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NEW WEAPONS IN THE
WAR OF CANCER
Lodovico Balducci M.D.
H. Lee Moffitt Cancer Center
Tampa, Florida
OK! So Now Are We Ready to Select Drugs
for Patients in a More Personalized Way?
The war on
Cancer started
With weapons of
Mass destruction
Continued
With conventional
weapons
And now has discovered
Smart weapons
Personalized oncology
• Targets of treatment
• Predictive factors
• Individual rescue
Smart weapons in medical oncology
•
•
•
•
•
Hormones
Monoclonal antibodies
Inhibitors of the signal transduction cascade
Drugs that reverse epigenetic changes
Others
Thalidomide derivatives
Proteosome inhibitors
Antisense
Prodrugs activated in neoplastic cells
Drugs that reverse multidrug resistance
General issues related to the use of
“smart drugs.”
• End-point of phase I trials: MTD vs target inhibition
• End point of phase II trials: response rate vs stable
disease
• Duration of treatment
• Combinations vs single agents
• Combination with chemotherapy
• Single vs multiple inhibitors
• Vertical and Horizontal inhibition of the signaling
cascade
• Mechanisms of resistance (the cancer guerrilla)
• Enough patients for clinical trials
GROWTH FACTOR
RECEPTOR
TKI
RAS
PI3K
PTEN
PDKI
AKT
Gsk3
MDM2
BAD
NF1 (RAS-GAP)
TUBERIN
FOXO
RHEB GTP
SUPPRESSION
p53
ACTIVATION
Bcl2
DECREASED
INCREASED
TRANSCRIPTION
CELL
PROLIFERATION
mTOR
HIF
AMPK
LKB1
RHEBGDP
Issues of “smart drugs” in the
older person
• Absorption
• Drug interactions
• Unexpected complications
A disease with multiple targets
Is an incurable disease
Checov
Combinations in Lung Cancer
EGFR
Inhibitor
VEGF
Inhibitor
Drug X
IGF-1R
Inhibitor
mTOR
Inhibitor
But which ones?
Designed for a
population, not an
individual patient.
EGFR
Inhibitor
STRATEGIES
• ANGIOGENESIS INHIBITORS +
CHEMOTHERAPY
• ANGIOGENESIS INHIBITORS +
TARGETED THERAPY
• CHEMOTHERAPY AND TARGETED
THERAPY
• HORIZONTAL INHIBITION
• VERTICAL INHIBITION
Breast cancer: bevacizumab +
paclitaxel
Progression-free Survival Probability
DTIC +/- Sorafenib Trial: PFS
Sorafenib + DTIC (39 events)
Median: 21.1 weeks (95% CI: 16.0, 28.0)
Placebo + DTIC (42 events)
Median: 11.7 weeks (95% CI: 6.1, 17.9)
1.00
0.75
Hazard Ratio = 0.665 (95%CI: 0.428, 1.034)
p = 0.068
0.50
0.25
0.00
0
14
29
43
57
71
86
Weeks From Randomization
McDermott et al. J Clin Oncol, in press.
Lapatinib pazopanib superior to lapatinib alone
Combinations that do not work
• Bevacizumab erlotinib in RCC
• Bevacizumab+ cetuximab (CAIRO2)
• Erlotinib + platinum chemotherapy
Gemzar and erlotinib vs Gemzar
erlotinib and bevacizumab
COMBINATION OF AGENTS TARGETING THE
SIGNAL TRANSDUCTION CASCADE
• VERTICAL BLOCKADE
• HORIZONTAL BLOCKADE
• OVERCOMING RESISTANCE
Vertical Combinations- Targeting of
VEGF at multiple levels
HIF
? TOR Inhibitor
(temsirolimus or RAD 001)
VEGF
Bevacizumab
KDR
Sorafenib
Sunitinib
Temsirolimus plus Bevacizumab
Merchan et al., ASCO 2007
Percent Reduction
40
Maximum Percent Reduction
of Target Lesions by Patient
20
*
0
-20
-40
-60
-80
Dose Level 1
Dose Level 2
* = PD (Clinical progression)
Combination Targeted Therapy
For Advanced NSCLC
Inhibitor
Erlotinib
Bevacizumab
Mechanism
Inhibits tumor cell growth and
blocks synthesis of
angiogenic proteins (e.g.,
bFGF, VEGF, TGF-a) by
tumor cells
Inhibits endothelial cells from
responding to the angiogenic
protein VEGF
bFGF
VEGF
TGF-a
Tumor
Endothelial cells
Herbst RS et al. J Clin Oncol. 2005;23:2544-2555.
Phase 2: Bevacizumab With
Chemotherapy Or Erlotinib in
Advanced NSCLC
Bevacizumab +
Erlotinib (n=39)
Previously
treated
advanced nonsquamous
NSCLC (n=120)
Chemotherapy
+ Bevacizumab
(n=40)
Chemotherapy
(n=41)
Median PFS
(months)
6 month PFS
rate (%)
12 month
OS rate
(%)
4.4
33.6
57.1
4.8
30.5
53.6
3.0
21.5
31.8
• Randomized, Multicenter Study
• Primary endpoint : safety and preliminary efficacy (PFS)
• Secondary endpoints: ORR (+ duration); duration of survival
Herbst RS et al. J Clin Oncol. 2007;25:4743-4750.
Example of vertical inhibition: lapatinib
+ trastuzumab
Phase I / II Sorafenib +
Bevacizumab Trial: Treatment
Regimen
Continue
Week
1 2

