I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Cattedra di Oncologia Medica e Laboratori di...

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I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Cattedra di Oncologia Medica e Laboratori di Terapia Molecolare Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica Università di Napoli “Federico II” Giampaolo Tortora

Transcript of I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Cattedra di Oncologia Medica e Laboratori di...

Page 1: I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Cattedra di Oncologia Medica e Laboratori di Terapia Molecolare Dipartimento di Endocrinologia e Oncologia.

I FARMACI MULTITARGETED

NEL CANCRO DELLA MAMMELLA

Cattedra di Oncologia Medica eLaboratori di Terapia Molecolare

Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica Università di Napoli “Federico II”

Giampaolo Tortora

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Farmaci che bloccano più recettori della stessa famiglia, per aumentare l’efficienza del “targeting” selettivo.

Farmaci che bloccano recettori e proteine di segnale di classi e funzioni diverse, per bloccare a più livelli la trasmisione di segnali.

Farmaci con bersagli multipli

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PKAIPI3K

PLC

GRB2 SOS p21ras Raf

MAPK

Cyclin D1

CDK

RbCell ProliferationCell Proliferation

E2Fmdm2

p53

PKC

SIGNALLING PATHWAYS IN CANCER CELLS

AKT

Bcl-2

mTOR

Angiogenesis

Invasionmetastasis

VEGFMEK

P

PP P

c-KITR

PDGFR,

HER/erbB

Apoptosis

PTEN

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P

EGFR/ErbB2 EGFR/ErbB3EGFR

Tortora et al., 2007

I recettori della famiglia ErbB/HER funzionano in coppia, formando omo- o eterodimeri

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Co-expression of EGFR and ErbB-2 has been observed in 10-30% primary human breast carcinomas.

Overexpression of both ErbB-2 and EGFR is associated with a poorer prognosis than overexpression of either receptor alone in breast cancer patients.

A recent study has demonstrated an adverse prognostic independent role of ErbB-2 and EGFR coexpression in a subset of radically resected early breast cancers. (Di Giovanna et

al., JCO, 23: 1152-1160, 2005).

Co-expression of EGFR and ErbB-2

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Phase I study of Erlotinib plus Trastuzumab and Taxol

Escalating doses of Erlotinib (25 to 150 mg); Taxol 80 or 90 mg/m2; Trastuzumab 2 mg/kg. Weekly administration with different schedules.

Selected the 1, 8, 15, 28 schedule and the recommended doses of Erlotinib 150 mg, Taxol 90 mg/m2, Trastuzumab 2 mg/kg.

14/16 patients had MBC, HER2+ (8 pre-treated with Tastuzumab).

Mild toxicity and PKA interaction.

1 CR and 2 PR in patients HER2+, taxane-resistant. In 2 cases also Trastuzumab-resistant.

Important the role of Taxanes ? Major activity of Erlotinib ?

A. Patnaik, ASCO 2005

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Doppi inibitori di EGFR e HER-2

Pertuzumab e Lapatinib

Page 8: I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Cattedra di Oncologia Medica e Laboratori di Terapia Molecolare Dipartimento di Endocrinologia e Oncologia.

Omnitarg Riconosce Epitopi diversi da Trastuzumab su HER2 e impedisce la etero-dimerizzazione EGFR-HER2

HER2

Ligand-binding domain(inactive)

Cell membrane

Tyrosine kinase domain

Omnitarg

Trastuzumab

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N

N

O O

NH

O O NH

S

O

N

N

NH

Cl

OO

O

F

N

O

N

N

O O

NH

Cl F

Erlotinib Gefitinib GW572016 Lapatinib

Small head group quinazolines Large head group quinazoline

Lapatinib inhibits EGFR and HER-2

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EGF20009: A Phase II, Randomized trial using Lapatinib as a first-line treatment in patients with FISH Positive Advanced or

Metastatic Breast Cancer

Response Investigator ReviewN=40

Independent ReviewN=40

CR 0 0

PR 12 (30%) 14 (35%)

