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Ovarian Cancer: Standards of Care and New Opportunities - PPT Presentation

Robert L Coleman MD Professor amp Vice Chair Clinical Research Department of Gynecologic Oncology MD Anderson Cancer Center Ovarian Cancer Liner Notes Globally 7 th most incident and lethal cancer ID: 816464

platinum paclitaxel cancer pld paclitaxel platinum pld cancer ovarian iii mos bevacizumab chemotherapy pfs gog carboplatin resistant phase brca

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Slide1

Ovarian Cancer: Standards of Care and New Opportunities

Robert L. Coleman, M.D.

Professor &

Vice Chair,

Clinical Research

Department of Gynecologic Oncology

M.D. Anderson Cancer Center

Slide2

Ovarian Cancer: Liner NotesGlobally 7

th most incident and lethal cancerNew cases: 225,000 annuallyDeaths: 140,000 annuallyBurden of disease is greater in developed countries

The

incidence increases with

age Almost 75% of cases present with advanced stage III / IV diseaseRisk of relapse of advanced stage disease is as high as 70%

CA Cancer, 2013

Slide3

Ovarian Cancer: Natural History

Symptoms

Diagnosis

Chemotherapy #1

Staging

Evaluation

? SLL

Progression

Chemo #2

Chemo #3+

Supportive

Care

Death

Secondary

Surgery

Maintenance

Duration

Progression-Free Survival

(12-28 mos)

Post Progression Survival

(12-38 mos)

Slide4

Slide5

Surgical Management of Primary Ovarian Cancer

Theoretical: Reduced the volume of hypoxic, poorly perfused cellsHost immunocompetence is improved with lower tumor burdenRecruitment of residual cells into G1 potentiating the effects of cytotoxic therapyRemoval of chemoresistant clonesPractical:

Biology

vs Brawn”

Slide6

% Progression-

free

Survival

0 mm

1-10 mm

> 10 mm

HR (95%CI)

1-10 mm vs. 0 mm: 2.52 (2.26;2.81)

>10 mm vs. 1-10 mm:

1.36 (1.24;1.50)

log-rank: p < 0.0001

% Overall Survival

0 mm

1-10 mm

> 10 mm

HR (95%CI)

1-10 mm vs. 0 mm: 2.70 (2.37; 3.07)

>10 mm vs. 1-10 mm:

1.34 (1.21; 1.49)

log-rank: p < 0.0001

The Impact

of

Residual Tumor: What Is Optimal Debulking?

Generated from 3 prospective Phase III trials (OVAR 3,5, & 7)

N = 3126 pts

DuBois

, Cancer (2009)115:1234

Slide7

Primary Approach: What’s Best?

N Engl J Med (2010) 363:943

PDS:

12

mos

NACT:

12

mos

HR

: 0.99

(0.87-1.13)

PDS: 29 months

IDS: 30 months

HR: 0.98 (0.85, 1.14)

PFS

OS

Slide8

Neoadjuvant Chemotherapy in Ovarian Cancer

9/21

/10

1/20

/11

Slide9

Primary Approach: What’s Best?

N Engl J Med (2010) 363:943

PDS:

12

mos

NACT:

12

mos

HR

: 0.99

(0.87-1.13)

PDS: 29 months

IDS: 30 months

HR: 0.98 (0.85, 1.14)

PFS

OS

Slide10

CHORUS

Chemotherapy Or Upfront Surgery

RCOG

ICON-8

OV.21

Neoadjuvant

Chemotherapy

X 3-4 courses

Randomized

IV-Arm IP-Arm

Pac/

Carbo

+ Pac/

Carbo

(IP) +

Pac (d8) Pac (IP, d8)

