2012 algorithm for management of advanced ovarian cancer bradley j. monk, md, facs, facog professor...

2012 ALGORITHM FOR MANAGEMENT OF ADVANCED OVARIAN CANCER

Bradley J. Monk, MD, FACS, FACOG

Professor and DirectorDivision of Gynecologic Oncology

Department of Obstetrics and GynecologyCreighton University School of Medicine atSt. Joseph’s Hospital and Medical Center,

a Member of Catholic Healthcare WestPhoenix, Arizona USA

[email protected]

Newly Diagnosed Advanced Ovarian Cancer

Ovarian Carcinoma: Incidence and Mortality

• Incidence in US women

– 21,880 cases in 2010

– Eighth most common cancer

– Second most common gynecologic cancer

– 1.5% lifetime risk of getting ovarian cancer

• Mortality in US women

– 14,850 deaths in 2010

– Fifth most common cause of cancer death

– Most common cause of death due to gynecologic cancer

– 1.0% lifetime risk of dying of ovarian cancer

ACS. Available at: http://www.cancer.org/

Cancer in the United Sates of America

ACS. Available at: http://www.cancer.org/

First-line Therapy Global Standard Treatment

IV Platinum + Taxane Chemotherapy(Carboplatin + Paclitaxel) x 6

2004 Consensus Statements on the Management of Ovarian Cancer:Final Document of the 3rd International GCIG Ovarian Cancer Consensus Conference (GCIG OCCC 2004).

Annals Of Oncology 16 (Supplement 8) Viii7–viii12, 2005

Surgery with maximum cytoreduction effort

Basis for Current Standard: Systemic Therapy

• Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin – GOG Protocol 111[1]

– EORTC-NCIC OV 10[2]

• Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy– AGO Trial[3]

– GOG Protocol 158[4]

1. McGuire WP, et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92:699-708.3. DuBois A, et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF, et al. J Clin Oncol. 2003;21:3194-3200.

1. Docetaxel instead of paclitaxel2. Neoadjuvant chemotherapy3. Intraperitoneal Chemotherapy4. Weekly dosing5. Adding a targeted agent (e.g. bevacizumab)6. Maintenance or consolidation chemotherapy after

complete remission

First-line Therapy: Acceptable but Uncommon

IGCS Meeting October 25th 2009 BangkokN Engl J Med. 2010 Sep 2;363(10):943-53

Randomization

Ovarian, tubal or peritonal cancerFIGO stage IIIc-IV (n = 718)

Primary Debulking Surgery

Neoadjuvant chemotherapy

3 x Platinum based CT

Interval debulking (not obligatory)

Interval debulking if no PD

3 x Platinum based CT

> 3 x Platinum based CT > 3 x Platinum based CT

Primary Endpoint: Overall survival

Secondary endpoints: Progression Free Survival, Quality of Life, Complications

NACT + IDS versus PDS: ITT

(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

Median survial

PDS: 29 months

IDS: 30 months

HR for IDS:0.98 (0.85, 1.14)


complete remission


Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer

GOG 1041

Improved outcome in CP-treated patients when cisplatin administered IP (relative risk, 0.76)

GOG 1142

Improved outcome in TP-treated patients when cisplatin administered IP (relative risk, 0.78)

GOG 1723

Improved outcome in TP-treated patients when paclitaxel and cisplatin administered IP

(relative risk, 0.73)

CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin.1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43.Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006.

GOG172: Ovarian (optimal III)GOG172: Ovarian (optimal III)GOG172: Ovarian (optimal III)GOG172: Ovarian (optimal III)

Cisplatin 75 mg/m2

Paclitaxel 135 mg/m2 (24 h)

Cisplatin 100 mg/m2 IP d1Paclitaxel 135 mg/m2 (24 h) IV d1Paclitaxel 60 mg/m2 IP d8

• Epithelial Ovarian CancerEpithelial Ovarian Cancer• Optimal Stage IIIOptimal Stage III• No prior therapyNo prior therapy• Elective Second-LookElective Second-Look

Open:Open: 23-Mar-9823-Mar-98Closed:Closed: 29-Jan-0129-Jan-01Accrual:Accrual: 416 pts (evaluable)416 pts (evaluable)

I

II

Armstrong, et al. Armstrong, et al. NEJMNEJM 354:34-43, 2006 354:34-43, 2006

GOG Protocol 172

By Treatment GroupP

ropo

rtion

Sur

vivi

ng

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months on Study0 12 24 36 48 60

Rx Group Alive Dead Total IV 93 117 210

Alive Dead Total

IP 117 88 205

IV median overall survival = 49.7 months

IP median overall survival = 65.6 months

Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03

IV = Intravenous; IP = Intraperitoneal.Adapted with permission from Armstrong DK, et al. N Engl J Med. 2006;354:34-43.

