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