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New Perspectives in Cancer
Therapy
Óren Smaletz
Programa de Oncologia
Hospital Israelita Albert Einstein
Disclosure of Potential Conflicts of
Interest
• Honoraria: Pfizer, Merck KGaA
• Research Funding: Pfizer
• Scientific Funding: Merck KGaA, Roche
CFM Resolution nº 1.595/2000
SBOC/SBC oct/2007
A 72-year-old man presented for evaluation of progressive dyspnea and cough
McMullan D and Cohen G. N Engl J Med 2006;354:397
Change in the US Death Rates* by Cause,
1950 & 2002
Rate Per 100,000
600
586.8
1950
500
2002
400
300
240.1
200
193.9
180.7
193.4
100
56.0
48.1
22.5
0
Heart
Diseases
Cerebrovascular
Diseases
Pneumonia/
Influenza
Cancer
* 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
Fight Against Cancer
• Surgery
• Radiotherapy
• Chemotherapy
• Targeted Therapy Agents
FDA Approved New Molecules for
Solid Tumor Use per Year
2002
2003
2004
2005
2006
2007
0
1
T argeted T herapy Agent
2
Cy totox ic Agent
3
Schrag, D., New Engl J Med 2004
Hanahan D, Cell 2000
The EGFR (erbB) Family and
Ligands
EGF
TGFa
Amphiregulin
b-cellulin
HB-EGF
Epiregulin
Heregulins
NRG2
NRG3
Heregulins
b-cellulin
100
44
36
48
100
82
59
79
100
33
24
28
HER1
EGFR
ErbB-1
HER2/neu
ErbB-2
HER3
ErbB-3
HER4
ErbB-4
Cysteine-rich
domains
Tyrosine kinase
domain
C-terminus
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
R
R
R R
R
R
Extracellular
Membrane
pY
pY
pY
pY
K
K
K
K
K
Intracellular
Substract
K
Substract
pY
pY
pY
Cellular effects
Signaling
Molecules
+
+
+
proliferation
apoptosis
angiogenesis
metastasis
EGFR Expression in Human Cancer
Tumors
Overexpression
associated with:
•
•
•
•
•
Invasion
Metastasis
Advanced disease
Poor outcome
Resistance to
chemotherapy,
hormonotherapy
radiotherapy
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
*lowest to highest published range of expression
Disease-free Survival and EGFR and
TGF-a Levels in Head and Neck Cancer
EGFR
TGFa
Proportion Surviving
1.0
low
low
medium
medium
0.8
0.6
0.4
0.2
high
high
p=.0001
p=.0001
0.0
0
1
2
3
4
Years after surgery
5
6/0
1
2
3
4
Years after surgery
Rubin Grandis J et al. JNCI 1998; 90: 824–832.
5
6
EGFR Mab Currently Approved
Clinical
activity
randomized
trials
Cetuximab
FDA ANVISA
Dosage
Head & Neck
Colon/Rectal
Y
Y
Y
Y
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
Mechanism of Action of anti-EGFR
Monoclonal Antibodies
Membrane
Cancer Cell
X
Cell proliferation
Apoptosis
X
Metastasis
X
Angiogenesis
Nucleus
X
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”)
Cetuximab and Irinotecan
218 patients
Irinotecan pretreated
Metastatic CRC
EGFR positive
Cetuximab
111 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
Panitumumab + BSC
463 EGFR +, M1
Colon/Rectal Cancer,
POD on standard
chemoRX
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 + BSC
287 patients
BSC
285 patients
Karapetis et al. New Engl J Med 2008
Take Home Message
• Moleculat Targeted Therapy – showtime
• Benefit is evident – as well as costs
• Who should receive? – Clinical oncology os
meeting science
Thank you
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