Rx Group Lost to Alive Dead TotalFollow-up

IV 5 78 127 210IP 11 93 101 205

GOG Protocol 172 Toxicity

No difference in QOL at 12 months

IV = Intravenous; IP = Intraperitoneal; GI = Gastrointestinal; QOL = Quality of life.Armstrong DK, et al. N Engl J Med. 2006;354:34-43.

IV, %(N = 210)

IP, %(N = 201)

G3/4 Leukopenia* 64 76

G3/4 Platelet 4 12

G3/4 GI* 24 46

G3/4 Renal* 2 7

G3/4 Neurologic Event* 9 19

G3/4 Fatigue* 4 18

G3/4 Infection* 6 16

G3/4 Metabolic* 7 27

G3/4 Pain* 1 11

*P ≤ 0.05

GOG 252:Stage II/III Disease: Small Volume Residual

GOG 252:Stage II/III Disease: Small Volume Residual

Carboplatin AUC=6 (IV)Paclitaxel 80 mg/m2 (d1, 8, 15 3h)Bevacizumab (C2+ C22) x 21 days

Cisplatin 75 mg/m2 (IP d2)Paclitaxel 135 mg/m2 (d1, 3h)Paclitaxel 60 mg/m2 (d8, IP)Bevacizumab (C2+ C22) x 21 days

• Epithelial Ovarian Cancer• Optimal Stage III• No prior therapy

• Phase III• PFS primary endpoint

Open: 27 Jul 2009Closed: 30 Nov 2011Accrual: 1100Study Chair: J Walker

I

III

IICarboplatin AUC=6 (IP)Paclitaxel 80 mg/m2 (d1, 8, 15 3h)Bevacizumab (C2+ C22) x 21 days

ClinicalTrials.gov Identifier: NCT00951496

1. Docetaxel instead of paclitaxel2. Neoadjuvant chemotherapy3. Intraperitoneal Chemotherapy4. Weekly dosing5. Docetaxel instead of paclitaxel6. Maintenance or consolidation chemotherapy after

complete remission


JGOG: Dose-Dense Weekly PaclitaxelJGOG: Dose-Dense Weekly PaclitaxelJGOG: Dose-Dense Weekly PaclitaxelJGOG: Dose-Dense Weekly Paclitaxel

Paclitaxel 180 mg/m2 Carbolatin AUC = 6

Carbolatin AUC = 6Paclitaxel 80 mg/m2/w x3

• Epithelial Ovarian or PeritonealEpithelial Ovarian or Peritoneal

• Stage II - IVStage II - IV

• No prior therapyNo prior therapy

• Stratfied: residual disease, Stratfied: residual disease, stage, and histologystage, and histology

• Primary endpoint: PFSPrimary endpoint: PFS

• Secondary endpoint: OSSecondary endpoint: OS

• Epithelial Ovarian or PeritonealEpithelial Ovarian or Peritoneal

• Stage II - IVStage II - IV

• No prior therapyNo prior therapy

• Stratfied: residual disease, Stratfied: residual disease, stage, and histologystage, and histology

• Primary endpoint: PFSPrimary endpoint: PFS

• Secondary endpoint: OSSecondary endpoint: OS

Accrual: 637 pts (intent-to-treat)Accrual: 637 pts (intent-to-treat)

I

II

Isonishi S, et al. Isonishi S, et al. J Clin OncolJ Clin Oncol. 2008; 26:A5506.. 2008; 26:A5506.

x6-9

x6-9

• Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapypatients completed all protocol therapy

• Improved PFS with dose-dense weekly paclitaxelImproved PFS with dose-dense weekly paclitaxel

• Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapypatients completed all protocol therapy

• Improved PFS with dose-dense weekly paclitaxelImproved PFS with dose-dense weekly paclitaxel

JGOG: Dose-Dense Weekly PaclitaxelJGOG: Dose-Dense Weekly PaclitaxelJGOG: Dose-Dense Weekly PaclitaxelJGOG: Dose-Dense Weekly Paclitaxel

Katsumata N et al Lancet. 2009 Oct 17;374(9698):1331-8.

