Unraveling the MolecularUnraveling the MolecularBasis of CancerBasis of Cancer

Hai T. Tran, Hai T. Tran, PharmDPharmD

Assistant ProfessorAssistant Professor

Pharmacology Pharmacology –– Research ResearchCancer Medicine and PharmacyCancer Medicine and Pharmacy

The University of TexasThe University of Texas

M. D. Anderson Cancer CenterM. D. Anderson Cancer Center

Houston, TexasHouston, Texas

Molecular Basis of CancerMolecular Basis of Cancer

Understand the complexity of cancer andUnderstand the complexity of cancer andappropriately identify potential targets forappropriately identify potential targets for

therapeutic interventiontherapeutic intervention

Causes of cancerCauses of cancer

Process of malignant transformationProcess of malignant transformation

Cell cycle controlCell cycle control

Roles of angiogenesis and growth factorsRoles of angiogenesis and growth factors

Effects of tyrosine kinase inhibitionEffects of tyrosine kinase inhibition

Biology of CancerBiology of CancerCancer by the Numbers 2006Cancer by the Numbers 2006

United States Estimated Cancer DeathsUnited States Estimated Cancer Deaths

Men (291,270) Women (273,560)26.8% Respiratory22.3% Digestive 15% Breast13.6% GU 3.6% Leukemia 3.5% Lymphoma15.3% Others

Respiratory 32.2%Digestive 25.8%GU 15.6%Leukemia 4.3%Lymphoma 3.7%CNS 2.5%Skin 2.4%Others 13.4%

American Cancer Society. Available at: http://www.cancer.org/ - Cancer Facts & Figures 2006.

Weinberg RA. The Biology of Cancer. 2007. Garland Science, Taylor & Francis Group, LLC, New York, NY, USA.

Biology of CancerBiology of CancerAbbreviated List of the Usual SuspectsAbbreviated List of the Usual Suspects

ChemicalsChemicals–– Hydrocarbons: Hydrocarbons: benzopyrenebenzopyrene, benzene, benzene

compounds, 2-napthylaminecompounds, 2-napthylamine–– Asbestos & tobacco exposuresAsbestos & tobacco exposures

Radiation exposureRadiation exposure Tumor virusesTumor viruses

–– DNA: HBV, SV40/polyoma, HPV16, HAV5, HSV-DNA: HBV, SV40/polyoma, HPV16, HAV5, HSV-8, 8, Shope fibroma Shope fibroma virusvirus

–– RNA: RSV, HTLV-1RNA: RSV, HTLV-1 Cellular Cellular oncogenesoncogenes

–– mycmyc, , erbBerbB, int-1,2,3; p53, GM-CSF, IL-2, IL-3,, int-1,2,3; p53, GM-CSF, IL-2, IL-3,k-rask-ras, Cyc-D1 & D2, Cyc-D1 & D2

Biology of CancerBiology of CancerA Learning Curve That Never PlateausA Learning Curve That Never Plateaus

Process of malignant transformationProcess of malignant transformation–– Accumulation of multiple genetic alterationsAccumulation of multiple genetic alterations

Escape from normal growth controlEscape from normal growth control Evade from apoptotic programEvade from apoptotic program Induction of sustained angiogenesisInduction of sustained angiogenesis Enhanced ability to metastasizeEnhanced ability to metastasize Ability to invade healthy tissuesAbility to invade healthy tissues

Identification of more than 300 cancer genesIdentification of more than 300 cancer genes–– Signal transduction, cell cycle progression, apoptosis,Signal transduction, cell cycle progression, apoptosis,

angiogenesis and invasionangiogenesis and invasion A very complex systemA very complex system

Biology of CancerBiology of CancerCell Cycle ControlCell Cycle Control

G2/M DNA Damage CheckpointG1/S DNA Checkpoint

Cell Signaling - Pathway Diagrams. Available at: http://www.cellsignal.com/reference/pathway/index.asp. Accessed October 12, 2006.Reprinted with permission from Cell Signaling Technology, Inc.

Biology of CancerBiology of Cancer p53 and Cell Deathp53 and Cell Death

Transcriptionblockage

Hypoxia Oncogene RadiationMissing

nucleotides

p53

DNArepair

Inhibition ofangiogenesis

ApoptosisCell cycle

arrest

Proliferation Senescence

Courtesy of Dr. H. Tran.

1. Hanahan D, Weinberg RA. Cell. 2000;100:57.2. Dvorak HF. N Engl J Med. 1986;315:1650.3. Folkman J. N Engl J Med. 1971;285:1182.4. Folkman J, et al. J Exp Med. 1971;133:275.

Biology of CancerBiology of CancerAngiogenesisAngiogenesis

Angiogenesis: formation of new blood vesselsAngiogenesis: formation of new blood vessels Heterotypic signaling and interactionsHeterotypic signaling and interactions11

–– Mitogenic Mitogenic growth factors: HGD, TGF-a, PDGFgrowth factors: HGD, TGF-a, PDGF–– Growth-inhibitory signals: TGF-bGrowth-inhibitory signals: TGF-b–– Trophic Trophic factors: IGF-1 & -2factors: IGF-1 & -2

Tumor Tumor —— ““a wound that never healsa wound that never heals””22

Observation: cancer cells located > 0.2 mm fromObservation: cancer cells located > 0.2 mm fromcapillaries stop growing and become apoptotic orcapillaries stop growing and become apoptotic ornecroticnecrotic3,43,4

Biology of Cancer Biology of Cancer —— Invasion and Metastasis Invasion and MetastasisThe The Angiogenic Angiogenic SwitchSwitch

• Tumor secretion of angiogenic factors stimulates angiogenesis• Neovascularization

– Makes rapid tumor growth possible by supplying oxygenand nutrients and removing waste

– Facilitates metastasis

Ferrara, N. The Oncologist. 2004;9:2. Reprinted with permission.

Biology of CancerBiology of CancerErbB/HER ErbB/HER Receptor Tyrosine Receptor Tyrosine KinasesKinases

Cell Signaling. ErbB/HER Signaling. Available at: http://www.cellsignal.com/reference/pathway/erbB.asp. Accessed October 12, 2006.Copyright 2005 - Cell Signaling Technology, Inc. Reprinted with permission.

Tumor

Inhibitor Angiogenic Inhibition VEGFR Inhibition

Mechanism Inhibits tumor cell growthand blocks synthesis ofangiogenic proteins (eg,EGFR, bFGF, VEGF,TGF-α) by tumor cells

Inhibits endothelial cellsfrom responding to theangiogenic protein VEGF

bFGFVEGFTGF-α

Endothelial cells

Sandler A, Herbst RS. Clin Cancer Res. 2006;12:4421s. Adapted from Herbst RS, et al. J Clin Oncol. 2005;23:2544. Reprintedwith permission from the American Society of Clinical Oncology.

Rationale for Combining Inhibitors of EGFR and VEGFRRationale for Combining Inhibitors of EGFR and VEGFRTargeting Both the Targeting Both the Tumor Tumor and Endothelial Cellsand Endothelial Cells

Biology of CancerBiology of CancerSignaling Control & NetworkingSignaling Control & Networking

Hanahan D, Weinberg RA. Cell. 2000;100:57. Reprinted with permission.