Pre-randomization

Strata for

NACT

or PDS

Randomized

Standard

Pac/

Carbo

Exp A

DD-Pac/

Carbo

Exp B

DD - Pac/DD-

Carbo

Slide11

Principle Approach: Iº Therapy

Chemotherapy

McGuire New

Engl

J Med (1996) 334:1

Ozols

, J

Clin

Oncol

(2003) 21:3194

Armstrong New

Engl

J Med (2006) 354:34

OS

Cytoxan

/Cisplatin

- - - Paclitaxel/Cisplatin

PFS

Slide12

International Phase III Experience

CP

CPG

CP

PLD

CT

C

P

CG

C

P

PLD-C

CE

Total

GOG0182-ICON5

864

864

862

861

861

4312

SCOTROC

538

539

1077

AGO-GINECO

635

647

1282

NSGO-EORTC-NCIC-GEICO

444

443

887

MITO

170

156

326

AGO-GINECO-GERCOR-NSGO

882

860

1742

NCIC-EORTC-GEICO OV16

410

409

819

MITO-2

410

410

820

Regimen Total:

4353

1724

1272

1426

861

539

1090

11265

No Significant

Effect

More

≠ Better

Different ≠ Better

Slide13

Moving The Bar: Primary TherapyDose-dense therapy

IP ChemotherapyBiologics: Anti-angiogenesis, PARPi, angiopoeitin inhibitors

Establishing a Front-Line Adjuvant Standard

Slide14

Dose Dense: Weekly Therapy

Ovarian Epithelial, PP, FTFIGO Stage II-IV

 

Paclitaxel 180mg/m

2

 

Carboplatin AUC 6.0

 

q

21 days (6-9 cycles

)

Dose density: 60 mg/m

2

/wk

 

Paclitaxel 80mg/m

2

, days 1, 8, 15 

Carboplatin AUC 6.0, day 1 

q 21 days (6-9

cycles)Dose density: 80 mg/m2

/wk (+33%)

Stratification;

Residual disease: <1cm, > 1cm

FIGO Stage: II vs. III vs. IV

Histology: clear cell/mucinous vs serous/others

R

Katsumata, Lancet 2009

Slide15

JGOG 3016: Long-Term Follow-Up

Katsumata N, ASCO Abstract 5003, 2012

Slide16

iPocc JGOG Trial: Schema

Epithelial Ovarian CancerStages II-IV

Including Bulky Tumor

Paclitaxel 80 mg/m

2

IV

Day 1,8,15

Carboplatin AUC 6 IV

Q21, 6-8 Cycles

Paclitaxel 80 mg/m

2

IV

Day 1,8,15

Carboplatin AUC 6 IP

Q21, 6-8 Cycles

Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, QOL

Accrual Goal: 746 pts / 511 events

Dose dense

−TCip

Dose dense

−TCivRANDOMIZATION

Slide17

GOG-0218 study schema

Previously untreated epithelial ovarian, primary peritoneal, or fallopian tube cancer

Stage III optimal (macroscopic)

Stage III

suboptimal

Stage IV

n

=1873

Stratification variables:

GOG performance status

Stage/debulking status

RANDOM

I

Z E

1:1:1

15 months

Paclitaxel 175 mg/m

2

Carboplatin AUC 6

Placebo

I

Arm

Cytotoxic (6 cycles)

Maintenance

(16 cycles)

(CP + PLA → PLA)

Carboplatin AUC 6

Paclitaxel 175 mg/m

2

Placebo

Bevacizumab

15 mg/kg

II

(CP + BEV

→ PLA)

Bevacizumab 15 mg/kg

Carboplatin AUC 6

Paclitaxel 175 mg/m

2

III

(CP + BEV

 BEV

)

Burger et al. N

Engl

J Med 2011;365:2473-83

Establishing a Front-Line Adjuvant Standard

Slide18

Stratification variables:

Stage & extent of debulking: I–III debulked ≤1cm

vs

stage

I–III debulked >1 cm

vs

stage IV and inoperable stage III

Timing of intended treatment start

≤4

vs

>4 weeks after surgery

GCIG group

Schema

Academic-led, industry-supported trial to investigate use of bevacizumab and to support licensing

