Targeted agents in Targeted agents in Gynecologic CancerGynecologic Cancer

Amit M OzaAmit M OzaAmit M. OzaAmit M. OzaProfessor of Medicine,Professor of Medicine,

Princess Margaret Hospital,Princess Margaret Hospital,University of TorontoUniversity of Torontoyy

CoCo--Chair Gynecology, NCIC CTGChair Gynecology, NCIC CTG

Targeted TherapiesTargeted TherapiesTargeted TherapiesTargeted Therapies

Incorporation of novel targeted therapiesIncorporation of novel targeted therapiesIncorporation of novel targeted therapiesIncorporation of novel targeted therapiesBiologic rationale Biologic rationale Prevalence of targetPrevalence of targetPrevalence of target Prevalence of target Characteristics of the targetCharacteristics of the target

Amenable to modulationAmenable to modulationAvailability of inhibitorAvailability of inhibitorEffect of target inhibition in patients Effect of target inhibition in patients –– activity activity

f i hibitf i hibitof inhibitorsof inhibitors

Therapies for intracellular targetsTherapies for intracellular targetsTherapies for intracellular targetsTherapies for intracellular targets

Virt e of promisc it o er fidelit ?Virt e of promisc it o er fidelit ?Virtue of promiscuity over fidelity?Virtue of promiscuity over fidelity?Complexity of signal transduction pathwaysComplexity of signal transduction pathwaysvalue of single targetvalue of single targetvalue of single targetvalue of single target

Combined approaches due to synergy Combined approaches due to synergy Eg target EGFR + ChemoEg target EGFR + ChemoEg target EGFR + ChemoEg target EGFR + ChemoSequential or concurrent therapySequential or concurrent therapyCombinations of targeted agentsCombinations of targeted agentsg gg g

Aberrations in multiple interAberrations in multiple inter--related pathwaysrelated pathwaysDevelop clinical and translational studiesDevelop clinical and translational studies

Molecular Pathways of InterestMolecular Pathways of InterestMolecular Pathways of InterestMolecular Pathways of InterestAngiogenesis Angiogenesis ––g gg g

Ovarian, Endometrial, Cervical Ovarian, Endometrial, Cervical PI3 Kinase PI3 Kinase –– AKT AKT –– mTOR mTOR --

Endometrial OvarianEndometrial OvarianEndometrial, OvarianEndometrial, OvarianEpigenetic mechanisms Epigenetic mechanisms ––

Ovarian, EndometrialOvarian, EndometrialEGFR targetingEGFR targeting

Ovarian, Cervical, endometrialOvarian, Cervical, endometrialPoly (ADPPoly (ADP ribose) polymerase inhibition (parpribose) polymerase inhibition (parpPoly (ADPPoly (ADP--ribose) polymerase inhibition (parp ribose) polymerase inhibition (parp inhibition) inhibition) ––

OvarianOvarian

Faivre et al Nature Reviews Drug Discovery 5 671–688 (August 2006) | doi:10 1038/nrd2062Faivre et al. Nature Reviews Drug Discovery 5, 671 688 (August 2006) | doi:10.1038/nrd2062

Rationale Rationale forfor AntiAnti--angiogenic angiogenic therapytherapy

As tumours increase in size, become dependent , pon vasculatureExploitable differences between normal and

ltumour vasculatureAffecting one blood vessel effects large numbers of tumour cellsof tumour cellsEndothelial cells are less likely to develop drug resistance due to slower rates of divisiones sta ce due to s o e ates o d s oMay actually be synergistic with cytotoxic May actually be synergistic with cytotoxic chemotherapy and radiotherapychemotherapy and radiotherapy

The Angiogenic Switch and The Angiogenic Switch and Antiangiogenic TherapyAntiangiogenic TherapyAntiangiogenic TherapyAntiangiogenic Therapy

Somatic mutation

Smallavascular

tumor

Tumor secretion of angiogenic factors

stimulates angiogenesis

Rapid tumor growth and metastasis

Angiogenic inhibitors may reverse this vascularization

Carmeliet and Jain. Nature. 2000;407:249.