Angiogenesis inhibitorsAngiogenesis inhibitors–– Bevacizumab*Bevacizumab*–– Interferon-Interferon-aa//bb∗∗–– ZD6474/ZD2171ZD6474/ZD2171–– LY317615LY317615–– ThrombospondinThrombospondin–– VEGF-TRAPVEGF-TRAP

Receptor-targeted therapyReceptor-targeted therapy–– Multi-targetedMulti-targeted

Imatinib mesylateImatinib mesylate** SunitinibSunitinib** SorafenibSorafenib** LapatinibLapatinib

–– Anti-HER2Anti-HER2 TrastuzumabTrastuzumab**

–– Anti-EGFRAnti-EGFR Erlotinib*Erlotinib* GefitinibGefitinib†

CetuximabCetuximab** PanitumumabPanitumumab**

*FDA approved for one or more indication.†Gefitinib is no longer available in the US except under clinical study or when continuing on therapy.

Current Biologic Agents Shopping ListCurrent Biologic Agents Shopping List Signal transduction/cell-cycle inhibitorsSignal transduction/cell-cycle inhibitors

–– VX-680VX-680

–– VorinostatVorinostat**

–– DecitabineDecitabine

–– BortezomibBortezomib**

–– DasatinibDasatinib

–– Stat-3 inhibitorsStat-3 inhibitors

Gene therapyGene therapy

–– Wild type p53Wild type p53

–– AntisenseAntisense

VaccinesVaccines

–– Tumor/dendritic Tumor/dendritic cellscells

–– PeptidesPeptides

–– Viral vaccinesViral vaccines

Targeted Therapies in CancerTargeted Therapies in CancerParadigm Shift?Paradigm Shift?

Not a new concept

“Cytostatic vs Cytotoxic”

Modest response rates with single agents

Combination with cytotoxics?

Now with survival data

Who should receive (“Individualized”)?

Where is the best setting (early, sequential)?

Cancer is a “Chronic Disease”

Courtesy of Dr. H. Tran.

Tissue screening

Proteomics

Genomics

Chemosensitivity

Mutations

Chemotherapy

Biologic therapy

Combination

Reassess tumor response

Validated biological markersand symptoms improvement

Continue

Maintenance

Switch therapies

Evolution of the Modern Treatment StrategyEvolution of the Modern Treatment StrategyPersonalized Cancer MedicinePersonalized Cancer Medicine

Photos courtesy of Edward S. Kim, MD.

How Do TargetedHow Do TargetedTherapies Work?Therapies Work?

Jon D. Herrington, Jon D. Herrington, PharmDPharmD, BCPS, BCOP, BCPS, BCOPHematology/Oncology Clinical SpecialistHematology/Oncology Clinical Specialist

Department of PharmacyDepartment of Pharmacy

Scott & White Memorial HospitalScott & White Memorial Hospital

Temple, TexasTemple, Texas

Purine synthesis Pyrimidine synthesis

Ribonucleotides

Deoxyribonucleotides

DNA

RNA

Proteins

MicrotubulesEnzymes, etc

Etoposide, teniposide

Irinotecan, topotecan

Tyrosine kinase inhibitors

Bortezomib

Monoclonal antibodies

Cytarabine, gemcitabine

Fluorouracil

Fludarabine, cladribine

Chabner BA, et al. Antineoplastic agents. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th ed. 2006.Reprinted with permission from the McGraw Hill Companies.

Traditional Chemotherapy TargetsTraditional Chemotherapy Targets

Mercaptopurine

MethotrexateHydroxyurea

Alkylating agents

Anthracyclines

L-asparaginase

Vinca alkaloids

Taxanes

Traditional Chemotherapy AgentsTraditional Chemotherapy Agents

AdvantageAdvantage

–– Activity in certain malignanciesActivity in certain malignancies

DisadvantagesDisadvantages

–– SelectivitySelectivity

Target rapidly dividing cellsTarget rapidly dividing cells

Minimal efficacy in advanced diseaseMinimal efficacy in advanced disease

–– ToxicitiesToxicities

Targeted TherapiesTargeted Therapies

AdvantagesAdvantages–– SelectivitySelectivity

Molecular targetsMolecular targets–– ToxicitiesToxicities

Decreased normal cell destructionDecreased normal cell destruction DisadvantagesDisadvantages

–– UnknownUnknown CombinationsCombinations Dosing regimensDosing regimens

–– Long-termLong-term–– CostCost

Types of Targeted TherapiesTypes of Targeted Therapies

Monoclonal antibodies (Monoclonal antibodies (MoAbsMoAbs))–– Engineered murine/human Engineered murine/human MoAbsMoAbs

that interact with a certain targetthat interact with a certain target MurineMurine ChimericChimeric HumanizedHumanized HumanHuman

Tyrosine kinase inhibitors (Tyrosine kinase inhibitors (TKIsTKIs))–– Small molecule inhibitors that interfereSmall molecule inhibitors that interfere

with TK activationwith TK activation Single inhibitorSingle inhibitor Multitargeted inhibitorMultitargeted inhibitor

TargetsTargets

Circulating targetsCirculating targets

–– egeg, VEGF, VEGF

Transmembrane targetsTransmembrane targets

–– egeg, EGFR, PDGFR, EGFR, PDGFR

Cell-membrane bound targetsCell-membrane bound targets

–– egeg, CD20, CD33, CD20, CD33

Targets for Available AgentsTargets for Available AgentsMonoclonal AntibodiesMonoclonal Antibodies

EGFR/HER1EGFR/HER1PanitumumabPanitumumab77

CD33CD33Gemtuzumab Gemtuzumab ozogamicinozogamicin44

CD52CD52AlemtuzumabAlemtuzumab55

VEGFVEGFBevacizumabBevacizumab99

HER2HER2TrastuzumabTrastuzumab88

EGFR/HER1EGFR/HER1CetuximabCetuximab66

CD20CD20RituximabRituximab11

Ibritumomab Ibritumomab tiuxetantiuxetan22

TositumomabTositumomab, iodine I-131, iodine I-13133

TargetTargetDrugDrug

Rituxan® [PI]. San Francisco, CA: Genentech, Inc; 2006. 2. Zevalin® [PI]. San Francisco, CA: Biogen Idec Inc and Genentech, Inc; 2005. 3. Bexxar® [PI].Research Triangle Park, NC: GlaxoSmithKline; 2005. 4. Mylotarg® [PI]. Philadelphia, PA: Wyeth Pharmaceuticals Inc; 2006. 5. Campath® [PI]. CambridgeMA : Genzyme Corporation; 2005. 6. Erbitux® [PI]. Branchburg, NJ, Princeton, NJ : Imclone Systems Inc and Bristol-Myers Squibb Company; 2006. 7.Vectibix TM [PI]. Thousand Oaks, CA,: Amgen Inc; 2006. 8. Herceptin® [PI]. San Francisco, CA: Genentech, Inc; 2005. 9. Avastin® [PI]. San Francisco, CA:Genentech, Inc; 2006.Courtesy of Dr. J. Herrington.