Paclitaxel 175 mg/m

2

Carboplatin AUC 5/6

Carboplatin AUC 5/6

Paclitaxel 175 mg/m

2

18 cycles

R

n=1528*

Bevacizumab 7.5 mg/kg q3w

1:1

*Dec 2006 to Feb 2009

Establishing a Front-Line Adjuvant Standard

Perrin, N

Engl

J Med 2011;365:2484-96

Slide19

Anti-VEGF Targeting: Frontline

PFS

Perren

, NEJM (2011) 365:2484

Burger, NEJM (2011) 365:2473

HR: 0.73

10.4

vs

13.9

mos

Median

D

: 3.5

mos

HR: 0.87

17.4vs 19.8

mos

Median

D

: 2.4

mos

GOG 218

ICON7

Slide20

Anti-VEGF Targeting: Frontline

Overall

Survival

Perren

, NEJM (2011) 365:2484

Burger, NEJM (2011) 365:2473

GOG 218

ICON7

Slide21

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0

6

12

18

24

30

36

0

2

4

6

8

10

12

14

16

18

20

0

6

12

18

24

30

36

-15

-10

-5

0

5

10

15

20

25

30

0

6

12

18

24

30

36

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0

6

12

18

24

30

36

14

vs

17

3 months’ difference

13.3 vs 16.5

3 months’ difference

Time (months)

Time (months)

GOG-0218

ICON7 (III suboptimal and IV subgroup)

GOG-0218 and ICON7:

Restricted Means Estimate – Benefit During Exposure Only?

Research Arm

Research Arm

Research Arm

Research Arm

Slide22

GOG Ovarian Strategy: 262

262

Suboptimal

(> 1 cm Residual)

Neoadjuvant allowed

CT Perfusion Scan

IV Paclitaxel 80 mg/m

2

weekly

IV Carboplatin AUC 6

q

3 wk

IV Bevacizumab 15 mg/kg (optional)

IV Paclitaxel 175 mg/m

2

IV Carboplatin AUC 6

IV Bevacizumab 15 mg/kg (optional)

Bevacizumab

q

3 wk

(If chosen)

Maintenance to Progression

N: 702/625 (OPEN only for ACRIN Component

Primary endpoint: PFS

Slide23

Phase III GOG 252 Schema

IV Paclitaxel 80 mg/m

2

days

1, 8,

15

IV Carboplatin AUC 6 day 1

Bevacizumab 15 mg/kg q3w

IV Paclitaxel 80 mg/m

2

days 1, 8, 15

IP Carboplatin AUC 6 day 1

Bevacizumab 15 mg/kg q3w

IV Paclitaxel 135 mg/m

2

day 1

IP Cisplatin 75 mg/m

2 day 2

IP Paclitaxel 60 mg/m2 day 8

Bevacizumab 15 mg/kg q3w

RANDOMIZATIONN = 1250

Walker JL.

Am Soc Clin Oncol Ed Book.

2009:308-312.

N: 1554 (CLOSED)

Primary

endpoint: PFS

Cycles 1-6*

Cycles 7-22*

Bevacizumab 15 mg/kg q3w

*Each

cycle is 3 weeks; †B

egin cycle 2.

Bevacizumab 15 mg/kg q3w

Bevacizumab 15 mg/kg q3w

Slide24

Other Pursuits in Front-Line TherapyVEGF TKI’sNintedanib (BIBF1120)PARPi

Veliparib (OVM1102)Angiopoeitin inhibitorsTRINOVA-3: Trebananib (AMG-386)

Slide25

Bottom Line…Determine good candidates for surgeryPotential for better selection tools, e.g. LaparoscopyOptimal radical resection

Goal: R0Adjuvant therapyIP and dose dense are my favorite optionsGood place for clinical trial

Slide26

Maintenance: The

Stakes are High!

