 y EGFR como LAPATINIB, aumentan la SLE en combinacin con capecitabina frente a capecitabina en pacientes con ca de mama avanzado, refractarias a trastuzumab.

Inhibidores de HSP-90, HDAC y del RANKL presentan datos iniciales de actividad prometedores

CONCLUSIONES II
Paclitaxel+bevacizumab aumenta el TTP en comparacin con paclitaxel solo en CMM SU 11248 parece eficaz en pacientes con CMM pretratado La quimioterapia metronmica es moderadamente eficaz en el CMM Estos datos sugieren que la terapia antiangiognica puede ser de utilidad en el cancer de mama Es necesario el estudio de la terapia antiangiogenica en el contexto del tratamiento adyuvante y neoadyuvante Es necesario encontrar factores predictivos de respuesta