new weapons in the war of cancer lodovico balducci m.d. h. lee moffitt cancer center tampa, florida

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 onCancer startedWith weapons ofMass destruction

ContinuedWith conventionalweapons

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

RECEPTORTKI

PI3K

PDKI AKT

RAS NF1 (RAS-GAP)PTEN

TUBERINFOXOGsk3

BADMDM2

RHEB GTP RHEBGDP

mTOR

LKB1AMPK

HIF

DECREASEDTRANSCRIPTION

INCREASEDCELLPROLIFERATION

ACTIVATIONBcl2SUPPRESSION

p53

Issues of “smart drugs” in the older person

• Absorption

• Drug interactions

• Unexpected complications

A disease with multiple targetsIs an incurable disease

Checov

Combinations in Lung Cancer

IGF-1RInhibitor

Drug XDrug X

EGFREGFRInhibitorInhibitor

VEGF Inhibitor

mTORInhibitor

EGFR Inhibitor

But which ones?But which ones?

Designed for a Designed for a population, not an population, not an individual patient. individual patient.

But which ones?But which ones?

Designed for a Designed for a population, not an population, not an individual patient. individual patient.

STRATEGIES

• ANGIOGENESIS INHIBITORS + CHEMOTHERAPY

• ANGIOGENESIS INHIBITORS + TARGETED THERAPY

• CHEMOTHERAPY AND TARGETED THERAPY

• HORIZONTAL INHIBITION

• VERTICAL INHIBITION

Breast cancer: bevacizumab + paclitaxel

DTIC +/- Sorafenib Trial: PFS

1.00

0.75

0.50

0.25

0.00

1.00

0.75

0.50

0.25

0.0000 14 14 29 29 43 43 57 57 71 71

Weeks From RandomizationWeeks From Randomization

Pro

gre

ssio

n-f

ree

Su

rviv

al P

rob

abil

ity

Pro

gre

ssio

n-f

ree

Su

rviv

al P

rob

abil

ity

86 86

Sorafenib + DTIC (39 events)Sorafenib + DTIC (39 events)

Median: 21.1 weeks (95% CI: 16.0, 28.0) Median: 21.1 weeks (95% CI: 16.0, 28.0)

Placebo + DTIC (42 events)Placebo + DTIC (42 events) Median: 11.7 weeks (95% CI: 6.1, 17.9) Median: 11.7 weeks (95% CI: 6.1, 17.9)

Hazard Ratio = 0.665 (95%CI: 0.428, 1.034)p = 0.068

Hazard Ratio = 0.665 (95%CI: 0.428, 1.034)p = 0.068

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

HIFHIF

KDRKDR

? TOR Inhibitor (temsirolimus or RAD 001)? TOR Inhibitor (temsirolimus or RAD 001)

BevacizumabBevacizumab

Sorafenib Sunitinib Sorafenib Sunitinib

Vertical Combinations- Targeting of VEGF at multiple levels

HIF

VEGF

Temsirolimus plus BevacizumabMerchan et al., ASCO 2007

-80

-60

-40

-20

0

20

40

* = PD (Clinical progression)

**

Dose Level 1Dose Level 1Dose Level 2Dose Level 2

Pe

rce

nt

Re

du

cti

on

Pe

rce

nt

Re

du

cti

on

Maximum Percent Reduction of Target Lesions by Patient

Maximum Percent Reduction of Target Lesions by Patient

Combination Targeted TherapyFor Advanced NSCLC

Herbst RS et al. J Clin Oncol. 2005;23:2544-2555.

Inhibitor Erlotinib BevacizumabBevacizumab

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

bFGFVEGFTGF-a

bFGFVEGFTGF-a

Endothelial cellsEndothelial cellsTumorTumor

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

Bevacizumab + Erlotinib (n=39)Bevacizumab + Erlotinib (n=39)

Chemotherapy(n=41)

Chemotherapy(n=41)

Chemotherapy+ Bevacizumab

(n=40)

Chemotherapy+ Bevacizumab

(n=40)

Previously treated

advanced non-squamous

NSCLC (n=120)

Previously treated

advanced non-squamous

NSCLC (n=120)

Herbst RS et al. J Clin Oncol. 2007;25:4743-4750.

• Randomized, Multicenter Study • Primary endpoint : safety and preliminary efficacy (PFS)• Secondary endpoints: ORR (+ duration); duration of survival

Phase 2: Bevacizumab With Chemotherapy Or Erlotinib in

Advanced NSCLC

Example of vertical inhibition: lapatinib + trastuzumab

Continue

CR treatment for

Week 1 2 3 4 5 6 7 8 9 PR 12 months or until

Stable tumor progression

A A A A Reevaluate

S Progression

Off treatment

Doses:Bevacizumab 3mg/kg, 5 mg/kg, 10mg/kg, IV infusion, q 2 weeksSorafenib- 200mg, 200mg BID, 400mg BID daily PO

Continue

CR treatment for

Week 1 2 3 4 5 6 7 8 9 PR 12 months or until

Stable tumor progression

A A A A Reevaluate

S Progression

Off treatment

Doses:Bevacizumab 3mg/kg, 5 mg/kg, 10mg/kg, IV infusion, q 2 weeksSorafenib- 200mg, 200mg BID, 400mg BID daily PO

Enhanced sorafenib-type toxicity

Enhanced sorafenib-type toxicity

Phase I / II Sorafenib + Bevacizumab Trial: Treatment

Regimen

Sosman et al

Targeted therapy in the elderly

• Effectiveness

• Toxicity

Copyright © American Society of Clinical Oncology

Ramalingam, S. S. et al. J Clin Oncol; 26:60-65 2008

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)

TOXICITY OF PC AND PCB IN PATIENTS 70+Ramalingam et al, JCO, 2008, 26, 60-65

TOXICITY PC PCB P

HEMATO NEUTROPENIA

FEVER

THROMBOCYTO

22

0.9

0

34

6.2

3.5

.06

0.03

.06

NON-HEMATOHYPERTENSION

PROTEINURIA

HEMORRHAGE

NAUSEA

ANOREXIA

.9

0

1.7

0

0.9

6.2

7.9

7.9

4.4

7.9

.03

.002

.03

.03

.01

TOXICITY PC ABD PCB IN PEOPLE 70+ AND YOUNGER PATIENTS

RAMALINGAM ET AL, JCO, 2008, 26, 60-65

TOXICITY PCB PC

>70 <70 >70 <70

NEUTROPENIA

MELENA

PROTEINURIA

WEAKNESS

NEUROPATHY

DIZZINESS

WORST GRADE TOXICITY

TRD

34 22

3.5 0

7.9 1.3

7.8 2.2

3.5 0.6

7.9 1.6

87 71

6.3 2.6

.02

.005

.001

.02

.05

.003

.001

.08

22 15

1.8 0

0 0

4.3 3.1

2.6 1.5

2.6 1.5

65 61

1.8 0

.08

.07

.07

Toxicity of cetuximab in the elderlyBouchachada et al, Crit Rev oncol

Hematol, 2008

• Skin Rash 75% (11% grade 3)

• Diarrhea 80% (20% grade 3 and 4)


Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682

Figure 2">


Hoering, A. et al. Clin Cancer Res 2008;14:4358-4367

Figure 1">


Hoering, A. et al. Clin Cancer Res 2008;14:4358-4367

Figure 2">

Conclusions

• Targeted therapy involves:Agents directed to a specific targetTargets predictive of response to treatmentOvercoming 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

new weapons in the war of cancer lodovico balducci m.d. h. lee moffitt cancer center tampa, florida

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