EGFR/HER1, HER2Lapatinib – investigational3

PDGFRα and β, VEGFR1, 2 and 3, Kit,Flt3, CSF-1R, Ret

Sunitinib7

PDGFRβ, VEGFR 2 and 3, Kit, Flt3, RafSorafenib6

Bcr-abl, Kit, Src family, Epha2, PDGFRβDasatinib5

Bcr-abl, Kit, PDGFRImatinib4

EGFR/HER1Erlotinib2

EGFR/HER1Gefitinib1

TargetDrug

EGFR = epidermal growth factor receptor; HER = human epidermal growth factor receptor; Kit = stem cell factor receptor; PDGFR = platelet derived growth factorreceptor; VEGFR = vascular endothelial growth factor receptors; Flt3 = Fms-like tyrosine kinase-3; CSF-1R = colony stimulating factor receptor Type 1; Ret =glial cell-line derived neutrophic factor receptor.

Iressa® [PI]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2005. 2. Tarceva® [PI]. Melv ille, NY and San Francisco, CA: OSI Pharmaceuticals, Inc andGenentech Inc; 2005. 3. Burris HA, et al. J Clin Oncol. 2005;23:5305. 4. Gleevec® [PI]. East Hanover, NJ: Novartis Pharmaceutical Corporation; 2005. 5.SprycelTM [PI]. Princeton, NJ: Bristol-Myers Squibb Company; 2006. 6. Nexavar® [PI]. West Haven, CT and Emeryv ille, CA: Bayer PharmaceuticalCorporation and Onyx Pharmaceuticals: 2006. 7. Sutent® [PI]. New York, NY: Pfizer Labs; 2006.

Courtesy of Dr. J. Herrington.

Tyrosine Tyrosine Kinase Kinase Inhibitors Molecular TargetsInhibitors Molecular Targets

Baselga J. Science. 2006;312:1175. Reprinted with permission from AAAS.

TrastuzumabHER2Breast cancer

ErlotinibGefitinib

EGFRLung cancer

ImatinibKIT

PDGFRGastrointestinalstromal tumors

ImatinibBCR-ABLChronic myelogenousleukemia

First-GenerationInhibitor

Tyrosine KinaseTargetCancer Type

First-Generation First-Generation TKIs TKIs and and MoAbsMoAbs

Cell Signaling. ErbB/HER Signaling. Available at: http://www.cellsignal.com/reference/pathway/erbB.asp. Accessed October 12, 2006.Copyright 2005 - Cell Signaling Technology, Inc. Reprinted with permission.

ErbB/HER/EGFR ErbB/HER/EGFR Signaling PathwaySignaling Pathway

Reprinted with permission from Krause DS, Van Etten RA. N Engl J Med. 2005;353:172. Copyright 2005 Massachusetts MedicalSociety. All rights reserved.

EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitors.

Targeting TK Receptors andTargeting TK Receptors andTheir Ligands for Cancer TherapeuticsTheir Ligands for Cancer Therapeutics

Overexpression of a normal receptor TK (EGFR), its ligand, or both. TK receptorsand their ligands can be specifically targeted extracellularly by monoclonal antibodiesand intracellularly by TKIs.

Mendelsohn J, Baselga J. Semin Oncol. 2006;33:369.;33;369.

Expected Results from Selective Expected Results from Selective MoAbsMoAbsand and TKIsTKIs

Cell cycle arrestCell cycle arrest

Apoptosis potentiationApoptosis potentiation

Angiogenesis inhibitionAngiogenesis inhibition

Inhibition of tumor cell invasion and metastasisInhibition of tumor cell invasion and metastasis

Chemotherapy and radiotherapy augmentationChemotherapy and radiotherapy augmentation

Gerber H-P, Ferrara N. Cancer Res. 2005;65:671. Reprinted with permission.

Hypothetical Model for Synergism BetweenHypothetical Model for Synergism BetweenCytotoxic Compounds and BevacizumabCytotoxic Compounds and Bevacizumab

Reprinted with permission from Krause DS, Van Etten RA. N Engl J Med. 2005;353:172.Copyright 2005 Massachusetts Medical Society. All rights reserved.

Mechanisms of Resistance to Mechanisms of Resistance to TKIsTKIs

Baselga J. Science. 2006;312:1175. Reprinted with permission from AAAS.

ErlotinibGefitinib

Trastuzumab

Imatinib

Imatinib

First-GenerationInhibitor

LapatinibHER2Breast cancer

IrreversibleInhibitors(EKB569)

EGFRLung cancer

SunitinibKIT

PDGFRGastrointestinalstromal tumors

DasatinibBCR-ABLChronicmyelogenousleukemia

Second-Generation

InhibitorTyrosine Kinase

TargetCancer Type

Second-Generation Second-Generation TKIsTKIs

ConclusionsConclusions

Targeted therapies have revolutionized theTargeted therapies have revolutionized thetreatment of malignanciestreatment of malignancies

Unique mechanisms will allow for future useUnique mechanisms will allow for future usein combination therapiesin combination therapies

Clinical Update: Efficacy and SafetyClinical Update: Efficacy and Safetyof Targeted Therapiesof Targeted Therapies

Cathy Eng, MDCathy Eng, MDAssistant ProfessorAssistant Professor

Department of Gastrointestinal Medical OncologyDepartment of Gastrointestinal Medical Oncology

The University of TexasThe University of Texas

M. D. Anderson Cancer CenterM. D. Anderson Cancer Center

Houston, TexasHouston, Texas

OverviewOverview

Discuss the role of targeted therapies in solid tumorsDiscuss the role of targeted therapies in solid tumors Discuss on-label FDA-approved agents in variousDiscuss on-label FDA-approved agents in various

malignanciesmalignancies–– ColorectalColorectal–– LungLung–– RenalRenal–– Breast cancerBreast cancer

Side effectsSide effects FutureFuture

–– Drugs of interestDrugs of interest

Treatment of Metastatic ColorectalTreatment of Metastatic ColorectalCancer (MCRC):Cancer (MCRC):

anti-VEGF and EGFR Inhibitionanti-VEGF and EGFR Inhibition

Efficacy of Bevacizumab (B)and Cetuximab (C) in MCRC

Phase III Pivotal Trial Results

Cunningham (prior irinotecanexposure)‡

Second-line: Giantonio(bevacizumab-naive)†

First-line: Hurwitz*

Trial

6.9

8.6

1.5

4.1

11

23

Cetuximab

Irinotecan + C

10.8

12.9

4.8

7.2

9

22

FOLFOX

FOLFOX + B

15.6

20.3

6.2

10.6

35

45

IFL

IFL+B

Median OS (mo)Median PFS or

TTP (mo)RR (%)Regimen

Hurwitz HI, et al. N Engl J Med. 2004;350:2335. Giantonio BJ, et al. 41st ASCO; May 13-17, 2005. Abstract 2.Cunningham D, et al. N Engl J Med. 2004;351:337.