Symptoms

Diagnosis

Chemotherapy #1

Staging

Evaluation

? SLL

Progression

Chemo #2

Chemo #3+

Supportive

Care

Death

Secondary

Surgery

Maintenance

What we know…

Rate of response is high (CR + PR) >75%

Second assessment operations find disease > 40% of CR’s

Clinical CR’s have >50% recurrence risk at 2 years

Pathological CR’s have >40% risk at 2 years

Option applies to CR’s and documented PR’s

Slide27

Maintenance Therapy Scorecard

Maintenance Beneficial?

Strategy

No

Yes

Prolonged

Initial

T

herapy

Short

Duration / Non-Cross

R

esistant

C

hemotherapy

High-Dose

C

hemotherapy

Intraperitoneal

Interferon-

Anti-CA-125 Ab

Biologic Agent (

MMPI, bevacizumab*)

✓*

Paclitaxel (6 months)

Paclitaxel (1 year)

✓#

Erlotinib

Slide28

Maintenance Trials:

Ongoing

Bevacizumab (GOG 252, 262)

Pazopanib

(OVAR-16)

Nintedanib (BIBF 1120)

Trebananib

(TRINOVA-3)

CVAC: Muc-1 Dendritic Cell vaccine

PARPi

,

pvKLH

+ OPT-821 [GOG-255] (II° maintenance)

FAKi

(GSK2256098) – GOG concept approved 8/11

EOC, PP, FT cancer

PaclitaxelX 12 mos

CTI-2103X 12 mos

No

TreatmentPaclitaxel

CarboplatinGOG-212

N = 1100 patientsSurvival primary endpointsQOL endpoints

28

Slide29

Bottom Line…Experimental but evidence of PFS impact has been demonstratedI always have the conversation (longest of any counseling session) but it is only infrequently taken by the patient

Slide30

Recurrent Therapy

: Ovarian Cancer

Symptoms

Diagnosis

Chemotherapy #1

Staging

Evaluation

? SLL

Progression

Chemo #2

Chemo #3+

Supportive

Care

Death

Maintenance

Secondary

Surgery

What we know

(Recurrence)

:

Nearly all patients will succumb to progression

Options are plentiful

Nothing a “homerun”

Slide31

Treatment Free Interval: Traditional Model

Time

from last platinum exposure (TFI)

Treatment

Completion

6

mos

Platinum Resistant/Refractory

Platinum Sensitive

Non-Platinum Treatment

Platinum Retreatment

Slide32

Treatment-Free Interval and Survival

Lauraine, Proc ASCO #829, 2002

0-3

Prog

0-3 Non PD

3-12

mos

12-18

mos

18+

mos

PFS (days)

90

176

174

275

339

OS (days)

217

375

375

657

957

Response (%)

9

24

35

52

62

Days

1000

900

800

700

600

500

400

300

200

100

Percentage

100

90

80

70

60

50

40

30

20

10

Slide33

Control

Experimental

N

TTP (wks)

P

OS (wks)

P

Comment

Paclitaxel

Topotecan

226

14

vs

23

NS

43

vs

61

NS

50% Cross-over

Paclitaxel (bolus)

Paclitaxel (weekly)

208

38 vs 26

NS

34 vs 59

NS

Less toxicity w/ weekly

Paclitaxel

Oxaliplatin

86

14

vs

12

NS

37

vs

42

NS

74% platinum resistant

Topotecan

PLD

481

17

vs

16

NS

57

vs

60

NS

54%

resistant

; OS

benefit in sensitive

Paclitaxel

PLD

214

22 vs 22

NS

5

6

vs

46

NS

All pts taxane

-naïve

Topotecan

Treosulfan

357

22

vs

12

0.001

56

vs

48

0.02

2

nd

– 3

rd

line

therapy

PLD

Gemcitabine

195

16

vs

13

NS

59

vs

55

NS

PLD

Gemcitabine

153

16 vs 20

NS

55

vs

50

NS

resistant

56% platinum resistant

PLD or

Topotecan

Canfosfamide

461

19

vs

9

<0.01

59

vs

37

(PLD:62

vs

Topo:47)