GOG 262: Stage III/IV Disease: Large Volume Residual

Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression

RANDOMIZE

N = 625Primary Endpoint = Progression free survivalActivated: Sep 27 2010Study Chair: J Chan

Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression



complete remission


23

Phase III Trial of Bevacizumab in the Primary Treatment of Advanced Epithelial Ovarian,

Primary Peritoneal, or Fallopian Tube Cancer: A Gynecologic Oncology Group (GOG) Study

R.A. Burger,R.A. Burger,11 M.F. Brady, M.F. Brady,22 M.A. Bookman, M.A. Bookman,33

J.L. Walker,J.L. Walker,44 H.D. Homesley, H.D. Homesley,55 J. Fowler, J. Fowler,66 B.J. Monk,B.J. Monk,77 B.E. Greer, B.E. Greer,88 M. Boente, M. Boente,99 S.X. Liang S.X. Liang1010

11Fox Chase Cancer Center, Philadelphia, PA; Fox Chase Cancer Center, Philadelphia, PA; 22Gynecologic Oncology Group Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY;

33University of Arizona Cancer Center, Tucson, AZ; University of Arizona Cancer Center, Tucson, AZ; 44University of Oklahoma University of Oklahoma Health Sciences Center, Oklahoma City, OK; Health Sciences Center, Oklahoma City, OK; 55Brody School of Medicine, Brody School of Medicine,

Greenville, NC; Greenville, NC; 66James Cancer Hospital at the Ohio State University, Hilliard, James Cancer Hospital at the Ohio State University, Hilliard, OH; OH; 77University of California, Irvine Medical Center, Orange, CA; University of California, Irvine Medical Center, Orange, CA; 88Seattle Cancer Seattle Cancer Care Alliance, Seattle, WA; Care Alliance, Seattle, WA; 99Minnesota Oncology and Hematology, Minneapolis, Minnesota Oncology and Hematology, Minneapolis,

MN; MN; 1010State University of New York at Stony Brook, Stony Brook, NY, USAState University of New York at Stony Brook, Stony Brook, NY, USA

J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1)J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1)N Engl J Med. 2011 Dec 29;365(26):2473-83.

GOG-0218: Schema

Front-line: Front-line: Epithelial OV, PP Epithelial OV, PP or FT canceror FT cancer

• Stage III optimal Stage III optimal (macroscopic)(macroscopic)

• Stage III Stage III suboptimalsuboptimal• Stage IVStage IV

n=1800 (planned)n=1800 (planned)

Carboplatin (C) AUC 6Carboplatin (C) AUC 6

Paclitaxel (P) 175 mg/mPaclitaxel (P) 175 mg/m22

PlaceboPlaceboBEV 15 mg/kgBEV 15 mg/kg

IIII

Stratification variables:Stratification variables:• GOG performance status GOG performance status

(PS)(PS)• Stage/debulking statusStage/debulking status

1:1:11:1:1

15 months15 months

Paclitaxel (P) 175 mg/mPaclitaxel (P) 175 mg/m22


PlaceboPlacebo

II

ArmArm

Cytotoxic Cytotoxic (6 cycles)(6 cycles)

BEV 15 mg/kgBEV 15 mg/kg


Paclitaxel (P) 175 mg/mPaclitaxel (P) 175 mg/m22IIIIII

MaintenanceMaintenance(16 cycles)(16 cycles)

GOG-0218: Investigator-Assessed PFS

Arm I CP

(n=625)

Arm IICP + BEV(n=625)

Patients with event, n (%)423

(67.7)418

(66.9)

Median PFS, months 10.3 11.2

Stratified analysis HR (95% CI)

0.908(0.759–1.040)

One-sided p-value (log rank) 0.080*

+ BEV (Arm II)+ BEV (Arm II)CP (Arm I)CP (Arm I)

*p-value boundary = 0.0116*p-value boundary = 0.0116

+ BEV → BEV maintenance (Arm III)+ BEV → BEV maintenance (Arm III)Pro

po

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n s

urv

ivin

g p

rog

ress

ion

fre

eP

rop

ort

ion

su

rviv

ing

pro

gre

ssio

n f

ree

Months since randomizationMonths since randomization

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0000 1212 2424 3636

Arm IIICP + BEV BEV

(n=623)

360 (57.8)

14.1

0.717 (0.625–0.824)

<0.0001*

Hazard ratio

Experimental arm (CP + BEV BEV;

Arm III) betterControl arm

(CP; Arm I) better

Stage 3 optimal (n=434) 0.618

Stage 3 suboptimal (n=496) 0.763

Stage 4 (n=318) 0.698

PS 0 (n=616) 0.710

PS 1/2 (n=632) 0.690

Age <60 years (n=629) 0.680

Age 60–69 years (n=409) 0.763

Age 70 years (n=210) 0.678

0.33 0.5 0.67 1.0 1.5 2.0 3.0

GOG-0218: Subgroup Analyses of PFSCP + BEV BEV (Arm III) vs CP (Arm I)

Treatment hazard ratioTreatment hazard ratio

2727

ICON7: a phase III Gynaecologic Cancer InterGroup (GCIG) trial of adding bevacizumab

to standard chemotherapy in women with newly diagnosed epithelial ovarian, primary peritoneal

or fallopian tube cancerTim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan Tim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan

Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Philip Beale, Andreas Cervantes, Amit Oza Philip Beale, Andreas Cervantes, Amit Oza

on behalf of GCIG ICON7 collaborators on behalf of GCIG ICON7 collaborators (MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG, (MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG,

GEICO, NCIC-CTG)GEICO, NCIC-CTG)ESMOESMO

2010N Engl J Med. 2011 Dec 29;365(26):2484-96.2010N Engl J Med. 2011 Dec 29;365(26):2484-96.