*RR comparison, P = .0024; PFS comparison, P < .001; OS comparison, P < .001.†RR comparison, P = <.0001; PFS comparison, P < .05; OS comparison, P < .05.‡RR comparison, P = .007; PFS comparison, P < .001; OS comparison, P = .48.RR = response rate; PFS = progression-free survival; TTP = time to progression; OS = overall survival; IFL = irinotecan + bolus5-fluorouracil/leucovorin; FOLFOX = infusional 5-fluorouracil/leucovorin + oxaliplatin.

Avastin® [PI]. San Francisco, CA: Genentech, Inc; 2006.

FDA June 2006FDA June 2006BevacizumabBevacizumab

Combination with intravenous 5-FUCombination with intravenous 5-FU––based chemotherapy, isbased chemotherapy, isadministered as an intravenous infusion (5 mg/kg or 10 mg/kg)administered as an intravenous infusion (5 mg/kg or 10 mg/kg)every 14 days until disease progressionevery 14 days until disease progression

The recommended dose of bevacizumab when used inThe recommended dose of bevacizumab when used incombination with bolus-IFL is 5 mg/kgcombination with bolus-IFL is 5 mg/kg

The recommended dose of bevacizumab when used inThe recommended dose of bevacizumab when used incombination with FOLFOX-4 is 10 mg/kgcombination with FOLFOX-4 is 10 mg/kg

This announcement does not take into account the dose to beThis announcement does not take into account the dose to beused with FOLFIRI and modified schedules of used with FOLFIRI and modified schedules of FOLFOXFOLFOX——ieie,,FOLFOX6 or FOLFOX7FOLFOX6 or FOLFOX7

IFL = irinotecan + bolus 5-fluorouracil/leucovorin; FOLFOX = infusional 5-fluorouracil/leucovorin + oxaliplatin; FOLFIRI = 5-fluorouracil/leucovorin + irinotecan

Facts of Approved BiologicsMetastatic Colorectal Cancer

CetuximabCetuximab22

–– Acne-type rashAcne-type rash

–– Paronychial Paronychial infectionsinfections

–– Electrolyte imbalance: Mg, CaElectrolyte imbalance: Mg, Ca

–– Hypersensitivity reactionHypersensitivity reaction

–– Weekly administrationWeekly administration

–– Approved for patients whoApproved for patients whohave progressed onhave progressed onirinotecan or irinotecanirinotecan or irinotecanintolerantintolerant

BevacizumabBevacizumab11

–– HypertensionHypertension–– Remote risk of GI perforationRemote risk of GI perforation–– ReversibleReversible

leukoencephalopathyleukoencephalopathysyndromesyndrome

–– Patients with history of Patients with history of ATEsATEsare at higher risk of recurrentare at higher risk of recurrenteventevent

–– q2wk or q3wkq2wk or q3wk–– Approved for front-line orApproved for front-line or

bevacizumab naivebevacizumab naive

1. Avastin® [PI]. San Francisco, CA: Genentech, Inc; 2006.2. Erbitux® [PI]. Branchburg, NJ and Princeton, NJ: Imclone Systems Incorporated and Bristol-Myers Squibb Company; 2006.

GI = gastrointestinal; ATEs = arterial thromboembolic events.

PD

Peeters M, et al. 97th AACR; April 1-5, 2006. Abstract CP-1.

Patients withadvanced EGFR+

CRC andNO prior anti-EGFR

or VEGF therapy(N = 1040)

Panitumumab(n = 231)

BSC (n = 232) Panitumumab(n = 174)

RANDOMIZATION

N = 463

Dose: 6 mg/kg q2wk

Phase III Phase III Panitumumab vsPanitumumab vsBest Supportive CareBest Supportive Care

EGFR = endothelial growth factor receptor; CRC = colorectal cancer; VEGF = vascular endothelial growth factor; BSC = bestsupportive care; PD = progressive disease.

Even

t-Fre

e Pr

obab

ility

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Weeks from Randomization0 8 16 24 32 40 48 56

Hazard ratio = 0.54 (95% CI: 0.44, 0.66)

Stratified log-rank testP < .000000001

Panitumumab

Best Supportive Care (BSC)

Patients at risk:PanitumumabBSC

231 118 49 31 13 5 1232 75 17 7 3 1 1

Panitumumab Panitumumab vs vs Best Supportive CareBest Supportive CareProgression-Free SurvivalProgression-Free Survival

Peeters M, et al. 97th AACR; April 1-5, 2006. Abstract CP-1. Reprinted with permission from Dr. Peeters.

Summary for FDA-Approved Drugs inSummary for FDA-Approved Drugs inMetastatic Colorectal Cancer (MCRC)Metastatic Colorectal Cancer (MCRC)

IFL has been replaced by its infusional counterpart (FOLFIRI)IFL has been replaced by its infusional counterpart (FOLFIRI) Front-line MCRC: bevacizumab + 5-FU based chemotherapyFront-line MCRC: bevacizumab + 5-FU based chemotherapy

(FOLFOX, FOLFIRI, or 5-FU)(FOLFOX, FOLFIRI, or 5-FU) The benefits of continuing bevacizumab following progression areThe benefits of continuing bevacizumab following progression are

unknown. Given the lack of data, its use cannot be advocatedunknown. Given the lack of data, its use cannot be advocatedfollowing progressionfollowing progression

Cetuximab is approved in combination with irinotecan followingCetuximab is approved in combination with irinotecan followingprogression on irinotecan or as a single agent if intolerant toprogression on irinotecan or as a single agent if intolerant toirinotecanirinotecan

Panitumumab was recently approved for the treatment of MCRCPanitumumab was recently approved for the treatment of MCRC(trials compared (trials compared panitumumab vs panitumumab vs BSC)BSC)

Biologics in Lung CancerBiologics in Lung Cancer

NSArm 1: 9.9 moArm 2: 10.1 mo

1) gemcitabine/cisplatin x 6 cycles + erlotinib (150 mg daily)2) gemcitabine/cisplatin

1172TALENT3

NSArm 1: 10.6 moArm 2: 10.5 mo

1) carboplatin/paclitaxel x 6 cycles+ erlotinib (150 mg daily)2) carboplatin/paclitaxel

1059TRIBUTE4

NSArm 1: 8.7 moArm 2: 9.8 moArm 3: 9.9 mo

Carboplatin/paclitaxel x 6 cycles +1) gefinitib 500 mg daily2) gefinitib 250 mg daily3) placebo

1037INTACT 22

NSArms 1&2: 9.9 moArm 3: 10.9 mo

Gemcitabine/cisplatin x 6 cycles +1) gefinitib 500 mg daily2) gefinitib 250 mg daily3) placebo

1093INTACT 11

P-valueMedian OSTreatmentN

1. Giaccone G, et al. J Clin Oncol. 2004;22:777. 2. Herbst RS, et al. J Clin Oncol. 2004;22:785. 3. Gatzemeier U, et al. 40thASCO; June 5-8, 2004. Abstract 7010. 4. Herbst RS, et al, J Clin Oncol. 2005;23:5892.

