desarrollo de terapias biológicas antonio gonzález martín centro oncológico md anderson...

Desarrollo de Terapias Biológicas

Antonio González MartínCentro Oncológico

MD Anderson Internacional España

AGENDA

• Avances en terapia anti-HER2

• Terapias biológicas en pacientes triple-negativo

• Terapias biológicas en pacientes con perfil luminal

Perfil HER-2

Pacientes HER-2 [+] / RE [+]

FISH +

Cross-talks entre HER2 y RECross-talks entre HER2 y RE

Estudio TransATAC: Tiempo a la Estudio TransATAC: Tiempo a la recurrencia en función recurrencia en función de HER2 HER2

HER2+HER2

n=839HR=2.30P=0.001

40 1 2 3 5 6

35

30

15

10

5

0

25

20

40 1 2 3 5 6

35

30

15

10

5

0

25

20

n=877HR=3.23P<0.0001

HER2+HER2

HR = hazard ratio.Update of Dowsett and Allred. Breast Cancer Res Treat. 2006;100(suppl 1):S21. Abstract 48.

Tamoxifen Patients

Years

Anastrozole Patients

Years

Pat

ien

ts (

%)

• HER2+ status was significantly associated with reduced time to recurrence for both tamoxifen and anastrozole

Tiempo a la Progresión

TAnDEM: Anastrozol ± Trastuzumab en CMM RE[+]/HER2[+]

TAnDEM: Anastrozol ± Trastuzumab en CMM RE[+]/HER2[+]

8

100

80

60

40

20

0 5 10 15 20 25 30 35 40 45

0

Meses

Anastrozol - HER2[+]

Anastrozol - Herceptin

Œ

Œ

Ž

Ž

Tamoxifen (Control estudios IA)3 IA (estudios fase III)

Estudios con IA en Primera Línea CMMEstudios con IA en Primera Línea CMMTiempo a la Progresión de tratamientoTiempo a la Progresión de tratamiento

TPT

2.4 m

4.8 m

5.5 / 6.0 / 6.4 m

9.4 / 10.5 / 10.7 m

Cortesía Dr. Antonio Llombart

Endpoint: PFS in RE+/HER-2+

Resistencia a Trastuzumab

Implicaciones Clínicas de Resistencia a TrastuzumabImplicaciones Clínicas de

Resistencia a Trastuzumab

• Prácticamente todas la pacientes metastásicas HER-2 positivo terminan progresando a trastuzumab

• Trastuzumab previene la mitad de recaídas en el tratamiento adyuvante, por tanto la mitad de recaídas no son evitadas.

Estructura Tratuzumab-DM1Estructura Tratuzumab-DM1

T-DM1 3,6 mg/kg IV cada 3 semanasFase I (ASCO 08): 44% respuestas en 9 pacientescon enfermedad medible

Criterios InclusiónCriterios Inclusión

• Carcinoma mama metastásico• Progresión terapia anti-HER-2

en 60 días previos• Tratamiento previo con

quimioterapia• No enfermedad cerebral activa

(sintomática o que fuera tratada en los 3 meses previos)

• Enfermedad medible

Trastuzumab-Resistentes55% lapatinib previo

Mediana 3 (1-12)Antraciclinas 76%

112 pacientes

8% enfermedad SNC

55% hepática50% pulmonar

Exposición Tratuzumab-DM1Exposición Tratuzumab-DM1

N=112

Mediana ciclos 5 (1-16+)

Pacientes con reducción dosis 3 (2.6%)

Toxicidad Grado 3/4Toxicidad Grado 3/4

Efectos AdversosEfectos Adversos

Toxicidad CardiacaToxicidad Cardiaca

Eficacia: Actividad antitumoralEficacia: Actividad antitumoral

Eficacia: Actividad antitumoralEficacia: Actividad antitumoral

ORR ORR confirmed

Lapatinib pretreated

(n=60)

38% (23/60)

(CI 26.1-51.8)

21.7% (13/60)

(CI 12.7-33.7)

Centrally confirmed HER-2

(n=64)

50% (32/64)

(CI 37.2-62.8)

34.4% (22/64)

(CI 22.9-47.3)

Fase I: Wong (ASCO 2006)• Administración oral diaria• TLD diarrea. Dosis recomendada: 240 mg /día• Respuesta en 8/29 pacientes pretratadas con trastuzumab

DiseñoDiseño

• Estudio fase II• Cáncer de mama estadio IIIB-IV HER-2 [+] por

FISH confirmado en laboratorio central• Dosis oral diaria: 240 mg• Dos ramas

– Brazo A: Trastuzumab previo (> 6 semanas)– Brazo B: NO trastuzumab previo

• Objetivo primario: PFS a 16 semanas

Efectos AdversosEfectos Adversos

EficaciaEficacia

EficaciaEficacia

Cambio Climático

Efficacy, safety, and tolerability of dual monoclonal antibody therapy with pertuzumab + trastuzumab in

HER2+ MBC patients previously treated with trastuzumab.