<0.0001

ASSIST-1 trial

All 3

rd

line

PLD

Patupilone

802

16

vs

16

NS

55

vs

57

NS

RR: 8%

vs

18% (

patupilone

)

Summary of Phase III Single Agent Trials:

Resistant Ovarian Cancer

Slide34

Control

Experimental

N

TTP (wks)

P

OS (wks)

P

Comment

PLD

PLD +

Trabectedin

228

16

vs

17.4

NS

N/A

N/A

RR: 16

vs

23%

Summary of Phase III Combination Trials: PR

Take home messages:

Many choices

No best cytotoxic agent

Combinations with non-targeted

cytotoxics

add morbidity only

Slide35

Control

Experimental

N

TTP (wks)

P

OS (wks)

P

Comment

PLD

PLD +

Trabectedin

228

16

vs

17.4

NS

N/A

N/A

RR: 16

vs

23%

Chemo

(Paclitaxel weekly, Gemcitabine,

Topotecan

)

Chemo +

Bevacizumab

361

14.8

vs

29.1

<0.001

N/A

N/A

RR: 12%

vs

27%

(RECIST)

Summary of Phase III Combination Trials: PR

Slide36

AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC)

Recurrent EOC

platinum resistant

≤ 2

prior therapies

no clinical or radiologic evidence of bowel involvement

Non-Platinum

C

hemotherapy

R

A

N

D

O

M

I

Z

E

Non-Platinum Chemotherapy + Bevacizumab 15

mg/kg

Chemotherapy Options

P

aclitaxel

80 mg/m

2

d 1,8,15, 22

q28

T

opotecan

4 mg/m2 d 1, 8 ,15 q28

or Topotecan

1.25 mg/m2

d 1-5 q21

PLD 40 mg/m2 d 1

q28

Stratified

chemotherapy

PFI (< 3 vs 3-6 mo)prior anti-angiogenesis

Treat to progression

Treat to

progression

N

=

361

Pujade-Lauraine

E, et al.

J

Clin

Oncol

.

2012; Suppl. Abstract LBA5002.

Slide37

AURELIA: Patient Characteristics

CharacteristicCT (n = 182) BEV + CT (n = 179)

Median

age, years

61

62

Serous/

adenocarcinoma at diagnosis

152 (84%)

156 (87%)

Histologic

g

rade at

diagnosis12/3

9 (5%)153 (84%)

10 (6%)147 (82%)Prior anti-angiogenic therapy

14 (8%)12 (7%)

2 prior chemotherapy regimens78 (43%)

72 (40%)PFI < 3 months

46 (25%)50 (28%)

ECOG PS01-299 (54%)80

(44%)107 (60%)70 (39%)

Measurable Disease144 (79%)

143 (80%)Ascites

54 (30)59 (34)

Pujade-Lauraine

E, et al. J Clin

Oncol

. 2012; Suppl. Abstract LBA5002.

Slide38

AURELIA Progression-Free Survival

1.0

0.8

0.6

0.4

0.2

0.0

6

12

T

ime (months)

Estimated Probability

18

30

24

182

93

37

8

1

1

0

0

20

179

140

88

18

4

1

1

49

0

BEV + CT

C

T

Number at risk

Events, n (%)

Median PFS, months

(95% CI)

166 (91%)

3.4

(2.2-3.7)

135 (75%)

C

T

(n = 182)

BEV + C

T

(n = 179)

6.7

(5.7-7.9)

HR (unadjusted)

(95% CI)

Log-rnak

P

-value

(2-sided, unadjusted)

0.48

(0.38-0.60)

< 0.001

3.4

6.7

Pujade-Lauraine

E, et al.

J

Clin

Oncol

.

2012; Suppl. Abstract LBA5002.