Unconfirmed PR* 3 (7.5%) 2 (5%)

SD 13 (32.5%) 14 (35%)

PD 10 (25%) 5 (12.5%)

Unknown 2 (5%)** † 5 (12.5%) ** †

*Two subjects considered to have a PR by investigator had <28 day confirmation scans.** One subject not evaluated due to death from multiple injuries prior to tumor assessment.† 1 subject by the investigator review and 4 subjects by independent review had only one timepoint and that timepoint did not meet the criteria for SD per the protocol (8 weeks). Sledge group updated from ASCO 2005 and SABCS

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Randomized Phase III Study EGF100151

• Progressive, HER2+ MBC or LABC

• Previously treated with anthracycline, taxane and trastuzumab*

• No prior capecitabine

Lapatinib 1250 mg po qd continuously +

Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk

Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk

Patients on treatment until progression or unacceptable toxicity, then followed for survival

Stratification:• Disease sites• Stage of disease

RANDOMIZE

*Trastuzumab must have been administered for metastatic disease

N=528

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Prior Therapy

Lapatinib + Capecitabine(n=160)

Capecitabine(n=161)

Anthracyclines 156 (98%) 156 (97%)

Taxanes 157 (98%) 159 (99%)

Trastuzumab 156 (97%) 156 (97%)

Metastatic 149 (93%) 146 (91%)

Adjuvant 7 (4%) 10 (6%)

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Time to Progession – ITT Population

70

10

20

30

40

50

60

70

80

90

0

100

* Censors 4 patients who died due to causes other than breast cancer

10 20 30 40 50 600Time (weeks)

CapecitabineLapatinib +

Capecitabine

0.00016P-value (log-rank, 1-sided)

69 (43%)45 (28%)Progressed or died*

19.736.9Median TTP, wk

161160No. of pts

0.51 (0.35, 0.74)Hazard ratio (95% CI)

% o

f p

atie

nts

fre

e fr

om

pro

gre

ssio

n*

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Time (weeks)0 10 20 30 40 50 60 70

Cu

mu

lati

ve P

rog

ress

ion

-Fre

e S

urv

ival

, %

0

10

20

30

40

50

60

70

80

90

100

Progression-Free Survival - ITT Population

0.000045P-value (log-rank, 1-sided)

73 (45%)45 (28%)Progressed or died

0.48 (0.33, 0.70)Hazard ratio (95% CI)

17.936.9Median PFS, wk

161160No. of pts

CapecitabineLapatinib +

capecitabine

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Overall Survival - ITT Population

0.800P value (log-rank, 2-sided)

29 (18%)29 (18%)Deaths

0.93 (0.55, 1.59)Hazard ratio (95% CI)

NRNRMedian OS

161160No. of pts

Time (weeks)0 10 20 30 40 50 70 90

Cu

mu

lati

ve S

urv

ival

%

0

10

20

30

40

50

60

70

80

90

100

CapecitabineLapatinib +

Capecitabine

60 80

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Brain Metastases as Site of Progression

Lapatinib + Capecitabine(n=160)

Capecitabine(n=161)

Patients with CNS metastases at baseline

2 2

Patients with CNS relapse* 4 11

Patients with CNS as only site of relapse

3 10

*P-value (Fisher’s exact, 2-sided) = 0.110

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Mean LVEF at Scheduled Assessments

Week 12 Week 18 Week 24 Week 36 Week 48Week 6Screening

Assessment

Lapatinib + Capecitabine

Capecitabine

Mea

n L

VE

F (

%)

80

75

70

65

60

55

50

n=160 n=160

n=108

n=92

n=84 n=67

n=63n=37

n=37 n=26

n=15n=9

n=7n=1

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EGF103009A Phase II Trial of Lapatinib (Tykerb) Monotherapy

in Patients With Relapsed/Refractory Inflammatory Breast Cancer (IBC):

