Ovarian Cancer: Standards of Care and New Opportunities

Robert L. Coleman, M.D.Professor & Vice Chair, Clinical Research

Department of Gynecologic OncologyM.D. Anderson Cancer Center

Ovarian Cancer: Liner Notes Globally 7th most incident and lethal cancer

– New cases: 225,000 annually

– Deaths: 140,000 annually

Burden of disease is greater in developed countries

The incidence increases with age

Almost 75% of cases present with advanced stage III / IV disease

Risk of relapse of advanced stage disease is as high as 70%

CA Cancer, 2013

Ovarian Cancer: Natural History

Symptoms

Diagnosis

Chemotherapy #1

Staging

Evaluation? SLL

Progression

Chemo #2 Chemo #3+

SupportiveCare

Death

SecondarySurgery

Maintenance

Duration

Progression-Free Survival(12-28 mos)

Post Progression Survival(12-38 mos)

Surgical Management of Primary Ovarian Cancer

Theoretical: – Reduced the volume of hypoxic,

poorly perfused cells– Host immunocompetence is

improved with lower tumor burden– Recruitment of residual cells into G1

potentiating the effects of cytotoxic therapy

– Removal of chemoresistant clones

Practical:– “Biology vs Brawn”

0%

25%

50%

75%

100%

0 12 24 36 48 60 72 84 96 108 120 132 144

% P

rogr

essi

on-f

ree

Surv

ival

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

0%

25%

50%

75%

100%

0 12 24 36 48 60 72 84 96 108 120 132 144

% O

vera

ll Su

rviv

al

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

Primary Approach: What’s Best?

N Engl J Med (2010) 363:943

(years)

0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment320 360 168 60 39 26 17 7 2

320 357 177 60 36 20 13 3 1

Upfront debulking surgery

Neoadjuvant chemotherapy

Progression-free survival

PDS: 12 mosNACT: 12 mosHR: 0.99 (0.87-1.13)

(years)

0 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment259 361 183 68 16 2

251 357 191 56 11 1

Upfront debulking surgery

Neoadjuvant chemotherapy

Overall survival

PDS: 29 monthsIDS: 30 monthsHR: 0.98 (0.85, 1.14)

PFS

OS

Neoadjuvant Chemotherapy in Ovarian Cancer

9/21/10 1/20/11

Primary Approach: What’s Best?

N Engl J Med (2010) 363:943

(years)

0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment320 360 168 60 39 26 17 7 2

320 357 177 60 36 20 13 3 1

Upfront debulking surgery

Neoadjuvant chemotherapy

Progression-free survival

PDS: 12 mosNACT: 12 mosHR: 0.99 (0.87-1.13)

(years)

0 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment259 361 183 68 16 2

251 357 191 56 11 1

Upfront debulking surgery

Neoadjuvant chemotherapy

Overall survival

PDS: 29 monthsIDS: 30 monthsHR: 0.98 (0.85, 1.14)

PFS

OS

CHORUSChemotherapy Or Upfront Surgery

RCOG

ICON-8

OV.21

Neoadjuvant Chemotherapy X 3-4 courses

Randomized

IV-Arm IP-ArmPac/Carbo + Pac/Carbo (IP) +

Pac (d8) Pac (IP, d8)

Pre-randomization Strata for NACT or PDS

Randomized

StandardPac/Carbo

Exp ADD-Pac/Carbo

Exp BDD - Pac/DD-Carbo

Principle Approach: Iº Therapy

Chemotherapy

GOG-111

Cisplatin 75 mg/m2

Cytoxan 750mg/m2

Cisplatin 75 mg/m2

Paclitaxel 135 mg/m2

GOG-158

Cisplatin 75 mg/m2

Paclitaxel 135 mg/m2

Carboplatin AUC 7.5

Paclitaxel 175 mg/m2

GOG-172

Cisplatin 75 mg/m2

Paclitaxel 135 mg/m2

Day1: IV Paclitaxel 135 mg/m2

Day 2: IP Cisplatin 100mg/m2

Day 8: IP Paclitaxel 60 mg/m2

McGuire New Engl J Med (1996) 334:1Ozols, J Clin Oncol (2003) 21:3194Armstrong New Engl J Med (2006) 354:34

