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

essio

n-fr

ee S

urvi

val

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 2320 357 177 60 36 20 13 3 1

Upfront debulking surgeryNeoadjuvant 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 2251 357 191 56 11 1

Upfront debulking surgeryNeoadjuvant 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 2320 357 177 60 36 20 13 3 1

Upfront debulking surgeryNeoadjuvant 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 2251 357 191 56 11 1

Upfront debulking surgeryNeoadjuvant chemotherapy

Overall survival

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

PFS

OS

CHORUSChemotherapy Or Upfront Surgery

RCOG

ICON-8

OV.21Neoadjuvant 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 7.5Paclitaxel 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

RANDOMI

Z 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

DOM

IZAT

ION

N =

125

0

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+ mosPFS (days) 90 176 174 275 339OS (days) 217 375 375 657 957Response (%) 9 24 35 52 62

Day

s1000

900

800

700

600

500

400

300

200

100

Percentage

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

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

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

0.06 12

Time (months)

Est

imat

ed P

roba

bilit

y

18 3024

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

0

BEV + CTCTNumber 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 <33‒6

96257

2.13.6

5.47.8

0.530.46

Measurable disease, cm

No (<1)Yes (1‒<5)

Yes (≥5)

74126161

3.73.33.3

7.57.56.0

0.460.500.47

Ascites YesNo

113248

2.53.5

5.67.6

0.400.48

Chemotherapy PaclitaxelPLD

Topotecan

115126120

3.93.52.1

10.45.45.8

0.460.570.32

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

24 0.82 P = 0.02C + P 66 12 29

AGO(n = 366) C 31 5.8 0.72

P = 0.003

17.3 0.96P = 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

33.0 0.99P = 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!