The Role of Small MoleculeThe Role of Small MoleculeAnti-EGFR Anti-EGFR TKIs TKIs in NSCLCin NSCLC

0 5 10 15 20 25

ErlotinibPlacebo

0

0.2

0.4

0.6

0.8

1.0

0

0.2

0.4

0.6

0.81.0

0 5 10 15 20 25Months on Study

Surv

ival

Rat

e

Months on Study

ErlotinibPlacebo

Herbst RS, et al. J Clin Oncol. 2005;23:5892. Reprinted with permission. From the American Society of Clinical Oncology.

Unselected Patients Never Smokers

Erlotinib Plus Chemotherapy in NSCLCErlotinib Plus Chemotherapy in NSCLC

Erlotinib PlaceboMedian survival (mo) 10.6 10.51-y survival rate (%) 46.9 43.8Hazard ratio 0.995 (P = .95)

Erlotinib Placebo P-ValueMedian survival (mo) 22.5 10.1 .01No. of patients 72 44

NSCLC = non–small cell lung cancer.

Sandler AB, et al. 41st ASCO; May 13-17, 2005. Abstract LB4.

• Treatment-naivestage IIIB or IVNSCLC

• No history ofhemoptysis

• No CNSmetastases

• ECOG PS 0–1

Carboplatin (C) AUC = 6 Paclitaxel(P) 200 mg/m2 and

q3wk for 6 cycles withBevacizumab (B) 15 mg/kg

(n = 434)

Carboplatin (C) AUC = 6 Paclitaxel(P) 200 mg/m2 and q3wk for 6 cycles

(n = 444)

RANDOMIZATION

Primary endpoint: OS

6.4 mo vs 4.5 mo(HR = 0.62, 95% CI: 0.53,

0.72, P < .0001)

Median PFS

12.5 mo vs 10.2 mo(HR = 0.77, 95% CI: 0.65, 0.93,

P = .007)27% vs 10% (P < .0001)

Median OSRR

E4599E4599 Phase III Trial of Paclitaxel + CarboplatinPhase III Trial of Paclitaxel + Carboplatin

+/- Bevacizumab in Advanced NSCLC+/- Bevacizumab in Advanced NSCLC

Summary of Biologic Agents in NSCLCSummary of Biologic Agents in NSCLC

4 large phase III studies failed to demonstrate a benefit in4 large phase III studies failed to demonstrate a benefit inoverall survival (OS) with the addition of overall survival (OS) with the addition of gefinitib gefinitib or erlotinib toor erlotinib tostandard chemotherapystandard chemotherapy–– Subset analysis revealed that patients who areSubset analysis revealed that patients who are

nonsmokers and Asians fared betternonsmokers and Asians fared better1,21,2

–– Patients with a mutation in the TK domain of the EGFRPatients with a mutation in the TK domain of the EGFRreceptor have improved OSreceptor have improved OS3-53-5

Exons Exons 18-2118-21–– Erlotinib is currently approved for use in surgicallyErlotinib is currently approved for use in surgically

unresectable NSCLC patientsunresectable NSCLC patients Bevacizumab in combination with Bevacizumab in combination with paclitaxel paclitaxel and and carboplatincarboplatin,,

was approved by the FDA (10/12/06) as first-line therapy forwas approved by the FDA (10/12/06) as first-line therapy forNSCLCNSCLC

1. Thomas SK, et al. Clin Lung Cancer. 2006;7:326. 2. Lim ST, et al. Br J Cancer. 2005;93:23. 3. Riely GJ, et al. Clin Cancer Res.2006;12:839. 4. Takano T, et al. J Clin Oncol. 2005;23:6829. 5. Tsao MS, et al. N Engl J Med. 2005;353:133.

Renal Cell CarcinomaRenal Cell CarcinomaMultitargeted Multitargeted Oral AgentsOral Agents

20 (6%)B. IFN-A (thrice weekly)

750

106

63

N

NotReached

11 vs 5HR = 0.415 (95%CI: 0.320-0.539)

P < .000001

PR:

103 (31%)

Randomized

A. sunitinibIIIMulticenter3

(ongoing)

NA8.3 (95% CI:

7.8–14.5)PR: 36(34%)

Sunitinib (50 mg/d,wk 1–4, repeat q6wk)

IIMotzer et al2

(previously treated,clear cell only)

II

Phase

Motzer et al1

(previously treated)

Agent

16.48.7 (95% CI:

5.5–10.7)PR: 25 (40%)

Sunitinib (50 mg/d,wk 1–4, repeat q6wk)

MedianOS (mo)

Median PFS orTTP (mo)RR (%)Design

1. Motzer RJ, et al. J Clin Oncol. 2006;24:16.2. Motzer RJ, et al. JAMA. 2006;295:2516. 3. Motzer RJ, et al. 42nd ASCO; June 2-6, 2006. Abstract # LBA3.

Efficacy of Sunitinib in Renal Cell CarcinomaEfficacy of Sunitinib in Renal Cell Carcinoma Phase II–III Pivotal Trials

RR = response rate; PFS = progression-free survival; TTP = time to progression; OS = overall survival; PR = partial response;CI = confidence interval.

PD

Eisen T, et al. 42nd ASCO; June 2-6, 2006. Abstract 4524.

Clear cell cancer patients,failed 1 prior therapy

< 8 mo prior,ECOG PS 0–1

Sorafenib 400 mg PO BID(n = 451)

Placebo(n = 452)

Sorafenib(n = 200)

RANDOMIZATION

Primary endpoint: OS

19.3 vs 15.9 moHR = 0.77

(95% CI: 0.63–0.95)P = .015

Median OS (mo):6-mo Postcrossover

19.3 vs 14.3 moHR = 0.74

(95% CI: 0.58–0.93)P = .01

24 wk vs 12 wkHR = 0.44

(95% CI = 0.35–0.55)P < .000001

Median OS (mo): with CensoredPlacebo Arm

Median PFS or TTP (mo)

Efficacy of Sorafenib in Renal Cell CarcinomaEfficacy of Sorafenib in Renal Cell Carcinoma Pivotal Phase III Trial (TARGET)Pivotal Phase III Trial (TARGET)

SunitinibSunitinib11

NauseaNausea

DiarrheaDiarrhea

StomatitisStomatitis

HyperlipasemiaHyperlipasemia

NeutropeniaNeutropenia

FatigueFatigue

Decrease in LVEFDecrease in LVEF(rare)(rare)

SorafenibSorafenib22

RashRash

FatigueFatigue

DyspneaDyspnea

HypertensionHypertension

1. Sutent® PI, Pfizer Labs, New York, NY, February 2006.2. Nexavar® PI, Bayer Pharmaceutical Corporation, West Haven, CT, Onyx Pharmaceuticals, Emeryville, CA, August 2006.

Associated Side EffectsAssociated Side EffectsSunitinib and SorafenibSunitinib and Sorafenib

Summary of Biologic AgentsSummary of Biologic Agentsin Metastatic Renal Cell Cancerin Metastatic Renal Cell Cancer

Both sunitinib and sorafenib clearly have a roleBoth sunitinib and sorafenib clearly have a rolein previously treated renal cell cancer and arein previously treated renal cell cancer and arecurrently FDA approvedcurrently FDA approved

Additional biologic agents are currently beingAdditional biologic agents are currently beingevaluated and have demonstrated promisingevaluated and have demonstrated promisingactivityactivity

Biologics in Breast CancerBiologics in Breast Cancer

Miller KD, et al. 41st ASCO; May 13-17, 2005. Late-breaking session.