Slide39

Subgroup analysis of PFS

aUnadjusted. bMissing n=8

Subgroup

No. of patients

Median PFS, months

HR

a

BEV + CT

better

CT

better

CT

BEV + CT

All patients

361

3.4

6.7

0.48

Age, years

<65

≥65

228

133

3.4

3.5

6.0

7.8

0.49

0.47

PFI,

months

b

<3

3‒6

96

257

2.1

3.6

5.4

7.8

0.53

0.46

Measurable disease, cm

No (<1)

Yes (1‒<5)

Yes (≥5)

74

126

161

3.7

3.3

3.3

7.5

7.5

6.0

0.46

0.50

0.47

Ascites

Yes

No

113

248

2.5

3.5

5.6

7.6

0.40

0.48

Chemotherapy

Paclitaxel

PLD

Topotecan

115

126

120

3.9

3.5

2.1

10.4

5.4

5.8

0.46

0.57

0.32

0.2 0.3 0.5 1 2 3 4 5

Slide40

Summary of best overall response rates

aTwo-sided chi-square test with Schouten correction

p=0.001

a

p<0.001

a

p<0.001

a

Patients (%)

Slide41

AURELIA: ConclusionsNo alarming safety signals

PLD – HFS, paclitaxel – neuropathy, all: myelosuppression)Toxicity may relate to exposure (longer on experimental arms)Bevacizumab augments outcomes (response, PFS) of standard chemotherapy

Paclitaxel may benefit to greater degree

Await OS data

CAVEATSNot placebo-controlled

Pretreatment characteristics: 80% measurable, 30% ascites, 8% prior AA therapyEach arm is equivalent to RP2

Slide42

Bottom Line…For platinum-resistant disease, I like:Weekly paclitaxel ± bevacizumabPLD

Gemcitabine + cisplatin (q 2 wk infusion)Try HARD to get onto clinical trialLots of options with interesting new agents

Slide43

NCCN Guidelines Version 2013

Therapy for Relapse > 6 months

NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v.1.2013.

Available at: http://

www.nccn.org

Slide44

DESKTOP-I: Surgical Endpoint of Surgery at Relapse

no residualsmedian OS 45.2 mo

residuals > 10 mm

residuals 1-10 mm

Survival probability

0

1.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0

12

24

36

48

Months from Randomization

Slide45

Secondary Cytoreduction: Multivariate Analysis Who Benefits?

Tay

,

Obstet

Gynecol

99:1008, 2002

Slide46

Secondary Cytoreductive Surgery

Chi DS, et al.

Cancer.

2006;106(9):1933-1939.

DFI = disease-free interval; mos = months; SC = secondary cytoreduction.

DFI

Single Site

Multiple Sites:

No Carcinomatosis

Carcinomatosis

6-12 mos

Suggest SC

Offer SC

No SC

12-30 mos

Suggest SC

Suggest SC

Offer SC

> 30 mos

Suggest SC

Suggest SC

Suggest SC

Goal of surgery: No gross residual disease

Slide47

AGO-OVAR DESKTOP III

(Protocol AGO - OVAR OP.4)

EOC, FT, PP

PFI

>

6No

prior

recurrence

chemotherapy

Complete

resection

seems feasible and positive

AGO score:PS

ECOG 0No

ascites > 500 mlPrior complete

debulking

or initial FIGO I/II

Secondary Cytoreduction

Chemo

Regimens

post-randomization

Carboplatin/paclitaxel Carboplatin

/gemcitabine Carboplatin/PLD

No

surgery

R

N = 150/408 planned

Slide48

PI: Coleman

Recurrent Ovarian, PPT and FT Cancer

TFI ≥ 6

mos

Yes

No

Randomize

Surgery

No Surgery

Carboplatin

Paclitaxel or

Gemcitabine

Carboplatin

Pac or Gem

Bevacizumab

Bevacizumab

GOG-213

To Chemotherapy

Randomization

Randomize

Surgical Candidate?