J Baselga et al. Abstract 3138

Efficacy, safety, and tolerability of dual monoclonal antibody therapy with pertuzumab + trastuzumab in

HER2+ MBC patients previously treated with trastuzumab.

J Baselga et al. Abstract 3138

Efficacy, safety, and tolerability of dual monoclonal antibody therapy with pertuzumab + trastuzumab in

HER2+ MBC patients previously treated with trastuzumab.

J Baselga et al. Abstract 3138

Efficacy, safety, and tolerability of dual monoclonal antibody therapy with pertuzumab + trastuzumab in

HER2+ MBC patients previously treated with trastuzumab.

J Baselga et al. Abstract 3138

Efficacy, safety, and tolerability of dual monoclonal antibody therapy with pertuzumab + trastuzumab in

HER2+ MBC patients previously treated with trastuzumab.

J Baselga et al. Abstract 3138

Efficacy, safety, and tolerability of dual monoclonal antibody therapy with pertuzumab + trastuzumab in

HER2+ MBC patients previously treated with trastuzumab.

J Baselga et al. Abstract 3138

Rationale for mTOR inhibitionRationale for mTOR inhibition

• Población muy pretratada– Mediana de regímenes previos = 6 (1-26)– 96% trastuzumab resistentes– 44% taxano resistentes

• Diseño: everolimus diario (5-10 mg) o semanal (30 mg)• Eficacia

– Población total (n=27): TR 41% (CR 5%) + DC 77%– Población trastuzumab y taxano resistente (n= 12): TR 67%

(CR 11%) + DC 100%

DC= CR/PR/SD > 16 semanas

RAD 001 (everolimus) in combination with weekly paclitaxel and trastuzumab in patients with HER-2

overexpressing MBC with prior resistance to trastuzumab : a multicenter phase I trial.

O’Reagan et al. Abstract 3119

RAD 001 (everolimus) in combination with weekly paclitaxel and trastuzumab in patients with HER-2

overexpressing MBC with prior resistance to trastuzumab : a multicenter phase I trial.

O’Reagan et al. Abstract 3119

Multicenter phase I clinical trial of daily and weekly RAD001 (everolimus) in combination with vinorelbine

and trastuzumab in patients with HER-2-overexpressing MBC with prior resistance to trastuzumab

Fasolo et al. Abstract 406

Multicenter phase I clinical trial of daily and weekly RAD001 (everolimus) in combination with vinorelbine

and trastuzumab in patients with HER-2-overexpressing MBC with prior resistance to trastuzumab

Fasolo et al. Abstract 406

• Población muy pretratada– Mediana de regímenes previos = 4 (2-12)– 100% trastuzumab resistentes

• Diseño: everolimus diario (10 mg) o semanal (30 mg20 mg)• Eficacia (n=37)

– CR 3%– PR 15%– CR+PR+SD > 6 meses: 50%

DC= CR/PR/SD > 16 semanas

Phase II of lapatinib and bevacizumab in HER-2 over-expressing MBC

Dickler et al. Abstract 3133.

Phase II of lapatinib and bevacizumab in HER-2 over-expressing MBC

Dickler et al. Abstract 3133.

Phase II of lapatinib and bevacizumab in HER-2 over-expressing MBC

Dickler et al. Abstract 3133.

Phase II of lapatinib and bevacizumab in HER-2 over-expressing MBC

Dickler et al. Abstract 3133.

Phase II of lapatinib and bevacizumab in HER-2 over-expressing MBC

Dickler et al. Abstract 3133.

Phase II of lapatinib and bevacizumab in HER-2 over-expressing MBC

Dickler et al. Abstract 3133.

Efectos adversos

Eficacia- PFS a 12 semanas: 69% (CI 54.9-81.3)- ORR: 13.3% (CI 5.1-28.8)

Nuevas combinaciones

en primera línea para pacientes

HER-2 [+]

Sunitinib presenta un mecanismo de acción doble: Antiangiogénico y Antitumoral intrínseco

Faivre S. Nat Rev Drug Discov 2007;6(9):734-45.