ICON7: Study Design

Stratification variables: Stratification variables: • Stage/surgeryStage/surgery• Time since surgeryTime since surgery• GCIG groupGCIG group *Might vary based on GCIG group*Might vary based on GCIG group

****Omit cycle 1 bevacizumab if <4 weeks from surgeryOmit cycle 1 bevacizumab if <4 weeks from surgery

Paclitaxel 175 mg/mPaclitaxel 175 mg/m22

Carboplatin AUC Carboplatin AUC 6*6*

AVASTINAVASTIN

Carboplatin AUC 6*Carboplatin AUC 6*

Paclitaxel 175 mg/mPaclitaxel 175 mg/m22

Arm A

Arm A

ArmArm BB

12 months12 months

Front-line EOC, Front-line EOC, PP or FT cancerPP or FT cancer

• Stage I-IIA (Gr 3 Stage I-IIA (Gr 3 or CC) or CC)

• Stage IIB/CStage IIB/C• Stage IIIStage III• Stage IVStage IV

n=1528 n=1528

Bevacizumab 7.5 mg/kgBevacizumab 7.5 mg/kg****

Primary endpoints: Primary endpoints: PFSPFS

Secondary Secondary endpoints: OS, RR, endpoints: OS, RR, safety, QOL, safety, QOL, cost-effectiveness,cost-effectiveness,translationaltranslational

No IRC presentNo IRC present

Perren, et al. ESMO 2010

Number at riskCP 764 723 693 556 464 307 216 143 91 50 25CPB7.5+ 764 748 715 647 585 399 263 144 73 36 19

Number at riskCP 764 723 693 556 464 307 216 143 91 50 25CPB7.5+ 764 748 715 647 585 399 263 144 73 36 19

1.00

0.75

0.50

0.25

0

1.00

0.75

0.50

0.25

0

Pro

po

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n a

live

wit

ho

ut

pro

gre

ssi

on

Pro

po

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n a

live

wit

ho

ut

pro

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on

Time (months)Time (months)

0 3 6 9 12 15 18 21 24 27 300 3 6 9 12 15 18 21 24 27 30

CP CPB7.5+

Events, n (%) 392 (51) 367 (48)

Median, months 17.3 19.0

Log-rank test p=0.0041

HR (95% CI) 0.81 (0.70–0.94)

17.3 19.0

CPCPB7.5+

ICON 7 PFS Benefit: Academic Analysis


ICON 7 Subgroups

No. of events/no. of patients

Origin of cancer Research Control HR

Age <60 202/449 210/450 0.84

60–69 134/242 142/237 0.76

≥70 31/73 40/77 0.82

ECOG PS 0 154/334 145/358 1.01

1 175/366 210/354 0.66

2 27/45 31/43 0.78

Histology Serous 274/525 278/529 0.85

Mucinous 12/19 10/15 0.77

Endometroid 26/60 25/57 0.81

Clear cell 22/67 22/60 0.90

FIGO I 6/54 9/65 0.73

II 14/83 19/80 0.72

III 277/523 290/522 0.79

IV 70/104 74/97 0.69

Residual disease

Optimal (≤1 cm) 226/559 233/552 0.87

Suboptimal (>1cm) 131/192 145/195 0.68

Grade Grade 1 10/41 16/56 0.76

Grade 2 86/175 77/142 0.77

Grade 3 267/538 294/556 0.81

Hazard ratio (fixed)

0 1 20.5 1.5

CP better

Age: Trend p=0.69, interaction p=0.83; ECOG: Trend p=0.027, interaction p=0.022Histology: Interaction test p=0.085; FIGO: Trend p=0.71, interaction p=0.91Residual disease: Trend p=0.10; Grade: Trend p=0.76, interaction p=0.95 CPB7.5+ better



complete remission


GOG 178—Investigating Paclitaxel as Consolidation

CR = Complete response.Markman M, et al. J Clin Oncol. 2003;21:2460-2465.

