Targeted agents in Targeted agents in Gynecologic Cancer - - PowerPoint PPT Presentation

Targeted agents in Targeted agents in Gynecologic Cancer Gynecologic Cancer

Amit M Oza Amit M Oza Amit M. Oza Amit M. Oza Professor of Medicine, Professor of Medicine, Princess Margaret Hospital, Princess Margaret Hospital, University of Toronto University of Toronto y Co Co-

• Chair Gynecology, NCIC CTG

Chair Gynecology, NCIC CTG

Targeted Therapies Targeted Therapies Targeted Therapies Targeted Therapies

Incorporation of novel targeted therapies Incorporation of novel targeted therapies Incorporation of novel targeted therapies Incorporation of novel targeted therapies

Biologic rationale

Biologic rationale

Prevalence of target

Prevalence of target Prevalence of target Prevalence of target

Characteristics of the target

Characteristics of the target

Amenable to modulation Amenable to modulation

Availability of inhibitor

Availability of inhibitor

Effect of target inhibition in patients

Effect of target inhibition in patients – – activity activity f i hibit f i hibit

• f inhibitors
• f inhibitors

Therapies for intracellular targets Therapies for intracellular targets Therapies for intracellular targets Therapies 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 pathways

Complexity of signal transduction pathways

value of single target

value of single target

value of single target

value of single target

Combined approaches due to synergy Combined approaches due to synergy

Eg target EGFR + Chemo

Eg target EGFR + Chemo

Eg target EGFR + Chemo

Eg target EGFR + Chemo

Sequential or concurrent therapy

Sequential or concurrent therapy

Combinations of targeted agents

Combinations of targeted agents g g g g

Aberrations in multiple inter Aberrations in multiple inter-

• related pathways

related pathways

Develop clinical and translational studies

Develop clinical and translational studies

Molecular Pathways of Interest Molecular Pathways of Interest Molecular Pathways of Interest Molecular Pathways of Interest

Angiogenesis Angiogenesis – g g g g

• Ovarian, Endometrial, Cervical

Ovarian, Endometrial, Cervical

PI3 Kinase PI3 Kinase – – AKT AKT – – mTOR mTOR -

• Endometrial Ovarian

Endometrial Ovarian

• Endometrial, Ovarian

Endometrial, Ovarian

Epigenetic mechanisms Epigenetic mechanisms – –

• Ovarian, Endometrial

Ovarian, Endometrial

EGFR targeting EGFR targeting

• Ovarian, Cervical, endometrial

Ovarian, Cervical, endometrial

Poly (ADP Poly (ADP ribose) polymerase inhibition (parp ribose) polymerase inhibition (parp Poly (ADP Poly (ADP-ribose) polymerase inhibition (parp ribose) polymerase inhibition (parp inhibition) inhibition) – –

• Ovarian

Ovarian

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

Rationale Rationale for

for Anti

Anti-

• angiogenic

angiogenic therapy therapy

As tumours increase in size, become dependent , p

• n vasculature

Exploitable differences between normal and l tumour vasculature Affecting one blood vessel effects large numbers

• f tumour cells
• f tumour cells

Endothelial cells are less likely to develop drug resistance due to slower rates of division es sta ce due to s o e ates o d s o May actually be synergistic with cytotoxic May actually be synergistic with cytotoxic chemotherapy and radiotherapy chemotherapy and radiotherapy

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

Somatic mutation Small avascular 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 tumour Angiogenesis is involved throughout tumour Angiogenesis is involved throughout tumour Angiogenesis is involved throughout tumour formation, growth and metastasis formation, growth and metastasis

Premalignant stage Malignant tumour Tumour growth Vascular invasion Dormant micrometastasis Overt metastasis (Avascular (Angiogenic (Vascularised (Tumour cell (Seeding in (Secondary tumour) switch) tumour) intravasation) distant organs) (S

• da y

angiogenesis)

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 vessels Normal blood vessels Tumour blood vessels Tumour blood vessels from normal vasculature from normal vasculature Normal blood vessels Normal blood vessels Tumour blood vessels Tumour blood vessels

Maturation factors N th f t Growth factors (VEGF) No growth factors Tight Leaky Integrins Fewer supporting cells Support cells Jain R. Nat Med 2003;9:685–93 Carmeliet P . Nat Med 2003;9:653–60

VEGF VEGF

Key mediator of Key mediator of angiogenesis angiogenesis angiogenesis angiogenesis Controls tumour growth by Controls tumour growth by

Stimulating tumour Stimulating tumour angiogenesis angiogenesis Maintaining tumour vasculature Maintaining tumour vasculature Increasing Increasing vascular

vascular permeability

permeability Affecting the normal immune Affecting the normal immune response response p Possible direct effect on tumour Possible direct effect on tumour cells cells