OS

Cytoxan/Cisplatin

- - - Paclitaxel/Cisplatin

PFS

International Phase III Experience

CP CPG CPPLD CTCP CGCP 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 ≠ BetterDifferent ≠ Better

Moving The Bar: Primary Therapy

Dose-dense therapy

IP Chemotherapy

Biologics: Anti-angiogenesis, PARPi,

angiopoeitin inhibitors

Establishing a Front-Line Adjuvant Standard

Dose Dense: Weekly Therapy

Ovarian Epithelial, PP, FTFIGO Stage II-IV

　 Paclitaxel 180mg/m2

　 Carboplatin AUC 6.0　 q 21 days (6-9 cycles)

Dose density: 60 mg/m2/wk

　 Paclitaxel 80mg/m2, 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, > 1cmFIGO Stage ： II vs. III vs. IVHistology ： clear cell/mucinous vs serous/others

R

Katsumata, Lancet 2009

JGOG 3016: Long-Term Follow-Up

Katsumata N, ASCO Abstract 5003, 2012

iPocc JGOG Trial: SchemaEpithelial Ovarian Cancer

Stages II-IVIncluding Bulky Tumor

Paclitaxel 80 mg/m2 IV Day 1,8,15Carboplatin AUC 6 IV

Q21, 6-8 Cycles

Paclitaxel 80 mg/m2 IV Day 1,8,15Carboplatin AUC 6 IP

Q21, 6-8 Cycles

Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, QOLAccrual Goal: 746 pts / 511 events

Dose dense−TCipDose dense−TCiv

RANDOMIZATION

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

RANDOMIZ E

1:1:1

15 months

Paclitaxel 175 mg/m2

Carboplatin AUC 6

Placebo

IArm

Cytotoxic (6 cycles)

Maintenance(16 cycles)

(CP + PLA → PLA)

Carboplatin AUC 6

Paclitaxel 175 mg/m2

PlaceboBevacizumab15 mg/kg

II(CP + BEV→ PLA)

Bevacizumab 15 mg/kg

Carboplatin AUC 6

Paclitaxel 175 mg/m2 III(CP + BEV

BEV)

Burger et al. N Engl J Med 2011;365:2473-83

Establishing a Front-Line Adjuvant Standard

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/m2

Carboplatin AUC 5/6

Carboplatin AUC 5/6

Paclitaxel 175 mg/m2

18 cycles

Rn=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

Anti-VEGF Targeting: FrontlinePFS

Perren, NEJM (2011) 365:2484Burger, NEJM (2011) 365:2473

HR: 0.7310.4 vs 13.9 mosMedian D: 3.5 mos

HR: 0.8717.4vs 19.8 mosMedian D: 2.4 mos

GOG 218 ICON7

Anti-VEGF Targeting: FrontlineOverall Survival

Perren, NEJM (2011) 365:2484Burger, NEJM (2011) 365:2473

GOG 218 ICON7

00.10.20.30.40.50.60.70.80.91.0

0 6 12 18 24 30 36

02468

101214161820

0 6 12 18 24 30 36

-15

-10

-5

0

5

10

15

20

25

30

0 6 12 18 24 30 36

0.00.10.20.30.40.50.60.70.80.91.0

0 6 12 18 24 30 36

14 vs 173 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

GOG Ovarian Strategy: 262

262Suboptimal

(> 1 cm Residual)Neoadjuvant allowed

CT Perfusion Scan

IV Paclitaxel 80 mg/m2 weeklyIV Carboplatin AUC 6 q 3 wkIV Bevacizumab 15 mg/kg (optional)

IV Paclitaxel 175 mg/m2

IV Carboplatin AUC 6IV Bevacizumab 15 mg/kg (optional)

Bevacizumab q 3 wk(If chosen)