RANDOMIZE

277 stage III/IV patients in completeclinical remission

Paclitaxel 175 mg/m2 every 28 days × 3 months

Paclitaxel 175 mg/m2 every 28 days × 12 months

GOG 178

Progression-free survival

0

20

40

60

80

100

0 12 24 36 48Months after registration

Paclitaxel 12 coursesPaclitaxel 3 courses

110At risk

112

Failed2034

Median,months

2821

P = .0023

Pe

rcen

tag

e

Markman M, et al. J Clin Oncol. 2003;21:2460-2465.

GOG-0212Phase III Maintenance Therapy Trial

Primary endpoint: survivalSecondary endpoints: PFS, toxicity, QoL

www.clinicaltrials.gov/ct2/show/NCT00108745.

Macromolecular complexMacromolecular complex of paclitaxel poliglumexof paclitaxel poliglumex

Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin

(Planned N = 1400-1550)

Paclitaxel Every 28 days for up to 12 courses

No treatment

Paclitaxel poliglumex Every 28 days for up to 12 courses

Recurrent Disease

CHEMOTHERPAY

Population Study Treatment PFS

Optimal Stage 3 GOG 114 IV Carb & Pac, IP Cis 28 mos

GOG 172 IV Pac, IP Cis & Pac 24 mos

GOG 158 IV Pac & Carb 21 mos

GOG 114 IV Pac & Cis 22 mos



Suboptimal 3 & 4 GOG 111 IV Pac & Cis 18 mos

GOG 162 IV Pac Cis 12 mos

GOG 152 IV Pac Cis 11 mos

All Stage 3 & 4 GOG 182 IV Pac/Carbo x 8 16 mos

When Does Advanced Ovarian Cancer Recur?

Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel.

Treatment Considerations and Goals:Recurrent Ovarian Cancer

• Treatment considerations in the management of recurrent ovarian cancer – Disease-free interval– Existing toxicities remaining due to the 1st-line therapy – Volume of disease at the time of relapse– Serologic relapse (CA-125)

• Primary goals of therapy for the treatment of recurrent ovarian cancer– Progression-free survival (PFS)– Increased survival– Prevention of symptoms– Palliation of symptoms– Quality of life (QoL)

Ovarian Cancer Treatment Considerations

First-Line Treatment Recurrent Disease

Cure Goal Palliation

High Toxicity Acceptance

Low

Less Important Convenience More Important

Recurrence After First-line Chemotherapy

PlatinumPlatinumSensitiveSensitive

> 6 Months> 6 Months

ChemotherapyChemotherapyDoubletDoublet

Platinum Platinum Refractory/ResistantRefractory/Resistant

< 6 Months< 6 Months

Non-PlatinumNon-PlatinumSingle AgentSingle Agent

The Traditional Treatment Paradigm

FDA-Approved Drugs in Ovarian Cancer

1978

Cis

plat

in

Car

bopl

atin

Altr

etam

ine

Pac

litax

elTo

pote

can

Lipo

som

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in (P

LD)

(acc

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)Li

poso

mal

dox

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icin

(ful

l)

Gem

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bine

(with

car

bopl

atin

)

2006

1989

1990

1992

1996

1999

2005

2009

Trab

ecte

din;

EU

onl

y

(with

PLD

)

1964

Mel

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in

1974

OCEANS

Stratification variables: Stratification variables: • Time to recurrenceTime to recurrence• Cytoreductive surgeryCytoreductive surgery

Gemcitabine 1000 mg/mGemcitabine 1000 mg/m22 d1/8d1/8

Carboplatin AUC 4Carboplatin AUC 4

Carboplatin AUC 4Carboplatin AUC 4

Gemcitabine 1000 mg/mGemcitabine 1000 mg/m22 d1/8d1/8

Arm A

Arm A

Arm BArm B

Placebo to progressionPlacebo to progression

Bevacizumab 15 mg/kg to progressionBevacizumab 15 mg/kg to progression

Platinum-Platinum-sensitive, sensitive, recurrentrecurrent

OC, PP, FTCOC, PP, FTC

No prior No prior bevacizumabbevacizumab

n=480n=480

Primary endpoint: Primary endpoint: PFSPFS

Secondary Secondary endpoints:endpoints:ORR, OS, DR, safetyORR, OS, DR, safety

Exploratory Exploratory endpoints:endpoints:IRC, CA 125 IRC, CA 125 response, ascitesresponse, ascites

IRC presentIRC present


242242 177177 4545 1111 33 00CG + PLCG + PL

OCEANS: Primary analysis of PFSCG + PL(n=242)

CG + BV(n=242)

Events, n (%) 187 (77) 151 (62)

Median PFS, months (95% CI)

8.4(8.3–9.7)

