Doble Bloqueo Vertical en Cáncer de Mama HER2 … · Doble Bloqueo Vertical en Cáncer de Mama...
Transcript of Doble Bloqueo Vertical en Cáncer de Mama HER2 … · Doble Bloqueo Vertical en Cáncer de Mama...
Doble Bloqueo Vertical en Cáncer de Mama HER2-positivo
Dr. Antonio Llombart Cussac
Hospital Arnau Vilanova, Valencia
CMM HER2[+]: Doble Bloqueo Vertical en 2014
• Trastuzumab (T) es la terapia de elección en tumores HER2-positivos
tanto en estadios iniciales como en enfermedad avanzada
• Lapatinib (anti HER2-TKI - small molecule) ha demostrado:
– En modelos preclínicos superioridad frente a T
– Inferioridad en estudios F2F tanto en estadios iniciales (ALTTO;
NeoQT x4) como enfermedad avanzada (NCIC; Cerebel)
• Estudios preclínicos demuestran una importante sinergia en la
combinación de ambos fármacos, justificando su exploración en
ensayos clínicos
• Lapatinib plus trastuzumab
resulted in complete tumor
remission in xenografts1
– Effect was durable: no tumor relapse
after 8 months post treatment
• Lapatinib induced accumulation of
inactive HER2 at plasma
membrane1
– Trastuzumab-mediated cytotoxicity was
higher with the addition of lapatinib in
MCF7/HER2 cells
•In vivo activity was consistent with
in vitro data demonstrating the
combination as synergistic
1. Scaltriti M et al. Oncogene. 2009;28:803-14.
Justificación del Doble Bloqueo
Lapatinib impide la fosforilación, proteolisis y degradación de HER2.
Lapatinib induce la acumulación de las formas inactivas de HER2, aumentando así la toxicidad celular mediada por anticuerpos.
K K K K Lapatinib
ATP
ErbB2 heterodimer
ErbB2 homodimer K K K K K K K K K K
K K
trastuzumab
NK cell
FcR
K = kinase domain ADCC = antibody-dependent cell cytotoxicity
Scaltriti M et al. Oncogene 2009; 28: 803-814.
Dimerización, fosforilación reducida e inhibición de la señalización.
Acúmulo de receptores inactivos, Estabilización de los dímeros, permite
aumento de la ADCC.
L sensibiliza células HER2[+] a T (in vitro)
Progressed
or died
Median
PFS
P-
value
Lapatinib
(n=145) 128 (88%)
8.1
weeks
0.008 Lapatinib +
trastuzumab
(n=146)
127 (87%) 12
weeks
ESTUDIO LT CMM PRETRATADA: SLP
6 Month PFS
Cu
mu
lati
ve %
aliv
e w
ith
ou
t p
rogr
ess
ion
148
148
L
L+T
53
73
21
42
13
27
5
8
0
2
13%
28%
0
20
40
60
80
100
10 20 30 40 50 60
Time from randomisation (weeks)
0
Blackwell KL et al. J Clin Oncol. 2010;28:1124-30.
HR: 0.73 (95% CI: 0.57, 0.93)
Patients
At Risk
HR-positive
Lap+Tras N=71
Lap N=70
PFS HR (95% CI)
Median PFS, wks
7.9 8.1 0.73
(0.51-1.04)
ORR 6% 6%
Lap+Tras N=75
Lap N=75
PFS HR (95% CI)
Median PFS, wks 15.4 8.2 0.73
(0.52-1.03)
ORR 15% 8%
Number at Risk
Lap+Tras 71 30 18 13 5
Lap 70 25 8 4 1
HR-negative
Lap+Tras 75 42 23 13 3 2
Lap 75 26 11 8 4
0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
Time from Randomization (Weeks)
Cu
mu
lati
ve
Pro
po
rtio
n A
live
wit
ho
ut
Pro
gre
ss
ion
Lap+Tras Lap
0 10 20 30 40 50
0.0
0.2
0.4
0.6
0.8
1.0
Time from Randomization (Weeks)
Cu
mu
lati
ve
Pro
po
rtio
n A
live
wit
ho
ut
Pro
gre
ss
ion
Lap+Tras Lap
EGF104900: SLP por status RE
Data on file
EGF104900: Supervivencia Global
Blackwell KL et al. J Clin Oncol. 2012;30:2585-92.
