New Perspectives in Cancer New Perspectives in Cancer TherapyTherapy

Óren SmaletzÓren SmaletzPrograma de OncologiaPrograma de Oncologia

Hospital Israelita Albert EinsteinHospital Israelita Albert Einstein

Disclosure of Potential Conflicts of Interest

• Honoraria: Pfizer, Merck KGaA

• Research Funding: Pfizer

• Scientific Funding: Merck KGaA, Roche

CFM Resolution nº 1.595/2000SBOC/SBC oct/2007

McMullan D and Cohen G. N Engl J Med 2006;354:397

A 72-year-old man presented for evaluation of progressive dyspnea and cough

Change in the US Death Rates* by Cause, 1950 & 2002

* Age-adjusted to 2000 US standard population.Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.2002 Mortality Data: US Mortality Public Use Data Tape, 2002, NCHS, Centers for Disease Control and Prevention, 2004

22.5

180.7

48.1

586.8

193.9

56.0

193.4

240.1

0

100

200

300

400

500

600

HeartDiseases

CerebrovascularDiseases

Pneumonia/Influenza

Cancer

1950

2002

Rate Per 100,000

Fight Against Cancer

• Surgery

• Radiotherapy

• Chemotherapy

• Targeted Therapy Agents

FDA Approved New Molecules for Solid Tumor Use per Year

0 1 2 3

2002

2003

2004

2005

2006

2007

Targeted Therapy Agent Cytotoxic Agent

Schrag, D., New Engl J Med 2004

Hanahan D, Cell 2000

EGFTGF

Amphiregulin-cellulinHB-EGF

Epiregulin Heregulins

NRG2NRG3

Heregulins-cellulin

Cysteine-richdomains

Tyrosine kinasedomain

HER1EGFRErbB-1

HER2/neuErbB-2

HER3ErbB-3

HER4ErbB-4

C-terminus

100

100

100

44

82

33

36

59

24

48

79

28

The EGFR (erbB) Family and Ligands

Família EGFR (Her)

Hudis NEJM 2007

Trastuzumab – mecanismo de ação

Hudis NEJM 2007

Trastuzumab in Breast Cancer

Trastuzumab – metastatic breast cancer

Slamon, NEJM 2001

Trastuzumab – metastatic breast cancer

Slamon, NEJM 2001

Trastuzumab – adjuvant treatment

Trastuzumab – adjuvant treatment

EGFR Signaling Pathways

Membrane

Extracellular

Intracellular

SignalingMolecules

Cellular effects + proliferation- apoptosis+ angiogenesis+ metastasis

K

R

K K

R

K

pY pY

pY pY

pY pY

Substract

SubstractpY

K

R

K

R RR

EGFR Expression in Human Cancer

Overexpression associated with:

• Invasion• Metastasis • Advanced disease• Poor outcome• Resistance to

chemotherapy, hormonotherapy radiotherapy

*lowest to highest published range of expression

Tumors Expression (%)*

NSCLC 50-90

Colorectal 45-80

Gastric 30-60

Pancreatic 30-50

Ovarian 35-60

Prostate 40-70

Breast 14-91

Head and Neck 70-100

Kidney 80-100

Rubin Grandis J et al. JNCI 1998; 90: 824–832.

Disease-free Survival and EGFR and TGF- Levels in Head and Neck Cancer

0 1 2 3 4 5 6/00.0

0.2

0.4

0.6

0.8

1.0

Years after surgery

Pro

po

rtio

n S

urv

ivin

g

EGFR

low

medium

highp=.0001

1 2 3 4 5 6

Years after surgery

TGF

high

medium

low

p=.0001

EGFR Mab Currently Approved

Clinical activity

randomized trials

FDA ANVISA Dosage

Cetuximab Head & NeckColon/Rectal

YY

YY

400 mg/m2 i.v. initial dose followed by 250 mg/m2 weekly

Panitumumab

Colon/Rectal Y N 6 mg/kg i.v. every 14 days

Cetuximab (Erbitux®)• IgG1 (chimerized antibody)• Exclusive for EGFR and its

heterodimers• Prevents ligand binding to

EGFR• High affinity. Kd = 0.39 nM

(M-225 Kd = 1 nM)

• 1 log > natural ligand• Stimulates receptor

internalization • Blocks receptor dimerization,

tyrosine kinase phosphorylation, signal transduction

Panitumumab (Vectibix®)

• fully human IgG2κ mAb• high affinity (Kd ~ 0.05 nM)• Upon binding, internalized and donwregulates

EGFR• Prevents

– receptor dimerization– EGFR-tyrosine autophosphorylation– activation of downstream signaling molecules

Apoptosis Nucleus

Mechanism of Action of anti-EGFR Monoclonal Antibodies

MetastasisXX

TGF

Membrane

AngiogenesisXX

CetuximabPanitumumab

Cell proliferationXX

XXCancer Cell

Cetuximab in Colorectal Cancer(“Bond Trial”)

• Eligibility criteria Pretreated metastatic colorectal cancer with irinotecan All patients had to be EGF-R positive

Primary end-point Tumor response

Cetuximab in Colorectal Cancer (“Bond Trial”)

Irinotecan pre-treated Metastatic CRCEGFR positive

Cetuximab and Irinotecan218 patients

Cetuximab111 patients

Cetuximab in Colorectal Cancer (“Bond Trial”)N OR (%) TTP

(months)Survival

(months)

C225 and Irinotecan

218 22.9 4.1 8.6

C225 111 10.8 1.5 6.9

p = 0.007

Cunningham et al., New Engl J Med 2004

Cunningham et al., New Engl J Med 2004

Panitumumab in Colon/Rectal Cancer

463 EGFR +, M1 Colon/Rectal Cancer,

POD on standard chemoRX

Panitumumab + BSC

BSC

Primary Endpoint: PFS

Minimum f/u 12 months

Van Cutsem et al., J Clin Oncol 2007

Panitumumab vs. BSC

Van Cutsem st al. J Clin Oncol 2007

Van Cutsem st al. J Clin Oncol 2007

Panitumumab vs. BSC

EGFR and K-RAS

• K-RAS mutation present in 40-45% patients

• When K-ras gene is mutated, K-ras protein (p21 ras) is active independently of EGFR activation

Khambata-Ford et al. JCO 2007

K-RAS mutation detection

• PCR test for mutation in codons 12 and 13 kras

Chen et al. Clin Chem 2004

pre-treated Metastatic CRC (no other option available)

Cetuximab + BSC287 patients

BSC285 patients

Kar

apet

is e

t al

. N

ew E

ng

l J

Med

200

8

Take Home Message

• Moleculat Targeted Therapy – showtime

• Benefit is evident – as well as costs

• Who should receive? – Clinical oncology os meeting science

Thank you

osmaletz@einstein.br