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

Latter related to stage/mitotic activity

Latter related to stage/mitotic activity -

• prognosis

prognosis

VEGF angiogenic and permeability factor: ascites

VEGF angiogenic and permeability factor: ascites

VEGF VEGF VEGF VEGF

Key mediator of Key mediator of angiogenesis angiogenesis

Normal

Stimulating tumour

angiogenesis

• Proliferation and migration of

endothelial cells endothelial cells

Maintaining tumour vasculature

• Survival of endothelial cells

Increasing vascular permeability

• Increases interstitial fluid

pressure Impairs delivery of O2,,

Cancer

2,

nutrients and drugs Hypoxic 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 the Agents Targeting the VEGF VEGF Agents Targeting the Agents Targeting the VEGF VEGF Pathway Pathway

↑ 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 – P P– P– – P – P P– P– – P – P P– P–

Ribozymes (Angiozyme) Migration, permeability, DNA synthesis, survival

L h i i A i i Lymphangiogenesis Angiogenesis

Single Agent Bevacizumab Single Agent Bevacizumab in Ovarian Cancer in 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 3/52 Bevacizumab 15mg/kg q 3/52 N=64 N=64 N=44 N=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 resistant courses, 55% platinum resistant 100% platinum resistant 100% 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 4.7months Median PFS 4.7months Median PFS 4.3months Median PFS 4.3months Median OS 17months Median OS 17months Median OS not reached Median OS not reached SE: Emesis, constipation, TE SE: Emesis, constipation, TE SE: Arterial TE, GI perforation, HT SE: Arterial TE, GI perforation, HT

Combination Bevacizumab Combination Bevacizumab R i i O i C R i i O i C Regimens in Ovarian Cancer Regimens in Ovarian Cancer

Carboplatin Paclitaxel Carboplatin Paclitaxel Cyclophosphamide Cyclophosphamide Erlotinib Erlotinib (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 2006 2006 Bevacizumab Bevacizumab 15 mg/kg q3w (+maintenance) 15 mg/kg q3w (+maintenance) 10 mg/kg q2w 10 mg/kg q2w 15 mg/kg q3w 15 mg/kg q3w Other drugs Other drugs Carboplatin AUC5 Carboplatin AUC5 Paclitaxel 175 mg/m Paclitaxel 175 mg/m2 q3/52 q3/52 Cyclophosphamide Cyclophosphamide 50 mg/d 50 mg/d Erlotinib 150 mg/d Erlotinib 150 mg/d

• Prev. regimens
• Prev. regimens

≤3 ≤3 ≤3 ≤3 g Pt sensitivity Pt sensitivity Pt Refractory Pt Refractory 4 refractory, 2 4 refractory, 2 resistant, 7 sensitive resistant, 7 sensitive Toxicity Toxicity 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↓, pain Na↓, pain perforation (2/13), HT perforation (2/13), HT

Response Response CT: CR 56%, PR 22% CT: CR 56%, PR 22% Ca Ca-

• 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) 7 4.1 4.1

Bevacizumab Bevacizumab Bevacizumab Bevacizumab

ICON ICON-7 Design 7 Design ICON ICON 7 Design 7 Design

Stratification factors: stage, residual disease status, country

• bservation

Carboplatin/paclitaxel 1520 stage IIB-IV patients p p p Carboplatin/paclitaxel + bevacizumab bevacizumab 6 cycles (4.5 months) 12 cycles (7.5 months) Treatment: Carboplatin AUC = 6 Paclitaxel 175 mg/m2 Paclitaxel 175 mg/m Bevacizumab 7.5 mg/kg (All treatments q 3 weeks)

Current Trials Current Trials Current Trials Current Trials

First Line First Line

• ICON 7: TC +/

ICON 7: TC +/ Bevacizumab 7 5mg/kg Bevacizumab 7 5mg/kg

• ICON 7: TC +/

ICON 7: TC +/- Bevacizumab 7.5mg/kg Bevacizumab 7.5mg/kg

Concurrent and maintenance Concurrent and maintenance – – 12 cycles 12 cycles Max:12 months Max:12 months

• GOG 218: TC +/

GOG 218: TC +/ B 15mg/kg B 15mg/kg

• GOG 218: TC +/

GOG 218: TC +/- B 15mg/kg B 15mg/kg

Concurrent Concurrent Maintenance Maintenance Max: 15months Max: 15months Max: 15months Max: 15months

Second Line Second Line

• TC +/

TC +/-

• AZD 2171

AZD 2171

C t C t Concurrent Concurrent Maintenance Maintenance

Maintenance Maintenance

• sorafenib

sorafenib

Anti Anti-angiogenics in OVCA angiogenics in OVCA Anti Anti angiogenics in OVCA angiogenics in OVCA