Died n (%) Median P-value
Lapatinib (n=145) 113 (78%) 9.5 months 0.026
Lapatinib + trastuzumab (n=146) 105 (72%) 14 months
Time from randomisation (months)
Su
rviv
al (%
)
HR: 0.74 (95% CI 0.57, 0.97)
6-month OS
80%
70%
12-month OS
41%
56% 53% of patients on
control arm (Lapatinib) did a cross over
0 5 10 15 20 25 30
0.0
0.2
0.4
0.6
0.8
1.0
Time from Randomization (Months)
Cu
mu
lati
ve P
rop
ort
ion
Ali
ve
Lap+Tras Lap
HR-positive HR-negative
Lap+Tras N=71
Lap N=70
OS HR (95% CI)
Median OS, mos
12.0 11.2 0.84
(0.5-1.23)
Lap+Tras N=75
Lap N=75
OS HR (95% CI)
Median OS, mos
17.2 8.9 0.62
(0.42-0.90)
Number at Risk
Lap+Tras 71 58 39 26 19 10
Lap 70 50 36 26 12 6
Lap+Tras 75 62 48 37 23 15 1
Lap 75 50 28 20 16 7
EGF104900: Supervivencia Global por Receptor Status
Tyverb Assessment report EMA/CHMP/69582/2013 Available online: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000795/WC500147870.pdf Last access Sept 2013
APROBACION EMA PARA LA POBLACIÓN CMM HER2[+]/RE[-]
EN ESPAÑA EN FASE FINAL DE
APROBACIÓN POR EL MINISTERIO
TRASTYVERE: Doble Bloqueo en la practica Clínica
• Retrospective analysis - Spain - compassive therapy L+ T treatment.
• Study approved by authorities and Ethics committees from all
participating centers. A signed consent form required for surviving
patients.
Major inclusion criteria were
• HER2[+] metastatic or locally advanced MBC;
• ECOG status 0 – 2;
• Progression on at least one prior line of trastuzumab for advanced
disease;
• L plus T treatment started before JAN/2012. Concomitant endocrine
therapy for hormone-positive patients as well as patients with brain
metastasis and/or prior exposure to L was allowed.
• Chemotherapy combinations excluded.
TRASTYVERE: EFICACIA
CONCLUSION: BLOQUEO T+L ENFERMEDAD AVANZADA
• Linea terapeutica eficaz en pacientes HER2/RE[-]
• Comportamiento no dependiente de Resistencia previa a
ambos farmacos
• Futuro:
• Consolidación de esquemas T+L incorporando quimio
(cape?) o terapia hormonal (Impacto en SG)
• Esquemas alternativos en 1ª 2ª linea a PERTU?
Estudios Neoadyuvantes de Doble Bloqueo
EGF106903 (Neo-ALTTO) EGF106988 (CHER-LOB)
LAP108895 (B41) LAP111591 (CALGB 40601)
NeoALTTO: SLE por STATUS HORMONAL
All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation
Lapatinib*
34 weeks 6 wks 12 weeks
3-weekly Trastuzumab
All (neo)adjuvant
chemo prior to anti-
HER2 therapy
Lapatinib + 3-weekly Trastuzumab
Lapatinib Weekly
Trastuzumab
wash out
ALTTO DISEÑO 1: SECUENCIAL TRAS QT (N= 4,613)
52 weeks
Tras alone: 8 mg/kg 6 mg/Kg iv, q21 days Lap alone: 1500 mg po qd Tras Lap: T 4 mg/kg 2 mg/Kg iv q7 days; L 1500 mg po qd Tras + Lap: T 8 mg/kg 6 mg/Kg iv, q21 days; L 1000 mg po qd
Weekly
Trastuzumab
Lapatinib*
34 weeks 6 wks 12 weeks
3-weekly Trastuzumab
Anthracycline-
based chemo first
52 weeks
Lapatinib + 3-weekly Trastuzumab
Lapatinib wash out
DISEÑO 2: CONCOMITANTE TRAS ANTRAS (N= 3,337)
w-P or 3-w D
w-P or 3-w D
w-P or 3-w D
w-P or 3-w D