Angiogenesis is involved throughout tumourAngiogenesis is involved throughout tumourAngiogenesis is involved throughout tumour Angiogenesis is involved throughout tumour formation, growth and metastasisformation, growth and metastasis

Premalignantstage

Malignanttumour

Tumourgrowth

Vascularinvasion

Dormantmicrometastasis

Overtmetastasis

(Avascular (Angiogenic (Vascularised (Tumour cell (Seeding in (Secondarytumour) switch) tumour) intravasation) distant organs)

(S o da yangiogenesis)

Stages at which angiogenesis plays a role in tumour progression

Adapted from Poon RT-P, et al. J Clin Oncol 2001;19:1207–25

g g g p y p g

Tumour vasculature differs Tumour vasculature differs

Normal blood vesselsNormal blood vessels Tumour blood vesselsTumour blood vesselsfrom normal vasculaturefrom normal vasculature

Normal blood vessels Normal blood vessels Tumour blood vesselsTumour blood vesselsMaturation factors

N th f t

Growth factors (VEGF)

No growth factorsTight

Leaky

Integrins Fewer supporting

cellsSupport cells

Jain R. Nat Med 2003;9:685–93Carmeliet P. Nat Med 2003;9:653–60

VEGFVEGF Key mediator of Key mediator of angiogenesisangiogenesisangiogenesisangiogenesis

Controls tumour growth by Controls tumour growth by

Stimulating tumour Stimulating tumour angiogenesis angiogenesis Maintaining tumour vasculature Maintaining tumour vasculature Increasing Increasing vascularvascular permeabilitypermeabilityAffecting the normal immune Affecting the normal immune response response ppPossible direct effect on tumour Possible direct effect on tumour cellscells

Ovarian cancer :Ovarian cancer :High VEGF secretion and expressionHigh VEGF secretion and expression

Latter related to stage/mitotic activity Latter related to stage/mitotic activity -- prognosisprognosisVEGF angiogenic and permeability factor: ascitesVEGF angiogenic and permeability factor: ascites

VEGFVEGFVEGFVEGFKey mediator of Key mediator of

angiogenesisangiogenesisNormal

Stimulating tumour angiogenesis

Proliferation and migration of endothelial cellsendothelial cells

Maintaining tumour vasculatureSurvival of endothelial cells

Increasing vascular permeability

Increases interstitial fluid pressure

Impairs delivery of O2,,

Cancer

2,nutrients and drugsHypoxic loop set up causing further production of VEGF

– May allow tumour cells to enter the circulation and metastasize

Konerding et al BJC 1999, 80; 724-32

Agents Targeting theAgents Targeting the VEGFVEGFAgents Targeting theAgents Targeting the VEGF VEGF PathwayPathway

↑ Permeability

Antibodies inhibiting VEGF(e.g. bevacizumab)

Antibodies inhibiting VEGF receptors Soluble VEGF receptors

(VEGF-TRAP)

VEGF

VEGF receptor-2

Cation channel

Small-molecules inhibiting VEGF receptors

(TKIs)(e.g. PTK-787)

– P– PP–

P–

– P– P

P–P–

– P– P

P–P–

Ribozymes(Angiozyme)

Migration, permeability, DNA synthesis, survival

L h i iA i i LymphangiogenesisAngiogenesis

Single Agent Bevacizumab Single Agent Bevacizumab in Ovarian Cancerin Ovarian Cancer

GOG 170D GOG 170D (Burger ASCO 2005)(Burger ASCO 2005) Cannistra et al Cannistra et al (ASCO 2006)(ASCO 2006)

Bevacizumab 15mg/kg q 3/52 Bevacizumab 15mg/kg q 3/52 Bevacizumab 15mg/kg q 3/52Bevacizumab 15mg/kg q 3/52