RANDOMIZATION

Paclitaxel 90 mg/m2 d 1, 8, 15of 28-d cycle

Paclitaxel 90 mg/m2

d 1, 8,15 of 28-d cycle +Bevacizumab 10 mg/kg d 1, 15

715 recurrent/metastatic breastcancer patients

E2100E2100Phase III Trial of Paclitaxel +/- Bevacizumab as First-LinePhase III Trial of Paclitaxel +/- Bevacizumab as First-Line

Therapy in Recurrent or Metastatic Breast CancerTherapy in Recurrent or Metastatic Breast Cancer

28%14%Response rate

11 months6 monthsOverall survival

(n = 330)(n = 316)

Paclitaxel + BevacizumabPaclitaxel

RANDOMIZATION

Capecitabine (2000 mg/m2/d) + lapatinib(1250 mg/d), d 1–14, repeat q21d

315 locally advanced ormetastatic Her 2+

cancer patients withrecurrent disease

Capecitabine (2500 mg/m2/d)d 1–14, repeat q21d

P = .00016

P-value

36.9 weeks vs 19.7 weeks

Median TTP

Geyer CE, et al. ASCO 2006. Abstract, SPS23.

EGF 100151EGF 100151Phase III Trial of Capecitabine +/- Lapatinib as Second-Phase III Trial of Capecitabine +/- Lapatinib as Second-Line Therapy in Recurrent or Metastatic Breast CancerLine Therapy in Recurrent or Metastatic Breast Cancer

TTP = time to tumor progression.

Geyer CE, et al. ASCO 2006. Abstract, SPS23.

Side Effects of LapatinibSide Effects of Lapatinib

DiarrheaDiarrhea

Palmar-plantar erythrodysesthesiaPalmar-plantar erythrodysesthesia

RashRash

Decreased left ventricular ejectionDecreased left ventricular ejectionfractionfraction

Summary of Biologic AgentsSummary of Biologic Agentsin Metastatic Breast Cancerin Metastatic Breast Cancer

Both bevacizumab and lapatinib haveBoth bevacizumab and lapatinib havedemonstrated advantages in metastatic anddemonstrated advantages in metastatic andrecurrent breast carcinomarecurrent breast carcinoma

Final data have yet to be reported on both ofFinal data have yet to be reported on both ofthese studiesthese studies

Neither bevacizumab nor lapatinib is currentlyNeither bevacizumab nor lapatinib is currentlyFDA approved for this indicationFDA approved for this indication

IIIAZD 2171, GW783034

(pazopanib)VEGFR 1-3

IIIAG-013736 (axitinib)VEGFR 1-3, PDGFR,

c-Kit

IIIZD6474 (vandetanib)EGFR/VEGFR-2

IIVEGF TrapVEGF-A, B, PIGF

Phase of DevelopmentName of DrugMolecular Target

CCI-779 (temsirolimus),RAD001 (everolimus)

Dasatinib, AZD0530

IIImTOR

II Src Kinase

New Agents on the HorizonNew Agents on the Horizonin Solid Tumorsin Solid Tumors

Courtesy of Dr. C. Eng.

Present and Future Role of TargetedPresent and Future Role of TargetedTherapies in Cancer CareTherapies in Cancer Care

Tarek MekhailTarek Mekhail, , MD, MD, MScMSc, FRCSI, , FRCSI, FRCSEdFRCSEd

Director, Lung Cancer Medical Oncology ProgramDirector, Lung Cancer Medical Oncology Program

Hematology/Medical OncologyHematology/Medical Oncology

The Cleveland ClinicThe Cleveland Clinic

Cleveland,Cleveland, OhioOhio

Drug Development ParadigmDrug Development Paradigm

Identifying a therapeutic targetIdentifying a therapeutic target

Preclinical activityPreclinical activity

Clinical drug developmentClinical drug development

Targeted TherapyTargeted Therapy

Anti-EGFRblocking

antibodies

Antiligandblocking

antibodies

Tyrosinekinase

inhibitors Ligand-toxin

conjugates

HER dimerizationinhibitors

TOXIN

Adapted from Noonberg SB, Benz CC. Drugs. 2000;59:753, with permission.

*Day 1 of treatment defined as tumor size 5–6 mm (3–5 days postimplantation).

Adapted from Sirotnak FM, et al. Clin Cancer Res. 2000;6:4885, with permission.

Control

Paclitaxel 25 mg/kgGefitinib 50 mg/kg

Gefitinib + paclitaxel

0

200

400

600

800

1000

1200

0 4 8 12 16 20 24 28 32 36Days Postimplantation

Tum

or V

olum

e (m

m3 )

Gefitinib + PaclitaxelGefitinib + PaclitaxelResponse in LX-1 Lung Tumor Xenografts withResponse in LX-1 Lung Tumor Xenografts with

Low Expression of Wild-Type HER1/EGFRLow Expression of Wild-Type HER1/EGFRP = paclitaxel d 1, 4, 8, and 11*

G = gefitinib d 1–5 and 8–12*

P P P P

G

Erlotinib 150 mg/d

CR + PR CR/PR + SD

% o

f Pat

ient

s

100

80

60

40

20

0

8.4 40

OS (mo) 1-y Survival (%)

Phase II Trial of Erlotinib in HER1/EGFRPhase II Trial of Erlotinib in HER1/EGFRPositive Patients with Advanced NSCLCPositive Patients with Advanced NSCLC

EfficacyEfficacy

OS = overall survival; CR = complete response; PR = partial response; SD = stable disease.

Perez-Soler R, et al. J Clin Oncol. 2004;22:3238.

N = 57

12.3

50.9

BR.21BR.21Phase III Trial of Phase III Trial of Erlotinib Erlotinib for Advanced for Advanced NSCLCNSCLC——SchemaSchema

End PointsPrimary: overall survivalSecondary: progression-free survival, overall response rate, duration of response, quality of life, safety

Erlotinib 150 mg/dn = 488

Placebon = 243

RANDOMIZE

*2:1 randomization to the experimental arm.PS = performance status; CR = complete response; PR = partial response; SD = stable disease;PD = progressive disease.

Shepherd FA, et al. N Engl J Med. 2005;353:123.

Locally advanced or metastatic NSCLCPS 0–3≥1 failed prior chemotherapy regimenNo prior malignancies or uncontrolled CNS metastases except basal cell skin cancersStratified by

• Center• PS (0/1 vs 2/3)• Response to prior therapy

(CR/PR:SD:PD)• Prior regimens (1 vs 3)• Prior platinum (yes vs no)

N = 731*

HR = hazard ratio.

Adapted from Shepherd FA, et al. N Engl J Med. 2005;353:123, with permission from the Massachusetts Medical Society.Copyright 2005. All rights reserved.