Slide49

A randomized trial evaluating cytoreductive surgery

in patients with platinum-sensitive recurrent ovarian cancer

R

A

N

D

OM

I

Z

E

Cytoreductive

surgery

Platinum-based

chemotherapy*

Primary outcome: OS

Secondary outcome: PFS, QoL, Complications

No surgery

SOC I

Shanghai Gynecologic Oncology Group

Available at: http://www.clinicaltrials.gov/ct2/show/NCT01611766 Accessed March 04, 2013.

N=420

Platinum-sensitive, first relapse

recurrent cancer of the

ovaries, fallopian tubes, or

peritoneum

PFI

>

6

mos

No prior chemotherapy

for this 1st relapse

Complete secondary

cytoreduction

predicting score (

iMODEL

)

FIGO stage

Residual disease after primary surgery

PFI

PS ECOG

CA125

Ascites at recurrence

Slide50

Outcomes in Recurrent Ovarian Cancer: PS

Trial

Treatment

RR (%)

PFS (mo)

HR

OS (mo)

HR

ICON 4

(n = 802)

C

54

9

0.76

P

< 0.001

24

0.82

P

= 0.02

C + P

66

12

29

AGO

(n = 366)

C

31

5.8

0.72

P

= 0.003

17.3

0.96

P

= 0.73

GC

47

8.6

18

OVA-301

(n = 417)

PLD

?

7.5

0.73

P

=0.017

24.1

0.83

P

= 0.11

PLD +

Trab

?

9.2

27.0

CALYPSO

(n = 976)

C + P

9.4

0.82

P

= 0.005

33.0

0.99

P

= 0.94

C + PLD

11.3

30.7

OCEANS

(

n = 484)

GC + PL

57

8.4

0.48

P

< 0.0001

35.2

*

1.03

*

P

= 0.84

GC + BV

79

12.4

33.3

*Data still maturing.

Take home messages:

PFS appears to be impacted from combination therapy

No OS effect to date

Post progression survival is dramatically increasing

Slide51

Bottom Line…For Platinum-sensitive disease, I like:Secondary cytoreduction if small volume and remote recurrence

However, I try HARD to get on clinical trial as this is a very biased situationPlatinum-based doubletsPLD, Gemcitabine and Paclitaxel with carboplatinIf I give gemcitabine doublet I give with bevacizumabLots of new trials coming online here as well

Slide52

Ovarian Cancer: Novel Targets

Matei, Expert Opin Investig

Drugs (2007) 16:1227

Slide53

Developmental Therapeutics: Targets

Pericyte

Tumor Endothelium

Tumor

Cell

Microenvironment

Slide54

Trebananib: Phase III Studies

Weekly paclitaxel +

Trebananib

ClinicalTrials.gov. NCT01204749.

Weekly paclitaxel + placebo

R

Recurrent

ovarian,

FT, PP cancer

R

Pegylated Liposomal Doxorubicin (PLD) +

Trebananib

Pegylated Liposomal Doxorubicin (PLD) + placebo

N = 900

Primary Objective: PFS

Secondary Objectives: OS, RR (RECIST and CA-125), Safety,

pK

, QOL

TRINOVA-1 Phase III Trial

TRINOVA-2 Phase III Trial

Recurrent

ovarian,

FT, PP cancer

Slide55

EC145 Phase III Randomized Study Design in Patients with Platinum Resistant Ovarian Cancer

Blinded Randomized study comparing EC145 + PLD vs. PLD alonePlatinum Resistant patients~600 Patients randomized 2:1Study objectives:Compare PFS between armsIndependent radiology reviewOS in EC20 ++ patients

Slide56

PARP Inhibitors in the Clinic

Nature 2005

BRCA

+/+

BRCA

-/-

BRCA

+/-

1000x

Slide57

Olaparib Development: Lessons Learned

1Phase I MTD 400 mg BIDExpansion Phase (N=39 BRCA+) = responsesPlatinum-sensitive > resistantPhase II

(BRCA+)

Dose effect (100 mg BID

vs 400 mg BID)2PARPi is best measured by PK (AUC

ss)2

Is as active as PLD (RP2)