3 4

5

A
A
A
6
7

8
9

CR
PR
Stable
treatment for
12 months or until
tumor progression
A Reevaluate
 S 
Enhanced sorafenibtype toxicity
Progression
Off treatment
Doses:
Bevacizumab 3mg/kg, 5 mg/kg, 10mg/kg, IV infusion, q 2 weeks
Sorafenib- 200mg, 200mg BID, 400mg BID daily PO
Sosman et al
Targeted therapy in the elderly
• Effectiveness
• Toxicity
Fig 1. Kaplan-Meier curves for (A) overall survival for elderly (PC v PCB), (B) PFS for elderly (PC v PCB),
(C) combined overall survival by age groups (PC + PCB), and (D) combined PFS by age groups (PC +
PCB)
Ramalingam, S. S. et al. J Clin Oncol; 26:60-65 2008
Copyright © American Society of Clinical Oncology
TOXICITY OF PC AND PCB IN PATIENTS 70+
Ramalingam et al, JCO, 2008, 26, 60-65
TOXICITY
PC
PCB
P
22
0.9
0
34
6.2
3.5
.06
0.03
.06
.9
0
1.7
0
0.9
6.2
7.9
7.9
4.4
7.9
.03
.002
.03
.03
.01
HEMATO
NEUTROPENIA
FEVER
THROMBOCYTO
NON-HEMATO
HYPERTENSION
PROTEINURIA
HEMORRHAGE
NAUSEA
ANOREXIA
TOXICITY PC ABD PCB IN PEOPLE 70+ AND
YOUNGER PATIENTS
RAMALINGAM ET AL, JCO, 2008, 26, 60-65
TOXICITY
PCB
>70
NEUTROPENIA
MELENA
PROTEINURIA
WEAKNESS
NEUROPATHY
DIZZINESS
WORST GRADE
TOXICITY
TRD
PC
<70
>70
<70
34
3.5
7.9
7.8
3.5
7.9
87
22
0
1.3
2.2
0.6
1.6
71
.02
.005
.001
.02
.05
.003
.001
22
1.8
0
4.3
2.6
2.6
65
15
0
0
3.1
1.5
1.5
61
.08
.07
6.3
2.6
.08
1.8
0
.07
Toxicity of cetuximab in the elderly
Bouchachada et al, Crit Rev oncol
Hematol, 2008
• Skin Rash 75% (11% grade 3)
• Diarrhea 80% (20% grade 3 and 4)
Fig 1.
Lin, W.-L. et al. J Clin Oncol; 26:2779-2780 2008
Figure 1">
Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682
Copyright ©2008 American Association for Cancer Research
Figure 2">
Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682
Copyright ©2008 American Association for Cancer Research
Figure 1">
Hoering, A. et al. Clin Cancer Res 2008;14:4358-4367
Copyright ©2008 American Association for Cancer Research
Figure 2">
Hoering, A. et al. Clin Cancer Res 2008;14:4358-4367
Copyright ©2008 American Association for Cancer Research
Conclusions
• Targeted therapy involves:
Agents directed to a specific target
Targets predictive of response to treatment
Overcoming resistance
• Targeted therapy has been very
successful in situations where a single or
few targets are responsible to maintain the
disease (CML, HER2 positive breast
cancer; some B cell malignancies)
Conclusions
• The combination of antiangiogenesis
agents with cytotoxic chemotherapy has
increased the activity of chemotherapy in
breast, colon, and lung cancer and in
melanoma
Conclusions
• The combination of 2 or more targeting
agents seems to be more effective and
safer when the inhibition is vertical, at
least in the case of inhibition of the signal
transduction cascade.
Conclusions
• The plethora of new agents require more
diversified clinical studies: this include
phase 0 studies to test the doses providing
full inhibition of the target and randomized
phase II studies to establish the value of
stable disease
• Scarcity of patients will make the need of
including older patients in clinical trials
more compelling
Conclusions
• Data on toxicity of targeted agents in
older individuals are limited: the risk of
thrombosis with avastin and of serious
cutaneous reactions with cetuximab
appears to increase with age
A CASE FOR GERIATRIC
ONCOLOGY
• A WORLD GOVERNED BY TECHNOLOGY IS A
WORLD OF SLAVES.
G. Bernanos: La France contre les robots