Maintenance to Progression

N: 702/625 (OPEN only for ACRIN ComponentPrimary endpoint: PFS

Phase III GOG 252 Schema

IV Paclitaxel 80 mg/m2 days 1, 8, 15IV Carboplatin AUC 6 day 1

Bevacizumab 15 mg/kg q3w†

IV Paclitaxel 80 mg/m2 days 1, 8, 15IP Carboplatin AUC 6 day 1

Bevacizumab 15 mg/kg q3w†

IV Paclitaxel 135 mg/m2 day 1 IP Cisplatin 75 mg/m2 day 2IP Paclitaxel 60 mg/m2 day 8Bevacizumab 15 mg/kg q3w†

RAN

DO

MIZ

ATIO

NN

= 1

250

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; †Begin cycle 2.

Bevacizumab 15 mg/kg q3w

Bevacizumab 15 mg/kg q3w

Other Pursuits in Front-Line Therapy

VEGF TKI’s

– Nintedanib (BIBF1120)

PARPi

– Veliparib (OVM1102)

Angiopoeitin inhibitors

– TRINOVA-3: Trebananib (AMG-386)

Bottom Line…

Determine good candidates for surgery

– Potential for better selection tools, e.g. Laparoscopy

Optimal radical resection

– Goal: R0

Adjuvant therapy

– IP and dose dense are my favorite options

– Good place for clinical trial

Maintenance: The Stakes are High!

Symptoms

Diagnosis

Chemotherapy #1

Staging

Evaluation? SLL

Progression

Chemo #2 Chemo #3+

SupportiveCare

Death

SecondarySurgery

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

Maintenance Therapy ScorecardMaintenance Beneficial?

Strategy No YesProlonged Initial Therapy ✓

Short Duration / Non-Cross Resistant Chemotherapy ✓

High-Dose Chemotherapy ✓

Intraperitoneal ✓

Interferon- ✓

Anti-CA-125 Ab ✓

Biologic Agent (MMPI, bevacizumab*) ✓ ✓*

Paclitaxel (6 months) ✓Paclitaxel (1 year) ✓#

Erlotinib ✓

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 Treatment

PaclitaxelCarboplatin

GOG-212

N = 1100 patientsSurvival primary endpoints

QOL endpoints 28

Bottom Line…

Experimental but evidence of PFS impact has been demonstrated

I always have the conversation (longest of any counseling session) but it is only infrequently taken by the patient

Recurrent Therapy: Ovarian Cancer

Symptoms

Diagnosis

Chemotherapy #1

Staging

Evaluation? SLL

Progression

Chemo #2 Chemo #3+

SupportiveCare

Death

Maintenance

SecondarySurgery

What we know (Recurrence): • Nearly all patients will succumb to progression• Options are plentiful • Nothing a “homerun”

Treatment Free Interval: Traditional Model

Time from last platinum exposure (TFI)

TreatmentCompletion 6 mos

Platinum Resistant/Refractory Platinum Sensitive

Non-Platinum Treatment Platinum Retreatment

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

Day

s1000

900

800

700

600

500

400

300

200

100

Percen

tage

100

90

80

70

60

50

40

30

20

10

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 56 vs 46 NS All pts taxane-naïve

Topotecan Treosulfan 357 22 vs 12 0.001 56 vs 48 0.02 2nd – 3rd line therapy

PLD Gemcitabine 195 16 vs 13 NS 59 vs 55 NS

PLD Gemcitabine 153 16 vs 20 NS 55 vs 50 NSresistant

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 trialAll 3rd 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

Control Experimental N TTP (wks) P OS (wks)

P Comment

PLDPLD +

Trabectedin228 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

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 Chemotherapy

RANDOMIZE Non-Platinum Chemotherapy

+ Bevacizumab 15 mg/kg

Chemotherapy Options• Paclitaxel 80 mg/m2 d 1,8,15, 22 q28• Topotecan 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

Stratifiedchemotherapy

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

Treat to progression

Treat to progressionN = 361

Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.