Anti VEGF Anti VEGF

• MoAB: Bevacizumab

MoAB: Bevacizumab

• AMG 386 + paclitaxel

AMG 386 + paclitaxel

• VEGF Trap

VEGF Trap – Sanofi Sanofi -

• Aventis

Aventis

• Oral TKIs

Oral TKIs – –

Sorafenib (Bay 43 Sorafenib (Bay 43-9006) 9006) Sorafenib (Bay 43 Sorafenib (Bay 43 9006) 9006)

In combination

In combination

Maintenance post chemotherapy

Maintenance post chemotherapy

Sunitinib Sunitinib AZD 2171 AZD 2171

Single agent

Single agent

ICON 6 in platinum sensitive ovarian cancer recurrence

ICON 6 in platinum sensitive ovarian cancer recurrence

PI3 Kinase-AKT-mTOR

The PI3 The PI3-

• kinase (PI3K) and mTOR pathways

kinase (PI3K) and mTOR pathways

key growth factor

key growth factor-

• mediated signal transduction pathways

mediated signal transduction pathways that regulate cell growth that regulate cell growth R l t ll th d lif ti i t R l t ll th d lif ti i t

Regulates cell growth and proliferation in response to

Regulates cell growth and proliferation in response to metabolic signals and cellular stress metabolic 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 ea 3 a d O coope a e o ac a e do s ea targets 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/AKT Cell proliferation Nutrients Glycolysis Lipid biosynthesis Signal transduction G i Energy Biosynthetic activity Gene expression mTOR DNA Viruses Viral replication pS6 kinase 4EBP1 HIF 1A VEGF TRANSLATI TRANSLATION CYCLIN A CDK ½ CDK INHIB Rb protein eIF4G ON TRANSLATION Rb 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 cancer cancer

PTEN PTEN PTEN PTEN

Tumour suppressor gene

Tumour suppressor gene

Encodes PI3

Encodes PI3-

• phosphatase which antagonizes

phosphatase which antagonizes PI3 kinase signaling PI3 kinase signaling

Negative regulator of PkB/Akt signaling

Negative regulator of PkB/Akt signaling

PTEN mutations common in endometrial PTEN mutations common in endometrial PTEN mutations common in endometrial PTEN mutations common in endometrial cancer cancer

enhanced PkB/Akt phosphorylation and

enhanced PkB/Akt phosphorylation and presumably activation presumably activation

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

RTK RTK Integrin G-protein receptor Nutrients

PTEN

PI3K PTEN PI4,5P2 PI4,5P3 Ras PTEN Akt P

PTEN mutations Common in endometrial ca

mTOR Rapamycin

Temsirolimus E li

P70s6k 4E-BP1

Everolimus Deforolimus

S6 ElF-4E

Ribosome Synthesis Translation Initiation

G1 Arrest

Increased protein synthesis, G1 progression and cell growth

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

IND.160a

(n = 28 evaluable patients)

eline

30 40 50

IND.160b

(n = 24 evaluable patients)

eline

80 90 100 110

hrinkage from Base

20

• 10

10 20

hrinkage from Base

10 20 30 40 50 60 70

Best % Tumour Sh

• 60
• 50
• 40
• 30
• 20

Best % Tumour Sh

• 70
• 60
• 50
• 40
• 30
• 20
• 10

B

• 70

B

• 80

Temsirolimus in Endometrial Temsirolimus in Endometrial Cancer Cancer

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 Months Months Months CR 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 SD Ti R SD Tissue: Response or SD Tissue: Response or SD

No correlation No correlation Histology Histology

PTEN loss of expression

PTEN loss of expression (61%) (61%)

PTEN mutations (55%)

PTEN mutations (55%)

gy gy

Grade 1 =5/5 and 2/2

Grade 1 =5/5 and 2/2

Grade 2 = 7/12 and 0/3

Grade 2 = 7/12 and 0/3 Grade 3 = 10/13 and 8/17 Grade 3 = 10/13 and 8/17

PTEN mutations (55%)

PTEN mutations (55%)

Cytoplasmic AKT

Cytoplasmic AKT

Nuclear AKT

Nuclear AKT TOR TOR

Grade 3 = 10/13 and 8/17

Grade 3 = 10/13 and 8/17

Serous = 5/6 and 5/8

Serous = 5/6 and 5/8

pmTOR

pmTOR

pS6 expression

pS6 expression

BUT: archival tissue BUT: archival tissue BUT: archival tissue BUT: archival tissue

• Expression at time of

Expression at time of metastatic disease? metastatic disease?

Single agent relevance Single agent relevance Single agent relevance Single agent relevance

Single agent activity seen. Single agent activity seen. Single agent activity seen. Single agent activity seen.

