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New Perspectives in Cancer New Perspectives in Cancer TherapyTherapy
Óren SmaletzÓren SmaletzPrograma de OncologiaPrograma de Oncologia
Hospital Israelita Albert EinsteinHospital Israelita Albert Einstein
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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
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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
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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
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Fight Against Cancer
• Surgery
• Radiotherapy
• Chemotherapy
• Targeted Therapy Agents
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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
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Schrag, D., New Engl J Med 2004
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Hanahan D, Cell 2000
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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
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Família EGFR (Her)
Hudis NEJM 2007
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Trastuzumab – mecanismo de ação
Hudis NEJM 2007
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Trastuzumab in Breast Cancer
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Trastuzumab – metastatic breast cancer
Slamon, NEJM 2001
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Trastuzumab – metastatic breast cancer
Slamon, NEJM 2001
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Trastuzumab – adjuvant treatment
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Trastuzumab – adjuvant treatment
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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
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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
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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
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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
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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
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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
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Apoptosis Nucleus
Mechanism of Action of anti-EGFR Monoclonal Antibodies
MetastasisXX
TGF
Membrane
AngiogenesisXX
CetuximabPanitumumab
Cell proliferationXX
XXCancer Cell
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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
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Cetuximab in Colorectal Cancer (“Bond Trial”)
Irinotecan pre-treated Metastatic CRCEGFR positive
Cetuximab and Irinotecan218 patients
Cetuximab111 patients
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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
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Cunningham et al., New Engl J Med 2004
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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
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Panitumumab vs. BSC
Van Cutsem st al. J Clin Oncol 2007
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Van Cutsem st al. J Clin Oncol 2007
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Panitumumab vs. BSC
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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
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K-RAS mutation detection
• PCR test for mutation in codons 12 and 13 kras
Chen et al. Clin Chem 2004
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pre-treated Metastatic CRC (no other option available)
Cetuximab + BSC287 patients
BSC285 patients
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Kar
apet
is e
t al
. N
ew E
ng
l J
Med
200
8
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Take Home Message
• Moleculat Targeted Therapy – showtime
• Benefit is evident – as well as costs
• Who should receive? – Clinical oncology os meeting science