Clinical Activity and Biologic Predictors of Response

Spector N, K Blackwell, J Hurley, J Harris, D Lombardi, S Bacus, SB Ahmed, H Boussen, M Frikha, FB Ayed

Cohort AErbB2+

Cohort BErbB1+/ErbB2-

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0%

50%

100%

Cohort AErbB2+

24 patients

5 enrolled patients were not evaluable (did not express target or died prior to Day 28)

Cohort BErbB1+/ErbB2-

12 patients

8.3%

17%SD

58%PD

17%pending

Preliminary Results: Treatment Response

62%PR

21%SD

17%PD

62% clinical responders

ErbB2 (IHC 3+/FISH+)p-ErbB2 positive

100%

PTEN deficient

69%

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The proposed phase II and III dose for this combination is 1000 mg/day lapatinib and standard weekly trastuzumab

The most frequent AEs with this combination were diarrhea, fatigue, nausea, and anorexia

The combination of lapatinib and trastuzumab was very active (6/27 CR+PR and 2/27 PR in the PK groups = 8% total) in this heavily pretreated population, all of whom had progressed on prior trastuzumab

Additional randomized studies are planned with lapatinib and trastuzumab

Storniolo et al., ASCO 2005 and SABCS

EGF10023:

Phase I, open-label study of the Safety, Tolerability and Pharmacokinetics of

Lapatinib in combination with Trastuzumab

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STUDI IN CORSO : ADIUVANTE, METASTATICO

E NEOADIUVANTE

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• The prevalence of certain ErbB heterodimers may cause an

alternative driving force for the growth of cancer cells

bypassing the blackade by specific inhibitors.

• For instance the heterodimer HER2-HER3 is an “odd couple”

with a powerful kinase activity.

Heterodimers formation

PEGFR/ERbB2

HER3/erbB3EGFR HER2/HER3

Tortora et al., 2007

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mTOR Pathway islinked to EGFR

and VEGF

Akt/PKB

PI3-K

PTENOxygen, energy, and nutrients

TSC2 TSC1

Growth factorsIGF-1, VEGF, ErbB, etc

Protein production

4E-BP1

S6

S6K1

elF-4E

mTORRas/Raf pathway kinases

Ras/Raf,

Abl, ER

Cell growth AngiogenesisCell division

XX XX XX

HIF-1

VEGF

-CCI-779 (temsirolimus)- RAD-001 (everolimus)- AP23573

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109 patients randomized to receive 75 mg or 250 mg i.v weekly.

Toxicity profile favored 75mg dose: Anaemia, hyperglycemia, hypophostatemia & hypertrigliceridemia as grade 3/4 events

Overall response: 9% (10 PRs), 26% MR

mTTP: 3 m, mOS: 15m

Phase III development ongoing in combination with letrozole

Chan, S. et al. J Clin Oncol; 23:5314-5322 2005

Randomized Phase II Trial with Temsirolimus/CCI-779 Randomized Phase II Trial with Temsirolimus/CCI-779 in advanced breast cancerin advanced breast cancer

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Progression of pro-Angiogenic activity in Breast cancer

VEGF VEGFbFGF

VEGFbFGFTGF

VEGFbFGFTGFPLGF

VEGFbFGFTGFPLGF

PD-ECGF

VEGFbFGFTGFPLGF

PD-ECGFEtc….