AURELIA: Patient CharacteristicsCharacteristic CT (n = 182) BEV + CT (n = 179)

Median age, years 61 62

Serous/adenocarcinoma at diagnosis 152 (84%) 156 (87%)Histologic grade at diagnosis12/3

9 (5%)153 (84%)

10 (6%)147 (82%)

Prior anti-angiogenic therapy 14 (8%) 12 (7%)2 prior chemotherapy regimens 78 (43%) 72 (40%)PFI < 3 months 46 (25%) 50 (28%)ECOG PS01-2

99 (54%)80 (44%)

107 (60%)70 (39%)

Measurable Disease 144 (79%) 143 (80%)Ascites 54 (30) 59 (34)

Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.

AURELIA Progression-Free Survival

1.0

0.8

0.6

0.4

0.2

0.0

6 12

Time (months)

Est

imat

ed

Pro

babi

lity

18 3024

182 93 37 8 1 1 0 020179 140 88 18 4 1 149

0

BEV + CT

CTNumber at risk

Events, n (%)

Median PFS, months

(95% CI)

166 (91%)

3.4

(2.2-3.7)

135 (75%)

CT(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.

Subgroup analysis of PFS

aUnadjusted. bMissing n=8

Subgroup No. of patients

Median PFS, months

HRaBEV + CT

betterCT

better CT BEV + CT

All patients 361 3.4 6.7 0.48

Age, years <65 ≥65

228133

3.43.5

6.07.8

0.490.47

PFI, monthsb <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

Summary of best overall response rates

Responders (RECIST and/or CA-125) (n=350)

RECIST responders (n=287) CA-125 responders (n=297)05

101520253035404550

12.6 11.8 11.6

30.927.3

31.8

CT BEV + CT

aTwo-sided chi-square test with Schouten correction

p=0.001ap<0.001a p<0.001a

Patie

nts

(%)

AURELIA: Conclusions No 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 CAVEATS

– Not placebo-controlled– Pretreatment characteristics: 80% measurable, 30% ascites, 8% prior AA

therapy– Each arm is equivalent to RP2

Bottom Line…

For platinum-resistant disease, I like:

– Weekly paclitaxel ± bevacizumab

– PLD

– Gemcitabine + cisplatin (q 2 wk infusion)

Try HARD to get onto clinical trial

– Lots of options with interesting new agents

NCCN Guidelines Version 2013Therapy for Relapse > 6 months

NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v.1.2013. Available at: http://www.nccn.org

DESKTOP-I: Surgical Endpoint of Surgery at Relapse

no residualsmedian OS 45.2 mo

residuals > 10 mm

residuals 1-10 mm

Surv

ival

pro

babi

lity

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

Secondary Cytoreduction: Multivariate Analysis Who Benefits?

Tay, Obstet Gynecol 99:1008, 2002

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

AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)

EOC, FT, PP• PFI > 6•No prior recurrence

chemotherapy•Complete resection

seems feasible and positive AGO score:

• PS ECOG 0• No ascites > 500 ml• Prior 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

PI: Coleman

Recurrent Ovarian, PPT and FT CancerTFI ≥ 6 mos

Yes No

Randomize

Surgery No Surgery CarboplatinPaclitaxel or Gemcitabine

CarboplatinPac or Gem

Bevacizumab

Bevacizumab

GOG-213

To Chemotherapy Randomization

Randomize

Surgical Candidate?

A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer

RANDOMIZE

Cytoreductivesurgery

Platinum-basedchemotherapy*

Primary outcome: OSSecondary 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=420Platinum-sensitive, first relapserecurrent cancer of the

ovaries, fallopian tubes, orperitoneum

PFI > 6 mosNo 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

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

240.82

P = 0.02C + P 66 12 29

AGO(n = 366) C 31 5.8

0.72P = 0.003

17.30.96

P = 0.73GC 47 8.6 18

OVA-301(n = 417)

PLD ? 7.5 0.73P=0.017

24.1 0.83P = 0.11PLD + Trab ? 9.2 27.0

CALYPSO (n = 976) C + P – 9.4

0.82 P = 0.005

33.00.99

P = 0.94C + PLD – 11.3 30.7

OCEANS (n = 484)