3

Phase II

(BRCA-

wt

)

HRD exists as somatic event (30%)4RR seen in BRCA-

wt, high grade serous5Genomic signature may identify these patients6

1Fong, NEJM 20092Audeh Lancet 2010

3Kaye, ASCO 20114TCGA, 2011

5Gehlmon, Lancet 20116

Konstantinopoulos, JCO 2010

Slide58

Study 19: Maintenance Olaparib

Olaparib

400 mg po bid

Randomized 1:1

Placebo

po bid

Patient eligibility:

Platinum-sensitive high-grade serous ovarian cancer

2 previous platinum regimens

Last chemotherapy: platinum-based with a

maintained response

Stable CA125 at trial entry

Randomization stratification factors:

Time to disease progression on penultimate platinum therapy

Objective response to last platinum therapy

Ethnic

descent

Primary ENDPOINT: PFS

Treatment

until

disease progression

Ledermann

,

N

Engl

J Med

2012

Slide59

Study 19: Secondary Maintenance

Ledermann, N Engl

J Med

2012

Slide60

PARP Inhibitors in Clinical Trials

Agent

Administration

Phase

Comments

Olaparib

(AZD-2281)

Oral

I, II, III

Single Agent and Combination, BRCA and non-BRCA, Platinum-sensitive and resistant, Primary and Recurrent

AZD-2461

Oral

I

FIH, Solid Tumors

Veliparib

ABT-888

Oral

I, II

Single Agent and Combination, BRCA and non-BRCA, Platinum-sensitive and resistant, Primary and Recurrent

(GOG-9923, PIS1004, GOG-280)

BMN 673

Oral

I, II

BRCA mutation carriers, Platinum Sensitive

CEP-9722

Oral

I

Combination, Solid Tumors

E7016

Oral

I

Combination, Solid Tumors

Niraparib

(MK4827)

Oral

I, II

Single Agent and Combination, BRCA and non-BRCA, Platinum-sensitive and resistant

Rucaparib

(CO-338)

Oral

I, II

BRCA mutation carriers, Platinum Sensitive

AG014699

IV

II

Single Agent, BRCA, Platinum-sensitive and resistant

Iniparib

(BSI-201)

IV

II, III

Combination (Gem/Cis or Carbo), Platinum-sensitive and resistant

Available at: http://www.clinicaltrials.gov.

Slide61

2013:Phase III Studies in Ovarian Cancer*

Front-line added to chemotherapy then as MaintenanceBevacizumab (GOG 262 imaging biomarker study)BIBF 1120 (OVAR 12) - closed

Trebananib (GOG 3001/TRINOVA-3)

Maintenance

alone

Polyglutamate paclitaxel (GOG 212)Pazopanib (OVAR 16) - closed

CVAC (MUC-1)

Platinum

-resistant

recurrent ovarian cancer

Karenitecin

Trebananib (

with Paclitaxel/TRINOVA-1 [closed] or PLD/TRINOVA-2)

Vintafolide (with PLD)Platinum-sensitive recurrent ovarian cancer

Bevacizumab (with chemotherapy - GOG 213)Trebananib (

with PLD or Paclitaxel)Trabectedin with PLD (in 6 – 12 month group/INOVATYON)

Water soluble formulation of Paclitaxel

*Phase II studies of PARP inhibitors,

and

Cabozantinib

may lead to FDA approvalPLD =

Pegylated Liposomal Doxorubicin

Slide62

Take Home MessagesOvarian cancer is a heterogeneous disease

Molecular sub-classification can describe dependency on different driving/survival mechanisms in otherwise morphologically similar tumorsConsistent patterns of chromosomal change suggests interdependency within individual tumorsTarget discovery has led to a flood of clinical trial developmentMost promising: angiogenesis, PI3K, HRD, EMTLagging are strategic solutions for induced and adaptive responses to treatment and study designs

Need for new composite endpoints (FDA discussions underway)

Slide63

Thanks!