12.4(11.4–12.7)

Stratified analysis HR (95% CI)Log-rank p-value

0.484 (0.388–0.605)

<0.0001

MonthsMonthsNo. at riskNo. at risk

242242 203203 9292 3333 1111 00CG + BVCG + BV

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

Pro

po

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n p

rog

res

sio

n f

ree

Pro

po

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n p

rog

res

sio

n f

ree

00 66 1212 1818 2424 3030

ASCO 2011

Duration of response CG + PL (n=139)

CG + BV (n=190)

Median, months 7.4 10.4

HR (95% CI) 0.534(0.408–0.698)

p<0.0001a

OCEANS: Objective Response

100

80

60

40

20

0

100

80

60

40

20

0

%%

78.5

57.4 PR = 61

PR = 48

CR = 17CR = 9

Difference: 21.1% p<0.0001

aCompared for descriptive purposes only

CG + PL (n=242)

CG + BV (n=242)

ASCO 2011

OCEANS: Interim OS

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n a

live

Pro

po

rtio

n a

live

00MonthsMonths

66 1212 3030 3636 4242

No. at risk:No. at risk:

1818 2424

242242 235235 195195 2626 88 00CG + PLCG + PL 131131 7777242242 238238 200200 4242 88 00CG + BVCG + BV 146146 8282

CG + PL(n=242)

CG + BV(n=242)

Events, n (%) 78 (32) 63 (26)

Median OS, months (95% CI)

29.9(26.4–NE)

35.5(30.0–NE)

Stratified analysis HR (95% CI)Log-rank p-value

0.751(0.537–1.052)

0.094a

NE = not estimableap-value does not cross pre-specified boundary of 0.001

ASCO 2011

Summary and Looking Towards the Future

Unanswered Questions Regarding Bevacizumab in Ovarian Cancer1.Best clinical setting (frontline vs recurrence)

2.Single agent or combination

3.Dose

4.Duration

5.Continuation beyond progression

6.Cost effectiveness

7.Impact on patient reported outcomes (PRO or QOL)

•Other agents that effect angiogenesis and the tumor vasculature active and in late stage development

NCCN “ Preferred” Agents in“Platinum Resistant” Ovarian Cancer

Level IIA

•Docetaxel•Etoposide, oral•Gemcitabine•PLD•Weekly paclitaxel•Topotecan•Bevacizumab

National Comprehensive Cancer Network (NCCN)www.nccn.org

Summary and Conclusions

• Advanced ovarian cancer is very lethal despite many active medicines

• IV carboplatin and paclitaxel standard adjuvant front-line therapy

• Little survival benefit in recurrent setting• No approved targeted agent• No agent approved since 2006

2012:Phase III Registration Studies in Ovarian Cancer*

Front-line added to chemotherapy then as Maintenance1. BIBF 1120 (OVAR 12)2. AMG 386 (with Carboplatin or Paclitaxel)

Maintenance alone1. Polyglutamate paclitaxel (GOG 212)2. Pazopanib (OVAR 16)

Platinum-resistant recurrent ovarian cancer 1. Karenitecin2. Bevacizumab (with chemotherapy - AURELIA)3. AMG 386 (with PLD or Paclitaxel)4. EC-145 (with PLD)

Platinum-sensitive recurrent ovarian cancer1. Bevacizumab (with chemotherapy - OCEANS, GOG 213)2. Trabectedin (with PLD)3. Cediranib (with chemotherapy - ICON7)4. Farletuzumab (with Carboplatin or Paclitaxel)5. Water soluble formulation of Paclitaxel *Phase II studies of PARP inhibitors, NKTR-102 and

XL-184 may lead to FDA approval

PLD = Pegylated Liposomal Doxorubicin

• Histologically or cytologically confirmed non-mucinous epithelial ovarian cancer including primary peritoneal or fallopian tube malignancies

• Measurable disease by CT or MRI scan

• Relapse within < 6 months after first-line platinum/taxane chemotherapy

• Up to 4 prior lines of therapy• Neurologic function: neuropathy

(sensory and motor) ≤CTCAE Grade 1

ClinicalTrials.gov Identifier: NCT00738699 (FAR122)

Co-Primary Endpoints = Progression-free survival and Overall survivalN = 550

Weekly paclitaxel (80mg/m2) x 12then 3 out of 4 weekswith placebo MORAb-003 2.5 mg/kg(N=367)

Weekly paclitaxel (80mg/m2) x 12then 3 out of 4 weekswith placebo (N=183)

RRAANNDDOOMMIIZZEE

Farletuzumab (MORAb-003): Phase II Farletuzumab (MORAb-003): Phase II Platinum Resistant PatientsPlatinum Resistant Patients

