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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