N=64N=64 N=44N=44

1 or 2 previous chemotherapy 1 or 2 previous chemotherapy Up to 3 prior chemotherapy courses, Up to 3 prior chemotherapy courses, courses, 55% platinum resistantcourses, 55% platinum resistant 100% platinum resistant100% platinum resistant

RR 18% (CR 5%) SD 55%RR 18% (CR 5%) SD 55% RR 16% (CR 0%) SD 25%RR 16% (CR 0%) SD 25%

6month PFS 38.7%6month PFS 38.7% 6 month PFS 27%6 month PFS 27%

Median PFS 4.7monthsMedian PFS 4.7months Median PFS 4.3monthsMedian PFS 4.3months

Median OS 17monthsMedian OS 17months Median OS not reachedMedian OS not reached

SE: Emesis, constipation, TESE: Emesis, constipation, TE SE: Arterial TE, GI perforation, HTSE: Arterial TE, GI perforation, HT

Combination Bevacizumab Combination Bevacizumab R i i O i CR i i O i CRegimens in Ovarian CancerRegimens in Ovarian Cancer

Carboplatin PaclitaxelCarboplatin Paclitaxel Cyclophosphamide Cyclophosphamide ErlotinibErlotinib(n=43, Penson, ASCO 2006)(n=43, Penson, ASCO 2006) (N=70) (Garcia JCO (N=70) (Garcia JCO

2007)2007)(n= 13)(n= 13) Friberg ASCO Friberg ASCO 20062006

BevacizumabBevacizumab 15 mg/kg q3w (+maintenance)15 mg/kg q3w (+maintenance) 10 mg/kg q2w10 mg/kg q2w 15 mg/kg q3w15 mg/kg q3w

Other drugsOther drugs Carboplatin AUC5Carboplatin AUC5Paclitaxel 175 mg/mPaclitaxel 175 mg/m22 q3/52q3/52

CyclophosphamideCyclophosphamide50 mg/d50 mg/d

Erlotinib 150 mg/dErlotinib 150 mg/d

Prev. regimensPrev. regimens 00 ≤3≤3 ≤3≤3gg

Pt sensitivityPt sensitivity Pt RefractoryPt Refractory 4 refractory, 2 4 refractory, 2 resistant, 7 sensitiveresistant, 7 sensitive

ToxicityToxicity Neuro, HT, PE, Wound Neuro, HT, PE, Wound III/IV (>5%): HT, fatigue, III/IV (>5%): HT, fatigue, Diarrhoea, GI Diarrhoea, GI healing (No GI perf, ATE)healing (No GI perf, ATE) Na↓, painNa↓, pain perforation (2/13), HTperforation (2/13), HT

ResponseResponse CT: CR 56%, PR 22%CT: CR 56%, PR 22%CaCa--125: CR 89%, PR 7%125: CR 89%, PR 7%

CR 0%, PR 25%, SD CR 0%, PR 25%, SD 50%50%

CR 1 (8%), PR 1 CR 1 (8%), PR 1 (8%) SD 7 (54%)(8%) SD 7 (54%)

Median PFS Median PFS (m)(m)

77 4.14.1

BevacizumabBevacizumabBevacizumabBevacizumab

ICONICON--7 Design7 DesignICONICON 7 Design7 DesignStratification factors: stage, residual disease status, country

observationCarboplatin/paclitaxel1520

stage IIB-IV patients

p p

pCarboplatin/paclitaxel +

bevacizumabbevacizumab

6 cycles(4.5 months)

12 cycles(7.5 months)Treatment:

Carboplatin AUC = 6Paclitaxel 175 mg/m2Paclitaxel 175 mg/mBevacizumab 7.5 mg/kg(All treatments q 3 weeks)

Current TrialsCurrent TrialsCurrent TrialsCurrent TrialsFirst LineFirst Line

ICON 7: TC +/ICON 7: TC +/ Bevacizumab 7 5mg/kgBevacizumab 7 5mg/kgICON 7: TC +/ICON 7: TC +/-- Bevacizumab 7.5mg/kgBevacizumab 7.5mg/kgConcurrent and maintenance Concurrent and maintenance –– 12 cycles12 cyclesMax:12 monthsMax:12 months

