Oncologia medica - Anticorpi anti HER

Cetuximab: properties

• IgG1 chimerised antibody

cetuximab

Ligand • Targets HER1, including

EGFRvIII

• Binds to HER1 with high

affinity (kd 0.1nM)

• Prevents HER1 ligand

binding

K K • Reduces ligand-induced

tyrosine kinase (TK) activity

• Stimulates receptor

internalisation

Cetuximab: mechanism of

action

• Inhibits cell-cycle

cetuximab

Ligand progression

• Potentiates apoptosis

• Decreases angiogenic

growth factor production

• Inhibits metastasis

K K formation

• Enhances the activity of

chemo- and radiotherapy

Signal transduction

Cetuximab: synergistic effects

with cisplatin on A431 xenografts

Control Cetuximab

Cisplatin Cetuximab + cisplatin

Cetuximab 100

6 Cisplatin

)

3 75

(cm (%)

4 Survival

size 50

Tumour 2 25

0

0 0 5 15 25 35 0 20 40 60 80 180

Days Days

Fan Z, et al. Cancer Res 1993;53:4637–42

Cetuximab: enhanced activity with 5-

fluorouracil on pancreatic (BxPC-3)

xenografts 38

Saline Cetuximab

1,200 5-FU Cetuximab +

)

3 5-FU

(mm 1,000

volume 800

600

tumour 400

Mean 200

0 0 5 10 15 20 25 30 35 40 45 50 55

Days after tumour implantation

Overholser J, et al. Cancer 2000;89:74–82

Synergistic effects of cetuximab and

radiation on human epidermoid tumour

cell xenografts

16 No treatment 18Gy

1 x cetuximab 1 x cetuximab + 18Gy

3 x cetuximab 3 x cetuximab + 18Gy

14

)

3

(mm 12

size 10

Tumour 8

6 Limit of accurate

detection

4 0 8 16 24 32 40 48 56 64 72 80

Days after initial treatment

Milas L, et al. Clin Cancer Res 2000;6:701–8

Treatment of refractory HT-29 colon ±

carcinoma xenografts with cetuximab

CPT-11

Cetuximab Cetuximab + CPT-11

CPT-11

Randomise

2,500 failed* mice

CPT-11

)

3

(mm into 3 groups

therapy

2,000

volume 1,500

tumour 1,000

Mean 500

0 0 10 20 30 40 50 60

Days

*failed: >2 fold increase in tumour volume

Prewett M, et al. Proc Am Assoc Cancer Res 2001;42:287 (Abstract 1543)

Cetuximab: possible modes

of action in cancer therapy

• HER1 blockade

• Synergy with other cancer therapies

based on a number of mechanisms

including

– blocked cell-cycle progression in

DNA-damaged cells

– increased apoptosis

– inhibition of tumour angiogenesis

Cetuximab: inhibition of VEGF,

IL-8 and bFGF protein production

200 VEGF

IL-8

(%) bFGF

150

production 100

Relative 50

0 Medium 10µg/mL 50µg/mL 1µg/mL 10µg/mL

alone lgG + EGF EGF cetuximab cetuximab

+ EGF + EGF

Perrotte P, et al. Clin Cancer Res 1999;5:257–65

Cetuximab: pharmacokinetics

• Non-linear and dose-dependent

• Saturation of drug-elimination pathways

occurs at doses between 200 and

2

400mg/m

• Current recommended dose level

2

– loading dose: 400mg/m 2

– weekly maintenance dose: 250mg/m

• Not altered by co-administration with

cisplatin

Cetuximab: safety and

tolerability profile

• 62% of patients reported drug-related adverse

events

• 12% of patients reported grade 3/4 adverse

events

• Most common adverse events (>5%)

– asthenia (18%)

– fever (16%)

– nausea (16%)

– skin rash/acne (15%)

Cetuximab: safety and

tolerability profile

Most clinically relevant adverse events

• Hypersensitivity reactions

– 4% of patients experienced grade 3/4

hypersensitivity reactions

– use of a test dose is advised

• Acne-like skin rash

– appears during the first few weeks of therapy

– usually resolves on cessation of treatment

or dose reduction

Cetuximab: summary

• Mode of action of cetuximab

– binds to HER1 with high affinity, blocking

growth-factor binding and receptor activation

– enhances tumour response to chemotherapy

or radiotherapy by a number of mechanisms

• Cetuximab pharmacokinetics

– non-linear and dose-dependent

– not altered by co-administration with cisplatin