Chemo naïve patients

Chemo naïve patients

Chemo treated patients

Chemo treated patients Chemo treated patients Chemo treated patients

High grade and serous histologies

High grade and serous histologies

Not isolated to patients with PTEN mutations

Not isolated to patients with PTEN mutations p

• r PTEN loss
• r PTEN loss

Level of activity encouraging. Level of activity encouraging.

Temsirolimus

Temsirolimus

Deforolimus

Deforolimus

Deforolimus Deforolimus

NCIC CTG Single agent Phase II Chemo-naïve patients Ariad/Merck Randomized Phase II Chemo-treated p N=30

Deforolimus vs Hormones N=150

Microsoft

• werPoint Presentatio

Microsoft

• werPoint Presentatio

Randomized Phase III clinical trial Randomized Phase III clinical trial Deforolimus vs Hormones ?Chemo-naïve or chemo-treated N=380

Combination Studies Combination Studies Combination Studies Combination Studies

Chemotherapy Chemotherapy Chemotherapy Chemotherapy

• NCIC CTG

NCIC CTG – – with carboplatin and paclitaxel with carboplatin and paclitaxel

• Phase I with Topotecan

Phase I with Topotecan p

Temsirolimus Temsirolimus Everolimus Everolimus

H l Th H l Th Hormonal Therapy Hormonal Therapy

• GOG: Temsirolimus +/

GOG: Temsirolimus +/-

• Hormones

Hormones

Randomized Phase II Randomized Phase II Randomized Phase II Randomized Phase II

Targeted Agents Targeted Agents

• GOG: Temsirolimus + bevacizumab

GOG: Temsirolimus + bevacizumab GOG: Temsirolimus bevacizumab GOG: Temsirolimus bevacizumab

Future Strategies Future Strategies Future Strategies Future Strategies

Phase II/III Phase II/III Phase II/III Phase II/III

Carbo/paclitaxel+mTOR inhibitor

Carbo/paclitaxel+mTOR inhibitor

Maintenance therapy following chemotherapy

Maintenance therapy following chemotherapy Maintenance therapy following chemotherapy Maintenance therapy following chemotherapy

Advanced stage disease Advanced stage disease

Synergy with other targeted agents Synergy with other targeted agents y gy g g y gy g g

VEGF

VEGF

EGFR

EGFR

HDAC inhibitors

HDAC inhibitors

Synergy with radiation Synergy with radiation y gy y gy

Novel Agents Novel Agents Novel Agents Novel Agents

Antiangiogenics Antiangiogenics mTOR inhibition mTOR inhibition Antiangiogenics Antiangiogenics Active in Ovarian Ca Active in Ovarian Ca Phase III underway Phase III underway mTOR inhibition mTOR inhibition Active in Endo Ca Active in Endo Ca Random Phase II Random Phase II – III III Phase III underway Phase III underway Agent/schedule Agent/schedule indication indication Random Phase II Random Phase II III III Agent/schedule Agent/schedule indication indication indication indication indication indication 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: PFS Arm A Paclitaxel 175 mg/m2 Placebo Carboplatin AUC6 Paclitaxel 175 mg/m2 Sub-optimally debulked Stage III/ IV OC N=2000 Arm B Placebo

Avastin (15 mg/kg)

Carboplatin AUC6 N=2000 Placebo Arm C Avastin (15 mg/kg) Paclitaxel 175 mg/m2 1:1:1 Randomization Cycles (q3wk)* 15 months* * Taxane consolidation therapy prohibited Stratification variables: PS (0-1 vs 2), stage (III vs IV)

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

Anti VEGF Anti VEGF Anti VEGF Anti VEGF

VEGF Trap

VEGF Trap – – Sanofi Sanofi -

• Aventis

Aventis Oral TKIs Oral TKIs

Oral TKIs

Oral TKIs –

Sorafenib (Bay 43 Sorafenib (Bay 43-

• 9006)

9006) Sunitinib Sunitinib Sunitinib Sunitinib AZD 2171 AZD 2171 – – ICON 6 in platinum sensitive ovarian ICON 6 in platinum sensitive ovarian cancer recurrence cancer recurrence

ICON 6 Design schema ICON 6 Design schema ICON 6 Design schema ICON 6 Design schema

2:3:3 RANDOMISATION Arm A Reference arm 6 cycles of chemotherapy Arm B Chemotherapy Plus AZD2171 Arm C Chemotherapy plus AZD2171 plus Placebo during Chemotherapy during Chemotherapy No Progressive disease Maintenance 21 1 f No Progressive disease Placebo No Progressive disease Placebo AZD2171 after chemotherapy Maximum 18 months from randomisation Maximum 18 months from randomisation Maximum 18 months from randomisation