w-P: weekly paclitaxel (80 mg/m2); 3-w D: q3 weeks docetaxel (75-100 mg/m2) All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation
34 weeks 6 wks 12 weeks
Tras alone: 4 mg/kg 2 mg/Kg iv, q7 days 6 mg/Kg iv, q21 days Lap alone: 750 mg po qd 1500 mg qd Tras Lap: T 4 mg/kg 2 mg/Kg iv q7 days; L 1500 mg po qd Tras + Lap: T 4 mg/kg 2 mg/Kg iv, q7 days 6 mg/Kg iv, q21 days; L 750 mg po qd 1000 mg qd
Weekly
Trastuzumab
Lapatinib*
28 weeks 6 wks 18 weeks
3-weekly Trastuzumab
Non-anthracycline-
based chemo with
anti-HER2 therapy
52 weeks
Lapatinib + 3-weekly Trastuzumab
Lapatinib wash out
DISEÑO 2B: CONCOMITANTE SIN ANTRAS (N= 431)
3-w D + carbo
3-w D + carbo
3-w D + carbo
3-w D + carbo
3-w D: q3 weeks docetaxel (75 mg/m2); carbo: carboplatin (AUC 6) All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation
28 weeks 6 wks 18 weeks
Tras alone: 4 mg/kg 2 mg/Kg iv, q7 days 6 mg/Kg iv, q21 days Lap alone: 750 mg po qd 1500 mg qd Tras Lap: T 4 mg/kg 2 mg/Kg iv q7 days; L 1500 mg po qd Tras + Lap: T 4 mg/kg 2 mg/Kg iv, q7 days 6 mg/Kg iv, q21 days; L 750 mg po qd 1000 mg qd
CARACTERISTICAS DE LA POBLACION
L + T
(N = 2,093)
T → L
(N = 2,091)
T
(N = 2,097)
Lymph Node Status
Not applicable (neoadjuvant chemotherapy) 168 (8%) 170 (8%) 181 (9%)
Node negative 845 (40%) 842 (40%) 844 (40%)
1-3 positive nodes 617 (29%) 617 (30%) 603 (29%)
>=4 positive nodes 463 (22%) 462 (22%) 469 (22%)
Pathological primary tumor size - largest diameter of invasive component
Missing 27 41 38
≤ 2cm 937 (45%) 938 (46%) 942 (46%)
> 2cm to ≤ 5cm 1,002 (49%) 980 (48%) 990 (48%)
> 5cm 127 (6%) 132 (6%) 127 (6%)
ALTTO: SLE
MFU = 4.5 yrs
*
* 97.5% CI
**
**p-value ≤ 0.025 required for statistical significance
SLE por STATUS HORMONAL
Interaction tests p = 0.70 L + T
p = 0.60 T L
MFU = 4.5 yrs MFU = 4.5 yrs
*
* 95% CI
*
* 95% CI
• Estudio negativo para el objetivo principal global y en todos los
sub-grupos (tendencia solida en RE[-] pero beneficio bruto
modesto <3%)
• No confirma observaciones previas del NeoALTTO (pCR y SLP)
Juicio de valor:
• Estudio con grandes criticas: racional científico; elevado numero
de variables; 4 brazos con 3 esquemas; dosis de L diferentes
• ¿Cual debe ser la responsabilidad de los grupos académicos
ante estudios negativos? = La prepotencia de la excelencia
Estudio ALTTO
Varios factores van a intervenir en la decisión:
• Novartis – GSK
• Subestudios Altto: PAM50
Futuro: Identificar poblaciones altamente sensibles al doble
bloqueo y que no precisen Quimioterapia
• Diversos estudios pequeños en marcha con ese objetivo
• Plataformas
• Marcadores especificos (quien se acuerda de p95)
¿Que perspectivas tiene el doble bloqueo?
Estudio PAMELA
ER [-] ER [+]
Central Review HER2 – FISH [+]
ER/PgR/Ki67 by IHC PAM50
Trastuzumab – Lapatinib (18 wks)
TL + AI or TAM (18 weeks)
Surgery
ULTRASOUND On week 6
In the absence of response: CT
added (wP x12)
SOLTI/GSK A.Llombart/A. Prats/J.Cortes/C.Peru/J.Baselga
Primary Objective: pCR (Breast) by PAM50 phenotype: HER2e+ vs. others Assuming a >40% difference in pCR rates: Total 135 patients