GOG 218: TC +/GOG 218: TC +/ B 15mg/kgB 15mg/kgGOG 218: TC +/GOG 218: TC +/-- B 15mg/kgB 15mg/kgConcurrentConcurrentMaintenanceMaintenanceMax: 15monthsMax: 15monthsMax: 15monthsMax: 15months

Second LineSecond LineTC +/TC +/-- AZD 2171AZD 2171

C tC tConcurrent Concurrent MaintenanceMaintenance

MaintenanceMaintenancesorafenibsorafenib

AntiAnti--angiogenics in OVCAangiogenics in OVCAAntiAnti angiogenics in OVCAangiogenics in OVCAAnti VEGFAnti VEGF

MoAB: BevacizumabMoAB: BevacizumabAMG 386 + paclitaxelAMG 386 + paclitaxelVEGF Trap VEGF Trap –– Sanofi Sanofi -- AventisAventisOral TKIs Oral TKIs ––

Sorafenib (Bay 43Sorafenib (Bay 43--9006)9006)Sorafenib (Bay 43Sorafenib (Bay 43 9006)9006)In combinationIn combinationMaintenance post chemotherapyMaintenance post chemotherapy

SunitinibSunitinibAZD 2171AZD 2171

Single agent Single agent ICON 6 in platinum sensitive ovarian cancer recurrenceICON 6 in platinum sensitive ovarian cancer recurrence

PI3 Kinase-AKT-mTOR

The PI3The PI3--kinase (PI3K) and mTOR pathways kinase (PI3K) and mTOR pathways

key growth factorkey growth factor--mediated signal transduction pathways mediated signal transduction pathways that regulate cell growththat regulate cell growth

R l t ll th d lif ti i tR l t ll th d lif ti i tRegulates cell growth and proliferation in response to Regulates cell growth and proliferation in response to metabolic signals and cellular stressmetabolic signals and cellular stress

PI3K and mTOR cooperate to activate downstream PI3K and mTOR cooperate to activate downstream 3 a d O coope a e o ac a e do s ea3 a d O coope a e o ac a e do s eatargets that regulate the translation of cell cycle targets that regulate the translation of cell cycle regulatory proteins regulatory proteins

mTOR Inhibitors inhibits translation of proteins regulating G1 phase

Metabolic programming of cells

PI3K/AKTCell proliferation

Nutrients

GlycolysisLipid biosynthesisSignal transduction

G iEnergyBiosynthetic activity

Gene expression

mTORDNA VirusesViral replication

pS6 kinase 4EBP1HIF 1AVEGF

TRANSLATI TRANSLATION

CYCLIN ACDK ½

CDK INHIBRb protein

eIF4G

ONTRANSLATIONRb protein

Faivre et al. Nature Reviews Drug Discovery 5, 671–688 (August 2006) | doi:10.1038/nrd2062

PTEN and mTOR in endometrial PTEN and mTOR in endometrial cancercancer

PTENPTENPTENPTENTumour suppressor geneTumour suppressor geneEncodes PI3Encodes PI3--phosphatase which antagonizes phosphatase which antagonizes PI3 kinase signalingPI3 kinase signalingNegative regulator of PkB/Akt signalingNegative regulator of PkB/Akt signaling

PTEN mutations common in endometrialPTEN mutations common in endometrialPTEN mutations common in endometrial PTEN mutations common in endometrial cancercancer

enhanced PkB/Akt phosphorylation and enhanced PkB/Akt phosphorylation and presumably activationpresumably activation

cycle turnover (angiogenesis and protein synthesis)cycle turnover (angiogenesis and protein synthesis)

RTK RTKIntegrin G-protein receptor NutrientsPTEN

PI3K

PTEN

PI4,5P2 PI4,5P3

Ras

PTEN

Akt PPTEN mutationsCommon in endometrial ca

mTORRapamycin

TemsirolimusE li

P70s6k 4E-BP1

EverolimusDeforolimus

S6 ElF-4E

Ribosome Synthesis

Translation InitiationG1 Arrest

Increased protein synthesis, G1 progression and cell growth

Waterfall plots of response Waterfall plots of response ––h ï d h dh ï d h dchemo naïve and chemo treated. chemo naïve and chemo treated.