• November 28, 2011– Study stopped by IDMC for futility– 40% of OS events = 161 deaths– HR boundaries PFS > 0.9 and OS > 1.00– Corresponding conditional power < 1% and

one sided P value was > 0.1985 for PFS and > 0.5000 for OS

– No new safety issues identified

Farletuzumab (MORAb-003): Phase II Farletuzumab (MORAb-003): Phase II Platinum Resistant PatientsPlatinum Resistant Patients

Imaging

AgentEC20 imaging agent

EC145 therapeutic

Folate Linked Imaging Agent and Drugs

Desacetylvinblastine

Folate

Spacer

Cleavable Bond

PRECEDENT – A Randomized Phase II Trial of PLD ± EC145 in Platinum-Resistant Ovarian Cancer (EC-FV-04)

PLD 50 mg/m2 q 28 daysEC145 2.5 mg/m2 q MWF every other wk

PLD 50 mg/m2RRAANNDDOOMMIIZZEE

Recurrent EOC1st or 2nd Relapse

< 6 mo platinum based therapy

N = 149

2:1 Randomization

1° EndpointPFSHR 0.68 at 95 events2° EndpointORR and OSCorrelate EC 20 scan and response

Optional EC20 Scan

n = 94

Naumann RW, et al. ASCO 2011. Abstract 5045.

PLD= Pegylated liposomal doxorubicin

+ Censored

Progression-Free SurvivalEC145/PLD

n = 100

PLD

n = 49

Median PFS 21.7 weeks 11.7 weeks

Hazard Ratio (2-sided P value) 0.626 (P = 0.031)

EC145 + PLD

PLD Alone

Pro

bab

ility

of

Pro

gre

ssio

n-F

ree

Su

rviv

al

Weeks From Randomization Date

PRECEDENT Trial Final PFS Results

Naumann RW, et al. ASCO 2011. Abstract 5045.PLD= Pegylated liposomal doxorubicin

EC145 + PLD

PLD Alone

Note: OS data are expected to mature late 2011. Current median follow-up: 25.6 wksCensoring rate: > 60%

Overall SurvivalEC145+PLD

n = 100

PLD Alone

n = 49

Hazard Ratio (2-sided P value) 0.879 (P = 0.680)

6-month survival rate 80.8% 71.8%

PRECEDENT Trial Preliminary Survival Results

Median Follow-up

Naumann RW, et al. ASCO 2011. Abstract 5045.PLD= Pegylated liposomal doxorubicin

Disappointing Mature Overall Survival (OS)

Press Release - Dec 13, 2011•The median OS in the EC145 study arm = 14.1 months• The median OS in the PLD control = 16.9 months•HR = 1.099 intent-to-treat

http://www.endocyte.com/wp-content/uploads/2011/04/2011.12.13_EU-Supplemental-Analysis.pdf

Study for Women With Platinum Resistant Ovarian Cancer Evaluating EC145 in Combination With Doxil®

(PROCEED)

• Placebo IV days 1,3,5 and15,17,19 of a 4-week cycle

• PLD 50 mg/m2 (IBW) every4 weeks.

• EC145 IV days 1,3,5 and15,17,19 of a 4-week cycle

• PLD 50 mg/m2 (IBW) every4 weeks.

RANDOMIZE


Estimated Enrollment: 500

Study Start Date: September 2010

Estimated Study Completion Date: July 2014

Estimated Primary Completion Date: August 2012

Primary Endpoint: PFS

Secondary Endpoints: OS, toxicity

• Primary or secondary platinum-resistant ovarian cancer.

• Measurable disease (RECIST v1.1-defined)

• Prior platinum-based chemotherapy for management of primary regimens

PLD= Pegylated liposomal doxorubicin

Phase II study of the oral PARP inhibitor olaparib (AZD2281) versus liposomal doxorubicin in ovarian cancer patients with BRCA1 and/or

BRCA2 mutations

Stan Kaye,Stan Kaye,11 Bella Kaufman, Bella Kaufman,2 2 Jan Lubinski,Jan Lubinski,3 3

Ursula Matulonis,Ursula Matulonis,44 Charlie Gourley, Charlie Gourley,55 Beth Karlan, Beth Karlan,6 6

Dianna Taylor,Dianna Taylor,77 Mark Wickens, Mark Wickens,77 James Carmichael James Carmichael77

1. Royal Marsden Hospital, Sutton, Surrey, UK1. Royal Marsden Hospital, Sutton, Surrey, UK

2. Chaim Sheba Medical Center, Tel Hashomer, Israel 2. Chaim Sheba Medical Center, Tel Hashomer, Israel

3. Pomeranian Medical University, Szczecin, Poland3. Pomeranian Medical University, Szczecin, Poland

4. Dana-Farber Cancer Institute, Boston, MA, USA4. Dana-Farber Cancer Institute, Boston, MA, USA

5. University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK5. University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK

6. Cedars-Sinai Medical Center, Los Angeles, CA, USA6. Cedars-Sinai Medical Center, Los Angeles, CA, USA

7. AstraZeneca, Alderley Park, Macclesfield, UK7. AstraZeneca, Alderley Park, Macclesfield, UK

Clinicaltrials.gov number, NCT00628251

ESMO 2010ESMO 2010

Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710.