BR.21BR.21Phase III Trial of Phase III Trial of Erlotinib Erlotinib for Advancedfor Advanced

NSCLCNSCLC——Overall Overall SurvivalSurvival

MedianSurvival (mo)

1-YearSurvival (%)

6.7 31

4.7 22

Erlotinib

Placebo

Months

0 6 12 18 24 30

100

80

60

40

0

20

Ove

rall

Su

rviv

al (

% P

atie

nts

)

HR = 0.70, P < .001

Ran

dom

izat

ion

Docetaxel + cetuximab

Pemetrexed

2nd- or 3rd-line therapyfor NSCLC

No priorEGFR,

docetaxel, orpemetrexed

Multicenter StudyN = 800Open

Primary Endpoint = Response

Pemetrexed + cetuximab

Docetaxel

http://clinicaltrials.gov

Phase III NSCLC Registration TrialPhase III NSCLC Registration TrialDocetaxel Docetaxel or or Pemetrexed Pemetrexed +/- +/- CetuximabCetuximab

Image courtesy of Dr. T. Mekhail.

AngiogenesisAngiogenesis

The Angiogenic Switch Is a Key Step forThe Angiogenic Switch Is a Key Step forTumor Growth and Risk of MetastasisTumor Growth and Risk of Metastasis

Angiogenicswitch

100 µm

Small tumor Nonvascular “Dormant”

Larger tumor Vascular Metastatic potential

Adapted from Ferrara, N. The Oncologist. 2004;9:2. Reprinted with permission.

Agents Targeting the VEGF PathwayAgents Targeting the VEGF Pathway

VEGFR-2VEGFR-1

Endothelial cell

Small-molecule VEGFRinhibitors– Vatalanib (PTK787)– Sunitinib (SU11248)– Sorafenib (BAY 43-9006)– ZD6474

Anti-VEGFRantibodies(IMC-1121b)

VEGFAnti-VEGFantibodies

(bevacizumab)

SolubleVEGFRs

(VEGF-Trap)

Adapted from Podar K, Anderson KC. Blood. 2005;105:1383, with permission.

BevacizumabBevacizumab

Recombinant humanizedRecombinant humanizedmonoclonal IgGmonoclonal IgG11 antibody antibody11

Recognizes all isoforms ofRecognizes all isoforms ofVEGF-AVEGF-A22

Estimated half-lifeEstimated half-lifeis approximately 20 daysis approximately 20 days(range, 11(range, 11––50)50)11

1Avastin [package insert] San Francisco, CA: Genentech; 2006.2Presta JL, et al. Cancer Res. 1997;57:4593.Image courtesy of Dr. T. Mekhail.

Bevacizumab, Carboplatin, and PaclitaxelBevacizumab, Carboplatin, and PaclitaxelPhase III First-Line Trial in NSCLC (E4599)Phase III First-Line Trial in NSCLC (E4599)

DesignDesignCP × 6

Carboplatin AUC 6 (q3wk) +paclitaxel 200 mg/m2

BCP × 6Bevacizumab (15 mg/kg

q3wk) to PD+

carboplatin AUC 6 (q3wk)(15 mg/kg q3wk)

+paclitaxel 200 mg/m2

Nocrossoverallowed inthis study

Primary end point: overall survivalPrimary end point: overall survival

Secondary end points include time-to-progression, overall response rate, tolerabilitySecondary end points include time-to-progression, overall response rate, tolerability

*1:1 randomization to the experimental arm.Sandler et al. 41st ASCO; May 13-17, 2005. Abstract LBA4 and oral presentation.

RANDOMIZATION

• Previously untreatedstage IIIB/IV NSCLC

• Nonsquamous NSCLC• No Hx of hemoptysis• No CNS metastases• ECOG PS 0–1• N = 855 eligible patients*

0 6 12 18 24 30 36

Months

Medians: 10.2, 12.5

12 mo 24 mo 43.7% 16.9% 51.9% 22.1%

HR = 0.77 (0.65, 0.93)

P = .007

0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty

CPBCP

Bevacizumab, Carboplatin, and PaclitaxelBevacizumab, Carboplatin, and PaclitaxelPhase III First-Line Trial in NSCLC (E4599)Phase III First-Line Trial in NSCLC (E4599)

Overall SurvivalOverall Survival

Sandler AB, et al. 41st ASCO; May 13-17, 2005. Abstract LBA4 and oral presentation. Reprinted with permission from the AmericanSociety of Clinical Oncology.

The FutureThe Future

Combination therapyCombination therapy

Multitargeted Multitargeted agentsagents

Clinical markers for responseClinical markers for response

Molecular markers for responseMolecular markers for response

Bevacizumab + ErlotinibBevacizumab + ErlotinibPhase I/II Trial in Recurrent NSCLC (OSI2486)Phase I/II Trial in Recurrent NSCLC (OSI2486)

Overall Overall Antitumor Antitumor Activity*Activity*

*By RECIST criteria (N = 40).† Total population.

Herbst RS, et al. J Clin Oncol. 2005;23:2544. Reprinted with permission from the American Society of Clinical Oncology.

26 (65)SD

8 (20)PR

6 (15)PD

0CR

No. of Patients (%)Best Response (N = 40†)

Phase I/II Trial of Phase I/II Trial of Bevacizumab Bevacizumab + + ErlotinibErlotinibin Recurrent NSCLCin Recurrent NSCLCCase History (Phase I)Case History (Phase I)

Pretreatment with Bevacizumab + Erlotinib

Posttreatment with Bevacizumab + Erlotinib

48-year-old African-American male with stage IIIB adenocarcinoma with pleural effusion CT scans at baseline and following 2 cycles of therapy (dose level I)

Herbst RS, et al. J Clin Oncol. 2005;23:2544. Reprinted with permission from the American Society of Clinical Oncology.

Heymach JV, et al. J Clin Oncol. 2005;23:3025.

Multitargeted Multitargeted ApproachesApproachesZD6474 in Advanced NSCLCZD6474 in Advanced NSCLC

Orally available inhibitor of 2 key pathways in tumor growthOrally available inhibitor of 2 key pathways in tumor growth

–– VEGFR-dependent tumor angiogenesisVEGFR-dependent tumor angiogenesis

–– EGFR-dependent tumor cell proliferation and survivalEGFR-dependent tumor cell proliferation and survival

Number of randomized phase II trials ongoing/completedNumber of randomized phase II trials ongoing/completed

–– ZD6474 vs gefitinibZD6474 vs gefitinib

–– Docetaxel +/- ZD6474Docetaxel +/- ZD6474

–– 3 arms: ZD6474 alone vs paclitaxel/carboplatin +3 arms: ZD6474 alone vs paclitaxel/carboplatin +ZD6474 or placeboZD6474 or placebo

Clinical Markers for Response BR.21Clinical Markers for Response BR.21Exploratory AnalysisExploratory Analysis——Survival by Smoking HistorySurvival by Smoking History

Never Smoked Current and Ex-smokers

HR = 0.42 (95% CI, 0.28–0.64)ORR = 24.7%

HR = 0.87 (95% CI, 0.71–1.05)ORR = 3.9%

Months0 5 10 15 20 25

Months

% S

urv

ival

0 5 10 15 20 25

100

80

60

40

0

20

100

80

60

40

0

20

Placebo(n = 42)

Erlotinib(n = 104)

Placebo(n = 187)

Erlotinib(n = 358)

% S

urv

ival

HR = hazard ratio; CI = confidence interval; ORR = overall response rate.

