Desarrollo de Terapias Biológicas Antonio González Martín Centro Oncológico MD Anderson...
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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