Randomized

1:1:1

Olaparib 200 mg bid in 28-day cycles

PLD 50 mg/m2 IV every 4 weeks

PD or withdrawal from treatment for

other reason

As above or max lifetime cumulative

dose reached

Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib (200 mg and 400 mg bid) with pegylated liposomal doxorubicin (PLD)

Study Design

Olaparib 400 mg bid in 28-day cycles

BRCA1/2 germline carriers with Ovarian CaProgressive or recurrent disease < 12 months after previous platinum-based chemotherapy

Patients in PLD group were allowed to cross over to

olaparib 400 mg bid on confirmed PD

Stats: HR 0.55 (median PFS of 4 to 7.3 mos)N planned: 90 (30/arm)

Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710. J Clin Oncol. 2011 Dec 27. [Epub ahead of print]

Progression-Free Survival

Olaparib 200 mg: 6.5 (5.6-8.0) months

Median PFS (80% CI)

Olaparib 400 mg: 8.8 (6.3-9.2) months

PLD 50 mg/m2: 7.1 (5.5-7.8) months

HR* vs PLD (80% CI)

Olaparib 200 mg: 0.91 (0.60-1.39); P = 0.78

Olaparib 400 mg: 0.86 (0.56-1.30); P = 0.63

Olaparib 200 mg + 400 mg: 0.88 (0.62-1.28); P = 0.66

Time From Randomization (months)

Pro

po

rtio

n o

f P

atie

nts

Pro

gre

ssio

n F

ree

0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 12108642

*HR < 1 favors olaparib.

32 03813212432 011217212833 038151825

Number of patients at risk:

Olaparib 200 mg

Olaparib 400 mg

PLD

Stats: HR 0.55 (median PFS of 4 to 7.3 mos)N planned: 90 (30/arm)

Olaparib 400 mg

Olaparib 200 mg

PLD

Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710. J Clin Oncol. 2011 Dec 27. [Epub ahead of print]

Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients

with platinum-sensitive relapsed serous ovarian cancer

Jonathan A. Ledermann

J Clin Oncol 29: 2011 (suppl; abstr 5003)

Maintenance Olaparib:Study design

Placebo(n=129)

Olaparib400mg bid,

orally(n=136)

Patients

•Platinum-sensitive high-grade serous ovarian cancer

•≥2 previous platinum regimens

•Maintained PR or CR following last platinum regimen

Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003)

Primary endpoint

PFS by RECIST

Secondary endpoints

TTP by CA-125 (GCIG criteria) or RECIST, OS, safety

Randomized 1:1

82 sites in 16 countries

Lederman J et al J Clin Oncol 29: 2011 (suppl; abstr 5003)

Progression-free survival

0

Time from randomization (months)

136 104 51 23 6 0 0

129 72 23 7 1 0 0

At risk (n)

Olaparib

Placebo

0.6

0.8

0.9

0

0.1

0.2

0.3

0.4

0.5

0.7

1.0

3 6 9 12 15 18

No. of events: Total patients (%)

Median PFS (months)

Olaparib60:136 (44.1)

8.4

Placebo93:129 (72.1)

4.8

Hazard ratio 0.35 (95% CI, 0.25–0.49)P<0.00001

Olaparib 400 mg bidPlacebo

Randomized treatmentPro

po

rtio

n o

f p

atie

nts

p

rog

ress

ion

fre

e

Lederman J et al J Clin Oncol 29: 2011 (suppl; abstr 5003)

Olaparib:Another PARP Inhibitor Abandoned in

Ovarian Cancer

Press Release - Dec 20, 2011•The previously reported progression free survival benefit is unlikely to translate into an overall survival benefit, the definitive measure of patient benefit in ovarian cancer•Attempts to identify a suitable tablet dose for use in Phase III studies have not been successful.

http://www.astrazeneca.com/Media/Press-releases/Article/20111220-az-updates-olaparib-TC5214-development

Thank You

[email protected]@chw.edu

2012 algorithm for management of advanced ovarian cancer bradley j. monk, md, facs, facog professor...

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