Activity and Safety of Sunitinib in Combination with Trastuzumab for the Treatment of Metastatic Breast

Cancer: Initial Results from a Phase II Study Bachelot T, Lluch A, Gutierrez M, Martin M. 4145

Activity and Safety of Sunitinib in Combination with Trastuzumab for the Treatment of Metastatic Breast

Cancer: Initial Results from a Phase II Study Bachelot T, Lluch A, Gutierrez M, Martin M. 4145

• 53 pacientes• HER-2 [+] avanzadas/metastásicas se

permitía tratamiento previo con 1 línea de QT así como tratamiento con trastuzumab o lapatinib.

• 43% recibieron trastuzumab previamente• Trastuzumab semanal o trisemanal dosis

estándar + sunitinib 37.5 mg/día

Sunitinib + Trastuzumab : Phase II Study Bachelot T, Lluch A, Gutierrez M, Martin M. 4145

Sunitinib + Trastuzumab : Phase II Study Bachelot T, Lluch A, Gutierrez M, Martin M. 4145

• Toxicidad– 9 pac supendieron

tratamiento por EA – 2 descensos de FEVI– 1 caso de trombopenia,

epistaxis, shock cardiogénico, pancreatitis, hypercalcemia, neutropenia y fistula anal.)

• Eficacia– ORR 24% – CR 4% + PR 20%– CI 95% 12.8-37.5

Tolerability of Sunitinib in Combination with Docetaxel and Trastuzumab as First-line Therapy for

HER2+ Advanced Breast CancerCardoso et al. Abstract 4120

Tolerability of Sunitinib in Combination with Docetaxel and Trastuzumab as First-line Therapy for

HER2+ Advanced Breast CancerCardoso et al. Abstract 4120

1ª línea

22 pac

1 pac (5.4%) T adyuvante

Gr 3 non-hematologic AEs were:• fatigue/asthenia (23%)• diarrhea (14%)• stomatitis (9%)• vomiting (9%).

ORR 77%

Perfil Triple Negativo

Copyright restrictions may apply.

Finn, R. S. Ann Oncol 2008 19:1379-1386; doi:10.1093/annonc/mdn291

Src activation by several pathways can lead to diverse effects on a tumor's clinical behavior

Src activation by several pathways can lead to diverse effects on a tumor's clinical behavior

Phase II Trial of Dasatinib in Triple-negative Breast Cancer: Results of Study CA180059

Finn R et al. Abstract 3118

Phase II Trial of Dasatinib in Triple-negative Breast Cancer: Results of Study CA180059

Finn R et al. Abstract 3118

Eligibility– triple-negative breast cancer (ER and PR-negative and Her2-normal, per institutional analysis)– measurable locally advanced or metastatic disease– prior anthracycline and/or taxane therapy, with 0–2 prior regimens in the advanced setting (70% pretreated)

AE grado 3 significativos:-Astenia-Diarrea-Derrame pleural-Edemas generalizados

Phase II Trial of Dasatinib in Triple-negative Breast Cancer: Results of Study CA180059

Finn R et al. Abstract 3118

Phase II Trial of Dasatinib in Triple-negative Breast Cancer: Results of Study CA180059

Finn R et al. Abstract 3118

ORR 4.7%ORR 4.7% Median PFS 8.3 wMedian PFS 8.3 w

PARP inhibitors in TNBCPARP inhibitors in TNBC

Randomized phase II of Carboplatin/Gemcitabine + BSI-201 in metastatic TNBC

O’Shaugnesy et al. Abstract 2120

Randomized phase II of Carboplatin/Gemcitabine + BSI-201 in metastatic TNBC

O’Shaugnesy et al. Abstract 2120

Eligibility– Metastatic TNBC– RECIST at least 1– 0–2 prior regimens

Results– 78 patients included– 56 patients evaluated for toxicity– No significant differences in toxicity– Efficacy results pending

Primary Objective– CBR (CR + PR + SD > 6 months

Perfil Luminal

Crosstalk between signal transduction and endocrine pathway

Safety of the anti-IGF-1R antibody CP-751,871 in combination con exemestane in patients with

advanced breast cancer. Ryan et al. Abstract 2136

Safety of the anti-IGF-1R antibody CP-751,871 in combination con exemestane in patients with

advanced breast cancer. Ryan et al. Abstract 2136

Inclusión– Estadio IIIB or IV– ER+– Postmenopausica– No IA en previos 12 meses

Toxicidad grado 3-4 -5% de reacciones alérgicas -12% incremento reversible GGT-14% de hiperglucemia-2% de cetoacidosis diabética.