IND.160a(n = 28 evaluable patients)

elin

e

30

40

50

IND.160b(n = 24 evaluable patients)

elin

e

8090

100110

hrin

kage

from

Bas

e

20

-10

0

10

20

hrin

kage

from

Bas

e

010203040506070

Best

% T

umou

r Sh

-60

-50

-40

-30

-20

Best

% T

umou

r Sh

-70-60-50-40-30-20-10

0

B

-70

B

-80

Temsirolimus in Endometrial Temsirolimus in Endometrial CCCancerCancer

Chemo Naïve Population(N 28 l bl )

Chemo treated patients(N 24 l bl )(N=28 evaluable) (N=24 evaluable)

No. Pts Med Dur Months

Med Dur MonthsMonths Months

CR 0 0

PR 7 (25%) 5.6 (2.8-20.2)

2 (8%) 4.3 (3.6-4.9)

SD 16 (57%) 9.5(3.1-13.4)

12 (50%) 3.5 (2.4-7.2)

PD 5 (18%) 10 (42%)PD 5 (18%) 10 (42%)

Correlative Studies in Archival Correlative Studies in Archival Ti R SDTi R SDTissue: Response or SDTissue: Response or SD

No correlationNo correlation HistologyHistologyPTEN loss of expression PTEN loss of expression (61%)(61%)PTEN mutations (55%)PTEN mutations (55%)

gygyGrade 1 =5/5 and 2/2Grade 1 =5/5 and 2/2Grade 2 = 7/12 and 0/3Grade 2 = 7/12 and 0/3Grade 3 = 10/13 and 8/17Grade 3 = 10/13 and 8/17PTEN mutations (55%)PTEN mutations (55%)

Cytoplasmic AKTCytoplasmic AKTNuclear AKTNuclear AKT

TORTOR

Grade 3 = 10/13 and 8/17Grade 3 = 10/13 and 8/17Serous = 5/6 and 5/8Serous = 5/6 and 5/8

pmTORpmTORpS6 expression pS6 expression

BUT: archival tissueBUT: archival tissueBUT: archival tissueBUT: archival tissueExpression at time of Expression at time of metastatic disease?metastatic disease?

Single agent relevanceSingle agent relevanceSingle agent relevanceSingle agent relevance

Single agent activity seen.Single agent activity seen.Single agent activity seen.Single agent activity seen.Chemo naïve patientsChemo naïve patientsChemo treated patientsChemo treated patientsChemo treated patientsChemo treated patientsHigh grade and serous histologiesHigh grade and serous histologiesNot isolated to patients with PTEN mutations Not isolated to patients with PTEN mutations ppor PTEN lossor PTEN loss

Level of activity encouraging. Level of activity encouraging. TemsirolimusTemsirolimusDeforolimusDeforolimus

Deforolimus Deforolimus NCIC CTG

Single agent Phase IIChemo-naïve patients

Ariad/Merck Randomized Phase II

Chemo-treatedpN=30 Deforolimus vs Hormones

N=150Microsoft

owerPoint PresentatioMicrosoft

owerPoint Presentatio

Randomized Phase III clinical trialRandomized Phase III clinical trialDeforolimus vs Hormones

?Chemo-naïve or chemo-treatedN=380

Combination StudiesCombination StudiesCombination StudiesCombination Studies

ChemotherapyChemotherapyChemotherapyChemotherapyNCIC CTG NCIC CTG –– with carboplatin and paclitaxelwith carboplatin and paclitaxelPhase I with TopotecanPhase I with Topotecanpp