Modified by Tortora, 2003 from Relf et al., Cancer Res. 1997

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PKAIPI3K

PLC

GRB2 SOS p21ras Raf

MAPK

Cyclin D1

CDK

RbCell ProliferationCell Proliferation

E2Fmdm2

p53

PKC

Cross-talk tra diverse vie di segnale : base Per l’ acquisizione di resistenza a terapie selettive

AKT

Bcl-2

mTOR

Angiogenesis

Invasionmetastasis

VEGFMEK

P

PP P

c-KITR

PDGFR,HER/erbB

Apoptosis

PTEN

IGF-R1

Endothelial cells

VEGFR1 VEGFR2

Tortora et al., 2006

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Novel Paradigm :“Multi-targeted therapy”

• Multiple targeted cells– Cancer cells– Endothelial cells– Pericytes– Fibroblasts

• Multiple molecular targets– HER– VEGF/VEGFR– PDGF/PDGFR– KIT/MET/RET– Others kinases

Angiogenesis

Receptor tyrosine kinases

Faivre et al. Sem Oncol, 2006

Serine/threonine kinases

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I recettori del VEGFI recettori del VEGF

VEGFR-1/Flt-1 VEGFR-2/KDR

VEGFR-3/Flt-4

LYMPHANGIOGENESIS

ANGIOGENESIS

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ZD6474/Vandetanib (VEGFR2 + EGFR + RET)

AE778 (VEGF-R2 + EGFR)

Sunitinib (VEGFRs + PDGFRs+ c-Kit)

Sorafenib (VEGFRs + PDGFRs + raf1 + MAPK + Erk + c-Kit)

PTK787/Vatalanib (VEGFRs + PDGF-Rs)

GW786024 (Pazopanib) (VEGFRs + PDGF-Rs+ c-Kit)

AG013736 (VEGFRs + PDGF-Rs

Multitargeted agents affecting VEGF-Rs and EGFR, PDGF-Rs, Kit etc.

Page 30: I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Cattedra di Oncologia Medica e Laboratori di Terapia Molecolare Dipartimento di Endocrinologia e Oncologia.

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

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A Multicenter Phase II Trial of ZD6474, a VEGFR-2 and EGFR TKI, in Patients with Previously Treated Metastatic Breast Cancer

Kathy D.Miller, JoseManuelTrigo, Catherine Wheeler, Alan Barge, Jacqui Rowbottom, George Sledge, and Jose Baselga

Miller KD, Clin Cancer Res 2005;11(9)May 1, 2005

100mg/d n=22

300mg/d n=24

There were no responses (only 1patient, in 300 mg/d group, had a SD for >24 weeks)

The median time to progression was similar in both groups: 45 days in the 300mg group; 44 days in the 100mg/d group.

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The endothelial cell-pericyte network of signals

Nature Review Cancer

• Pericytes protects endothelial cells from apoptosis and overexpress PDGF-R• PDGF-R is overexpressed in many tumors• PDGF-R and VEGF cooperate

Page 33: I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Cattedra di Oncologia Medica e Laboratori di Terapia Molecolare Dipartimento di Endocrinologia e Oncologia.

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

Page 34: I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Cattedra di Oncologia Medica e Laboratori di Terapia Molecolare Dipartimento di Endocrinologia e Oncologia.

SU11248 increased activity in combination with Docetaxel in a breast cancer model

Complete regression in 33% of mice, with no regrowth 3 months after dosing stopped on day 72

SU11248

Ave

rag

e T

um

or

Vo

lum

e, m

m3

Days After Dosing BeganDocetaxel

0

500

1,000

1,500

0 10 20 30 40 50 60 70

Abrams et al. Mol Cancer Ther. 2003;2:1011-1021, with permission.

Vehicle controlSU11248 40 mg/kg per day PO

Docetaxel 15 mg/kg IV once per week x 3SU11248 40 mg/kg per day + docetaxel 15 mg/kg once per week x 3

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Phase II study of Sunitinib in MBC

Miller et al., ASCO 2005 e SABC

6 weeks cycle (50 mg/day for 28 d. and 2 weeks rest).

64 pts enrolled (84% HER-2 negative/unknown; 56% ER pos).

82% with (multiple) visceral sites. Heavily pretreated (several previous CT regimens in adjuvant setting and in metastatic setting).

Asthenia and diarrhea major grade 2 toxicities. 40% grade 3 neutropenia.

51 evaluable for responses. PR: 7 (14%); SD > 6 mo: 1 (2%).