GC + PL 57 8.4 0.48 P < 0.0001

35.2* 1.03*

P = 0.84GC + 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

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 situation

– Platinum-based doublets

» PLD, Gemcitabine and Paclitaxel with carboplatin

» If I give gemcitabine doublet I give with bevacizumab

Lots of new trials coming online here as well

Ovarian Cancer: Novel Targets

Matei, Expert Opin Investig Drugs (2007) 16:1227

Developmental Therapeutics: Targets

PericyteTumor

Endothelium

Tumor Cell

Microenvironment

Trebananib: Phase III Studies

Weekly paclitaxel + Trebananib

ClinicalTrials.gov. NCT01204749.

Weekly paclitaxel + placebo

RRecurrent ovarian,FT, PP cancer

R

Pegylated Liposomal Doxorubicin (PLD) + Trebananib

Pegylated Liposomal Doxorubicin (PLD) + placebo

N = 900Primary Objective: PFSSecondary 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

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

Blinded Randomized study comparing EC145 + PLD vs. PLD alone

Platinum Resistant patients

~600 Patients randomized 2:1

Study objectives:

– Compare PFS between arms

– Independent radiology review

– OS in EC20 ++ patients

PARP Inhibitors in the Clinic

Nature 2005

BRCA +/+

BRCA -/-

BRCA +/-

1000x

Olaparib Development: Lessons Learned

1Phase I – MTD 400 mg BID– Expansion Phase (N=39 BRCA+) = responses

» Platinum-sensitive > resistant Phase II (BRCA+)

– Dose effect (100 mg BID vs 400 mg BID)2

– PARPi is best measured by PK (AUCss)2 – Is as active as PLD (RP2)3

Phase II (BRCA-wt)– HRD exists as somatic event (30%)4

– RR seen in BRCA-wt, high grade serous5

– Genomic signature may identify these patients6

1Fong, NEJM 20092Audeh Lancet 20103Kaye, ASCO 20114TCGA, 20115Gehlmon, Lancet 20116Konstantinopoulos, JCO 2010

Study 19: Maintenance Olaparib

Olaparib 400 mg po bid

Randomized 1:1

Placebopo 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

Study 19: Secondary Maintenance

Ledermann, N Engl J Med 2012

PARP Inhibitors in Clinical TrialsAgent 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

VeliparibABT-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.

2013:Phase III Studies in Ovarian Cancer*Front-line added to chemotherapy then as Maintenance

1. Bevacizumab (GOG 262 imaging biomarker study)2. BIBF 1120 (OVAR 12) - closed3. Trebananib (GOG 3001/TRINOVA-3)

Maintenance alone4. Polyglutamate paclitaxel (GOG 212)5. Pazopanib (OVAR 16) - closed6. CVAC (MUC-1)

Platinum-resistant recurrent ovarian cancer 7. Karenitecin8. Trebananib (with Paclitaxel/TRINOVA-1 [closed] or PLD/TRINOVA-2)9. Vintafolide (with PLD)

Platinum-sensitive recurrent ovarian cancer10. Bevacizumab (with chemotherapy - GOG 213)11. Trebananib (with PLD or Paclitaxel)12. Trabectedin with PLD (in 6 – 12 month group/INOVATYON)13. Water soluble formulation of Paclitaxel

*Phase II studies of PARP inhibitors, and Cabozantinib may lead to FDA approval

PLD = Pegylated Liposomal Doxorubicin

Take Home Messages Ovarian cancer is a heterogeneous disease Molecular sub-classification can describe dependency on different

driving/survival mechanisms in otherwise morphologically similar tumors– Consistent patterns of chromosomal change suggests interdependency within

individual tumors

Target discovery has led to a flood of clinical trial development– Most promising: angiogenesis, PI3K, HRD, EMT

Lagging are strategic solutions for induced and adaptive responses to treatment and study designs

Need for new composite endpoints (FDA discussions underway)

Thanks!