V Jornada Growing Up

Tratamiento dirigido a diana:

eficacia y toxicidad

Anticuerpos Monoclonales
contra el EFGR
Dra. Mara Vernica Pereira Daz, R4
Tutora: Dra. Laura Vidal
Servicio de Oncologa Mdica
Hospital Clnic de Barcelona
22 Enero 2012
 Outline
EGFR signalling pathway
Monoclonal antibodies
Cetuximab
Panitumumab
Indicaciones clnicas
EFGR mAB in colorectal cancer
EGFR mAB in head and neck cancer
Toxicidades y su manejo
 EGF
TGFa Heregulinas
Ligandos
Amfiregulina b-celulina
HB-EGF NRG2
b-celulina Heregulinas NRG3

Dominio
extracelular

Membrana
Dominio
Tirosn-
kinasa

EGFR HER2 HER3 HER4

 The Development of Monoclonal
Antibodies

Mouse Chimeric Humanized Fully Human

100% ~34% ~10% 100%

Mouse Protein Mouse Protein Mouse Protein Human Protein

cetuximab panitumumab
(IgG1) (IgG2)

Yang XD, et al. Crit Rev Oncol Hematol 2001;38:17-23.

 Panitumumab Inhibits Ligand Binding to EGFR and
Dimerization

EGF, TGF or other ligands Inhibition of EGF

binding to EGFR binding to EGFR

Panitumumab

This may lead to:

A fully human lgG2 monoclonal Cell proliferation
antibody to EGFR Cell survival
High affinity, KD = 5 x 10-11 M Angiogenesis
Inhibits ligand-induced EGFR Metastatic spread

tyrosine phosphorylation
1. Yang XD, et al. Crit Rev Oncol Hematol. 2001;38(1):17-23. 2. Foon KA, et al. Int J Radiat Oncol Biol Phys. 2004;58(3):984-990.
 Potential relationship between KRAS status and response to epidermal growth factor
receptor (EGFR) monoclonal antibodies, alone or in combination with irinotecan, in
chemotherapy-refractive patients.

Wong R , Cunningham D JCO 2008;26:5668-5670

2008 by American Society of Clinical Oncology

 Recent developments with Erbitux:
Recurrent and/or metastatic SCCHN

EXTREME study: Erbitux + platinum/5-FU in first line

recurrent and/or metastatic SCCHN
Primary endpoint (OS) was met
Significant improvements in OS, PFS and response rate
Addition of Erbitux did not adversely influence QoL

Breakthrough advances
Erbitux + platinum/5-FU is the first systemic treatment to show an overall
benefit over platinum/5-FU alone in recurrent and/or metastatic SCCHN
 EGFR is a potent mediator of
radioresistance
Posibles mecanismos1-3:
Upregulation of Bcl-2 (down-regulation of apoptotic response induced by
RT [or CT])
Upregulation of DNA repair mechanisms (repair of potential lethal damage
RT [or CT] induced)
Upregulation of cyclin D activating cell proliferation (enlarging proportion of
cells in radioresistant phase of cell cycle)

Blockade of EGFR signal transduction increases

RT activity4 and enhances apoptotic response5

CT, chemotherapy
1 Ke Liang MS, et al. Int J Radiat Oncol Biol Phys 2003;57:246254;2 Mendelshon J. J Clin Oncol 2002;20:1s13s;
3 Ochs J. Int J Radiat Oncol Biol Phys 2004;58:941949
4 Huang S-M, et al. Clin Cancer Res 2000;6:21662174; 5 Harari P, et al. Int J Rad Oncol 2001:49;427433
 Erbitux + RT in locally advanced SCCHN:
Phase III study design
RT (n=213)
Stage III and IV
non-metastatic
R
SCCHN Erbitux + RT (n=211)
(n=424) Erbitux initial dose (400 mg/m2)
Stratified by 1 week before RT
KPS Erbitux (250 mg/m2) + RT (weeks 28)b
Nodal involvement
Tumor stage
RT regimena

Primary endpoint: Duration of locoregional control

Secondary endpoints: OS, PFS, RR, and safety

a
Investigators choice; bUAB regimen: Robert F. J Clin Oncol (2001)

Bonner J, et al. N Engl J Med 2006;354:567578

 Erbitux in locoregionally advanced SCCHN:
Efficacy summary

Erbitux + RT demonstrated significant efficacy benefits over

RT alone

20-month increase in median survival

26% reduction in risk of death

10-month increase in median locoregional control

32% reduction in locoregional relapse

Bonner J, et al. N Engl J Med 2006;354:567578

 Toxicidad por anti EGFR
monoclonal antibodies
Frecuencia Efecto adverso
>10% - Hipomagnesemia
- Aumento en los niveles de enzimas hepticas
- Reacciones cutneas
- Reacciones leves o moderadas en la perfusin
1-10% - Deshidratacin
- Hipocalcemia
- Cefalea
- Conjuntivitis
- Diarrea, nuseas, vmitos, anorexia.
- Reacciones graves relacionadas con la perfusin.
- Cansancio
<1% - Blefaritis, queratitis.
- TVP, TEP.
 ERUPCIN CUTNEA
ACNEIFORME

Grado Lesin Extensin Sntomas AVD Infeccin

Grado 1 ppulas / <10% +/- prurito /
pstulas hiperestesia
Grado 2 ppulas / 10-30% +/- prurito / Dificulta
pstulas hiperestesia instrumentales
Grado 3 ppulas / >30% +/- prurito / Dificulta Local: atb
pstulas hiperestesia bsicas tpicos
Grado 4 ppulas / cualquiera +/- prurito / Extendida:
pstulas hiperestesia atb iv
 ERUPCIN CUTNEA ACNEIFORME

1 2

3
RECOMENDACIONES GENERALES

Desde una semana antes y durante el tto:

Lavado diario con agua tibia (no caliente).

Evitar irritantes: NO jabones, perfumes, desodorantes,
lociones con alcohol.
S: geles de ducha basados en aceites / avena.
Uso diario de cremas hidratantes (prevencin sequedad).
NO aloe vera.
Evitar:
Exposiciones al sol (hasta 3 meses despus del tto).
Afeitado con navaja (maquinilla elctrica).
Tintes de cabello con amoniaco.
MODIFICACIN DOSIS
 CONCLUSIONES I

EGFR juega un papel importante en la regulacin de

mltiples mecanismos de subsistencia tumoral y su
expresin esta asociada con un peor pronstico.

En CCR avanzado se ha demostrado el beneficio de los

anticuerpos monoclonales Cetuximab y Panitumumab en
pacientes KRAS wt ( factor predictivo).

Es de practica clnica habitual la determinacin del estado

de KRAS en pacientes con CCR avanzado.
 CONCLUSIONES II

En carcinoma de cabeza y cuello avanzado se ha

demostrado la eficacia del Cetuximab en regmes basados
en platino. No existe marcador predictivo de respuesta.

El rush acneiforme es una toxicidad caracterstica de estoa

agentes y en CCR avanzado se asocia a mayor beneficio
clnico.

Un manejo adecuado de las toxicidades permite menos

interrupciones en el tratamiento.
MUCHAS GRACIAS!