TemsirolimusTemsirolimusEverolimusEverolimus

H l ThH l ThHormonal TherapyHormonal TherapyGOG: Temsirolimus +/GOG: Temsirolimus +/-- Hormones Hormones

Randomized Phase IIRandomized Phase IIRandomized Phase IIRandomized Phase II

Targeted AgentsTargeted AgentsGOG: Temsirolimus + bevacizumabGOG: Temsirolimus + bevacizumabGOG: Temsirolimus bevacizumabGOG: Temsirolimus bevacizumab

Future StrategiesFuture StrategiesFuture StrategiesFuture Strategies

Phase II/IIIPhase II/IIIPhase II/IIIPhase II/IIICarbo/paclitaxel+mTOR inhibitorCarbo/paclitaxel+mTOR inhibitorMaintenance therapy following chemotherapyMaintenance therapy following chemotherapyMaintenance therapy following chemotherapyMaintenance therapy following chemotherapy

Advanced stage diseaseAdvanced stage disease

Synergy with other targeted agentsSynergy with other targeted agentsy gy g gy gy g gVEGFVEGFEGFREGFRHDAC inhibitorsHDAC inhibitors

Synergy with radiationSynergy with radiationy gyy gy

Novel AgentsNovel AgentsNovel AgentsNovel Agents

AntiangiogenicsAntiangiogenics mTOR inhibitionmTOR inhibitionAntiangiogenicsAntiangiogenicsActive in Ovarian CaActive in Ovarian CaPhase III underwayPhase III underway

mTOR inhibitionmTOR inhibitionActive in Endo CaActive in Endo CaRandom Phase IIRandom Phase II –– IIIIIIPhase III underwayPhase III underway

Agent/scheduleAgent/scheduleindicationindication

Random Phase II Random Phase II IIIIIIAgent/scheduleAgent/scheduleindicationindicationindicationindication indicationindication

Combinations with other targeted agents

Radiation?Radiation?

Indications?

GOG 218 Proposal (US)GOG 218 Proposal (US)GOG 218 Proposal (US)GOG 218 Proposal (US)Carboplatin AUC6 Primary endpoint: OS

Secondary endpoint: PFSArm A

Paclitaxel 175 mg/m2

Placebo

Carboplatin AUC6

Paclitaxel 175 mg/m2

Sub-optimally debulked

Stage III/ IV OC

N=2000

Arm B

PlaceboAvastin (15 mg/kg)

Carboplatin AUC6

N=2000 Placebo

Arm C

Avastin (15 mg/kg)

Paclitaxel 175 mg/m21:1:1 Randomization

Cycles (q3wk)*15 months*

* Taxane consolidation therapy prohibited

Stratification variables: PS (0-1 vs 2), stage (III vs IV)

New Drugs in Ovarian CancerNew Drugs in Ovarian CancerNew Drugs in Ovarian CancerNew Drugs in Ovarian Cancer

Anti VEGFAnti VEGFAnti VEGFAnti VEGFVEGF Trap VEGF Trap –– Sanofi Sanofi -- AventisAventisOral TKIsOral TKIsOral TKIs Oral TKIs ––

Sorafenib (Bay 43Sorafenib (Bay 43--9006)9006)SunitinibSunitinibSunitinibSunitinibAZD 2171 AZD 2171 –– ICON 6 in platinum sensitive ovarian ICON 6 in platinum sensitive ovarian cancer recurrencecancer recurrence

ICON 6 Design schemaICON 6 Design schemaICON 6 Design schemaICON 6 Design schema2:3:3 RANDOMISATION

Arm AReference arm

6 cycles of chemotherapy

Arm BChemotherapy

PlusAZD2171

Arm CChemotherapy

plusAZD2171

plusPlacebo

during Chemotherapy

during Chemotherapy

No Progressive disease

Maintenance21 1 f

No Progressive diseasePlacebo

No Progressive diseasePlacebo

AZD2171 after chemotherapy

Maximum 18 months from randomisation

Maximum 18 months from randomisation

Maximum 18 monthsfrom randomisation