Endpoint: PFS

Anastrazole

Gefitinib

Anastrazole + Gefitinib (SABCS 08)Anastrazole + Gefitinib (SABCS 08)

Valero (A#3131) Mauriac (A#6133)

A+G A+Pl A+G A+Pl

N 93 71

CBR 49% 34% 25% 24%

PFS 14,5 8,2

HR 0,55 (0,32-0,94)

PFS@1y 45.7% 44.1%

TAS-108 a new antiestrogenTAS-108 a new antiestrogen

Phase II with TAS-108 presented at SABCS 2008

Phase II with TAS-108 presented at SABCS 2008

Buzdar et al. A#2131 Iwata et al. A#2132

N 146 97

Dose (mg)

40 80 120 40 80 120

RR 6% 4% 2% 9.1% 9.4% 6.3%

CBR 21% 20% 5.3% 30% 25% 25%

PFS days

105 111 78 120 112 109

CONCLUSIONES

• Las pacientes HER-2/RE [+] precisan bloqueo de ambas vías.– El estudio EGF 30008 avala el empleo de lapatinib y

letrozol• Comenzamos a disponer de estrategias activas

en resistencia a trastuzumab– T-DM1, Neratinib, Pertuzumab, inh m-TOR…

• La pacientes triple-negativo siguen buscando su diana– Src, PARP…

• El futuro de las pacientes luminales puede ser la asociación de hormonoterapia con el bloqueo de otras vías de señalización– IGFR, HER-1…

Muchas Gracias

Hudis C. N Engl J Med 2007;357:39-51

Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab

Adjuvant trastuzumab for 1 yearincrease DFS

Adjuvant trastuzumab for 1 yearincrease DFS

Favour Trastuzumab

HR 0.48 (95% CI 0.41-0.57)

1.00.5

B31/N9831

HR 0.61 (95% CI 0.48-0.76)BCIRG 006

HR 0·64 (95% CI 0·54-0·76)HERA

Neoadjuvant trastuzumab increase pCR

Neoadjuvant trastuzumab increase pCR

0

10

20

30

40

50

60

70

T -> FEC TH->FECH TH->FECH QT QTH

MD ANDERSON EXPERIENCE NOAH

pCR(%)

Trastuzumab in 1st line of MBC increase OS

Trastuzumab in 1st line of MBC increase OS

H0648g

Slamon et al. N Eng J Med 2001

M77001

Marty et al. J Clin Oncol 2005

Mantener terapia anti-HER2 tras progresión a T aumenta las SLEMantener terapia anti-HER2 tras progresión a T aumenta las SLE

N Eng J Med, 2006 ASCO 2008 ASCO 2008

Lapatinib + C > C Trastuzumab + C > C T + L > L

Mantener terapia anti-HER2 tras progresión a T aumenta las SLEMantener terapia anti-HER2 tras progresión a T aumenta las SLE

Lapatinib + capecitabinebetter than capecitabine

N Eng J Med, 2006

Trastuzumab + capecitabinebetter than capecitabine

ASCO 2008

Mantener terapia anti-HER2 tras progresión a T aumenta las SLEMantener terapia anti-HER2 tras progresión a T aumenta las SLE

Lapatinib + trastuzumab > lapatinib

72

RO (%) TPT (ms) SG (ms)

AC + H N = 278 56 7,8 27

P + H N = 186 41 6,9 22

D + H N = 186 61 10,6 24,1

ANA + H N = 207 20 4,8 28,5

Slamon D, et al. N Engl J Med 2001;344:783–92Marty et al. J Clin Oncol. 2005;23: 4265-74

AC, doxorubicin & cyclophosphamide; P, paclitaxel; D, docetaxel; H, herceptin

Estudios en Primera Línea CMM – HER2[+]Estudios en Primera Línea CMM – HER2[+]TPT y SGTPT y SG

Copyright restrictions may apply.

Finn, R. S. Ann Oncol 2008 19:1379-1386; doi:10.1093/annonc/mdn291

Src plays a key role in several signal transduction pathways implicated in cell growth, survival,

motility, and angiogenesis

Src plays a key role in several signal transduction pathways implicated in cell growth, survival,

motility, and angiogenesis

Características pacientesCaracterísticas pacientes