Reprinted from Clin Lung Cancer, 7, Clark GM, et al, Smoking History and Epidermal Growth Factor Receptor Expression asPredictors of Survival Benefit from Erlotinib for Patients with Non-Small-Cell Lung Cancer in the National Cancer Institute of CanadaClinical Trials Study BR.21, pp 389-394, Copyright © 2006, with permission from Cancer Information Group.

Molecular Markers for ResponseMolecular Markers for Response

EGFR mutation status by gene sequencingEGFR mutation status by gene sequencing

EGFR gene copy number by fluorescenceEGFR gene copy number by fluorescencein situ hybridizationin situ hybridization

EGFR protein expression byEGFR protein expression byimmunohistochemistryimmunohistochemistry

b pVHL HIF=a

VEGFR EGFRPDGFR

Sunitinib, Sorafenib,AG-013736

Sorafenib

Bevacizumab

RAF

Erlotinib

Kaelin WG. Nat Rev Cancer. 2002;2:673. Reprinted with permission.

Renal Cell CarcinomaRenal Cell CarcinomaTargets of Single AgentsTargets of Single Agents

VEGF TGF-aPDGF

RAFSorafenib

1. Nexavar® [package insert]. West Haven, CT: Bayer Pharmaceuticals Corporation; and Emeryville, CA: Onyx Pharmaceuticals;2006. 2. Sutent [package insert]. New London, CT: Pfizer Labs; 2006. 3. Rugo HS, et al. J Clin Oncol. 2005;23:5474. 4. Avastin[package insert]. San Francisco, CA: Genentech Inc, 2006. 5. Atkins MB, et al. J Clin Oncol. 2004;22:909.

Molecular Targeted Therapies for RCCMolecular Targeted Therapies for RCCTarget InhibitionTarget Inhibition

SorafenibSorafenib11

–– VEGFR, PDGFR, RAFVEGFR, PDGFR, RAF SunitinibSunitinib22

–– VEGFR, PDGFRVEGFR, PDGFR AG-013736AG-01373633

–– VEGFR, PDGFRVEGFR, PDGFR BevacizumabBevacizumab44

–– VEGFVEGF Temsirolimus Temsirolimus (CCI-779)(CCI-779)55

–– mTORmTOR

*Single planned analysis. Independently assessed.†PFS analysis performed March, 2005 (data cut-off Jan 28, 2005).Adapted from Escudier B., 41st ASCO; May 13-17, 2005, with permission.

Pro

po

rtio

n o

f P

atie

nts

Pro

gre

ssio

n-F

ree

0

0.25

0.50

0.75

1.00

Median PFS†

Sorafenib (n = 451) = 24 weeksPlacebo (n = 452) = 12 weeksHazard ratio (S/P) = 0.44(95% CI: 0.35, 0.55)P < .000001

0 6054484236302418126

Time from Randomization (wk)

PlaceboSorafenib

Censored observation

Phase III, randomized double-blind, placebo-controlled trial* Patients with cytokine-refractory RCC were randomized 1:1

to sorafenib (400 mg BID) or placebo Primary endpoint: overall survival

TARGET TrialTARGET TrialSorafenib Sorafenib vs vs Placebo Progression-Free Survival inPlacebo Progression-Free Survival in

Cytokine-Refractory RCCCytokine-Refractory RCC

21 June 2005 17 October 2005

Escudier B, et al. Eur J Cancer Suppl. 2005;3:226 (abstract 794). Reprinted with permission.

TARGET TrialTARGET TrialTumor ResponseTumor Response

Sunitinib Sunitinib vs vs InterferonInterferonPhase III Study DesignPhase III Study Design

N = 750

Stratification factors

● LDH ≤1.5 vs >1.5 x ULN

● ECOG PS 0 vs 1

● Presence vs absenceof nephrectomy

Sunitinib(n = 375)

IFN alfa(n = 375)

Motzer RJ, et al. 42nd ASCO; June 2-6, 2006. Abstract LBA3. Reprinted with permission from the American Society of Clinical Oncology.

RANDOMIZATION

Sunitinib Sunitinib vs vs InterferonInterferonProgression-Free SurvivalProgression-Free Survival

Motzer RJ, et al. 42nd ASCO; June 2-6, 2006. Abstract LBA3. Reprinted with permission from the American Society of Clinical Oncology.

No. at Risk (Sunitinib): 235 90 322No. at Risk (IFN alfa): 152 42 180

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14Time (Months)

00.10.20.30.40.50.60.70.80.91.0

Prog

ress

ion-

Free

Sur

viva

l Pro

babi

lity

SunitinibMedian: 11 months(95% CI: 10–12)

IFN alfa Median: 5 months(95% CI: 4–6)

Hazard Ratio = 0.415(95% CI: 0.320–0.539)P < .000001

(Independent Central Review)

Most Common SideMost Common Side Effects AssociatedEffects Associatedwith Marketed Targeted Agentswith Marketed Targeted Agents

Diarrhea, hypertension, bleeding, mucositis, skin abnormalities,altered taste

Sunitinib6

Rash, diarrhea, hand-foot skin reaction, fatigue, hypertension,alopecia

Sorafenib5

Diarrhea, rash, acne, dry skin, nausea, vomitingGefitinib4

Rash, diarrhea, anorexia, fatigue, dyspnea, coughErlotinib3

Acneform rash, asthenia/malaise, diarrhea, nausea, abdominalpain, vomiting

Cetuximab2

Asthenia, pain, abdominal pain, headache, hypertension,diarrhea, nausea, vomiting

Bevacizumab1

Most Common ToxicitiesAgent

1. Avastin [package insert] San Francisco, CA: Genentech; 2006. 2. Erbitux® [package insert]. Branchburg, NJ: Imclone SystemsIncorporated; and Princeton, NJ: Bristol-Myers Squibb Company; 2006. 3. Tarceva™ [package insert]. Melville, NY: OSIPharmaceuticals Inc, and Genentech, Inc; 2005. 4. Iressa [package insert]. Wilmington, DE: AstraZeneca; 2005. 5. Nexavar®

[package insert]. West Haven, CT: Bayer Pharmaceuticals Corporation; and Emeryville, CA: Onyx Pharmaceuticals; 2006.6. Sutent [package insert]. New London, CT: Pfizer Labs; 2006.

Raising The BarRaising The BarToxicity ProfileToxicity Profile

Absence of traditional side effectsAbsence of traditional side effects

Manageable toxicityManageable toxicity

The FutureThe Future

Overcoming evolving resistanceOvercoming evolving resistance

Combination with other agentsCombination with other agents

Treatment of earlier stage of the diseaseTreatment of earlier stage of the disease

Individualizing treatmentIndividualizing treatment

Cure!Cure!