No clear correlation between response and ER or HER-2 status.

KD Miller, HJ Burstein, AD Elias, HS Rugo, MA Cobleigh, AC Wolff, PD Eisenberg, MD Pegram, M Collier, BJ Adams, CM Baum

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Ongoing studies with Sunitinib

Phase III randomized study of Sunitinib + capecitabine vs capecitabine in pretreated advanced breast cancer patients

430 pts. Primary endpoint: PFS

Phase 2 randomized, double blind study of Sunitinib in combination with Trastuzumab in 1st line for MBC. Primary endpoint: Response Rate

2 Phase I studies of Sunitinib in combination with Paclitaxel (or with Docetaxel) in 1st line for MBC.

20 pts. each Primary endpoint: Safety

Phase III randomized study of Sunitinib vs capecitabine in advanced breast cancer patients who failed both taxane and anthracycline (or failed a taxane and anthracycline therapy is not indicated).

700 pts. Primary endpoint: PFS

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Ongoing studies with Sunitinib

Phase 1-2 study of Sunitinib in combination with Exemestane in 1st line for MBC.

70 pts. Primary endpoint: PFS, Safety

Phase 2 randomized study of Sunitinib vs Standard of care in previously treated Triple receptor negative (ER, PR, HER2) BC.

200 pts. Primary endpoint: PFS

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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

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SorafenibPhase II trial in metastatic breast cancer patients failing

anthracycline and/or taxane

Limited single-agent activity. Only 1/23 patients responding to therapy. Moreno-Aspitia A et al., JCO 24:18S, 2006 (abstract #577)

A phase I trial combining sorafenib with bevacizumab

Dose escalation trial in 34 patients with multiple tumor types. Both toxicity and efficacy are increased compared with single-agent therapy. Azad N et al., ASCO 2006, abstract # 3004

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• 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)

PTK787/ZK 222584 PTK787/ZK 222584 (Vatalanib)(Vatalanib)PTK787/ZK 222584 PTK787/ZK 222584 (Vatalanib)(Vatalanib)

A phase I/II study of vatalanib in combination with trastuzumab in HER-2-overexpressing MBC

Page 41: I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Cattedra di Oncologia Medica e Laboratori di Terapia Molecolare Dipartimento di Endocrinologia e Oncologia.

Analysis of the phase I study showed good tolerability and activity.

The Phase II is ongoing and has currently enrolled over 60 patients. (Rugo et l., 2006).

International Phase I/IItrial with AG-013736 plus docetaxel vs.

docetaxel plus placebo in first-line MBC.

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Anti-VEGFRs, c-Kit and PDGFRs GW786034 (Pazopanib)

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Horizontal and Vertical blockadeHorizontal and Vertical blockade

Combinations of targeted agents to block signaling with:

• an horizontal blockade : EGFR, VEGF and PDGFR.

• a vertical blockade : at two levels of the same pathways: HIF + VEGF or VEGF+VEGFR

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GW786034 (Pazopanib) in combination with Lapatinib in breast cancer xenografts

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relapsed or refractory inflammatory breast cancer

overexpressing ErbB2(n=320)

Lapatinib 1500 mg/day +placebo

Primary endpoint: PFS

Secondary endpoint: overall Response Rate, time-to-response, response duration, quality of life, overall survival (OS), safety and tolerability, biomarkers, pharmacokinetics and pharmacogenomics

Patients in the bevacizumab plus CP arm may receive single-agent bevacizumab until disease progression

PD*

PDLapatinib 1500 mg/day +Pazopanib 800 mg/day

Phase III Randomized double blind study with Pazopanib in combination with Lapatinib in MBC

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CONCLUSIONI

I farmaci multitargeted sono agli esordi nella terapia dei tumori della mammella.

Molti studi sono in corso e prevedono analisi genomiche e farmacodinamiche che ptrebbero aiutare a interpretare I risultati e a selezionare I pazienti.