Fernando Cotait Maluf

Chairof Medical OncologyDepartment

São José Hospital

São Paulo São Paulo Brazil

•Advancedstagesatdiagnosis (~75%)

•Highlychemotherapy-sensitive

• Complete clinicalresponse to platinum-based CT: 70-85%

•Stage III: 20-25% of complete remissionat 5y

• 81 studies

• 6885 patients

•StageIIIandIV

•Cytoreductivesurgeryfollowedbyplatinum-based CT

Bristowet al. J ClinOncol, 2002

• CT platinum-basedversus CT NON platinum-based1,2

• HR death: 0.88 [0.79 – 0.98]

OvarianCancerMeta-Analysis Project (GynecolOncol, 2002) 1

AdvancedOvarianCancerTrialistsGroup (2002) 2

OvarianCancerMeta-Analysis Project (J ClinOncol, 1991) 3

•CT anthracyline-basedversus CT NON anthracyline-based3

•Absolutesurvivalbenefit: 5% ( p = 0.02)

•CisplatinversusCarboplatin1,2

• HR death: 1.02 [0.93 – 1.12]

•Platinum-dosenotassociatedwithsurvivalbenefit3

•MONOCT platinum-basedversus POLICT platinum-based1,2

• HR death: 0.91 [0.75 – 1.05]

OvarianCancerMeta-Analysis Project (GynecolOncol, 2002) 1

AdvancedOvarianCancerTrialistsGroup (2002) 2

ICON 3: CarboplatinvsCarboplatin + Paclitaxel

GOG 111 andOV 10(Intergroup)

McGuireetal, N Eng J Med, 1996;

n=386,suboptimalcytoreduction III/IV

SLPSG

PT 18m 38m

PC 13m 24m

Piccartetal, J Nat CancerInst, 2000;

n=668, debulkingsurgery, II-IV

SLPSG

PT 17m 35m

PC 12m 25m

Standard arm IV

D1 D2

IV IV

D1 Paclitaxel IV 135mg/m2/24hs

D2 CisplatinIV 75mg/m2

D1 D2 D8

IVIP IP

Experimental arm IV/IP D1 Paclitaxel EV 135mg/m2/24hs

D2 CisplatinIP100mg/m2

D8 PaclitaxelIP60mg/m2

GOG 172

Armostrong e al, NEJM, 2006;

N=429, optimaldebulkingsurgery, stage III

SLPSG

PT IV 19m 50m

PT IV/IP 24m 65m

Only 42% ofptscompletedtreat. IV/IP arm

GOG randomized studies: IV vs IP

PFS (m) %Advantage OS (m) %Advantage

IV IP IV IP

Alberts -- -- 41 49

Markman 22 28 27 52 63

Armstrong 19 24 20 50 65 25

* Statisticallysignificant : p < 0.05

AdvancedOvaria

nCancer

(n = 637)

RANDOMIZATION

CarboplatinAUC 6 + Paclitaxel

180mg/m2

q 21 days x 6 cycles

Katsumata N, Lancet: 374, 2009

CarboplatinAUC 6 + Paclitaxel

80mg/m2 d1,8,15

q 21 days x 6 cycles

Katsumata N, Lancet: 374, 2009

Progression-freeSurvival Overall Survival

AdvancedOv

arianCancer

(III/IV)

(n = 718)

RANDOMIZATION

PrimaryCitoreduc

tion

Vergote I, NEJM: 363 2010

Platinun-CT

x 3 cycles

IntervalCytored

uction

Platinun-CT

x 3 cycles

Platinun-CT

x 6 cycles

Vergote I, NEJM: 363 2010

OverallSurvival Overall Survivalvs Residual Disease

Vergote I, NEJM: 363 2010

Citoreduction CT CT Citoreduction

Complete resection

20.4% 50.0%

Vergote I, NEJM: 363 2010

Citoreduction CT

CT Citoreductio

n

Pos-op Death 2.5% 0.7%

Hemorraghe G III/IV 7.1% 4.1%Infection 8.1% 1.7%

DVT/PE 2.5% 0%

GOG-0218: Scheme

Stratification

• PS

• Stage/Citoreduction BEV 15 mg/kg

15 months

Paclitaxel (P) 175 mg/m2

Carboplatin(C) AUC 6

Carboplatin(C) AUC 6

Paclitaxel (P) 175 mg/m2

Carboplatin(C) AUC 6

Paclitaxel (P) 175 mg/m2

Placebo

PlaceboBEV 15 mg/kg

First-line : Epithelial

OV, PP or F

• Stage III optimal

• Stage III suboptimal

• Stage IV

n=1800 (planned)

R

A

N

D

O

M

I

Z

E

I

II

III

Arm

1:1:1

GOG-218: Progression-Free SurvivalArm I

CP

(n=625)

Arm II

CP + 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) 0.080a

+ BEV (Arm II)CP (Arm I)

+ BEV → BEV maintenance (Arm III)Pro

po

rtio

n s

urv

ivin

g p

rog

ress

ion

fre

e

Months since randomization

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 12 24 36

Arm III

CP + BEV BEV

(n=623)

360

(57.8)

14.1

0.717

(0.625–0.824)

<0.0001a

Adverse event (grade when limited), n (%)

Arm I

CP

(n=601)

Arm II

CP + BEV

(n=607)

Arm III

CP + BEV BEV

(n=608)

GI eventsa (grade ≥2) 7 (1.2) 17 (2.8) 16 (2.6)

Hypertension (grade ≥2) 43 (7.2)b 100 (16.5)b 139 (22.9)b

Proteinuria (grade ≥3) 4 (0.7) 4 (0.7) 10 (1.6)

Pain (grade ≥2) 250 (41.7) 252 (41.5) 286 (47.1)

Neutropenia (grade ≥4) 347 (57.7) 384 (63.3) 385 (63.3)

Febrile neutropenia 21 (3.5) 30 (4.9) 26 (4.3)

Venous thromboembolic event 35 (5.8) 32 (5.3) 41 (6.7)

Arterial thromboembolic event 5 (0.8) 4 (0.7) 4 (0.7)

CNS bleeding 0 0 2 (0.3)

Non-CNS bleeding (grade ≥3) 5 (0.8) 8 (1.3) 13 (2.1)

RPLS 0 1 (0.2) 1 (0.2)

GOG-218: Select Adverse EventsOnset between cycle 2 and 30 days after date of last treatment

RPLS = reversible posterior leukoencephalopathy syndromeaPerforation/fistula/necrosis/leak

bp<0.05

ICON 7: Scheme

• Open-label study

• Endpoints

– primary: PFS

– secondary: RR, OS, safety, QoL, cost effectiveness, translational

• Stratification

– FIGO stage/surgery; time since surgery; GCIG group

Paclitaxel 175mg/m2 q3w

CarboplatinAUC6* q3w

Bevacizumab 7.5mg/kg q3w

Paclitaxel 175mg/m2 q3w

CarboplatinAUC6* q3w

18 cycles

Stage I or IIa (grade

3 or clear cell) or

stage IIb–IV EOC,

PP, FTC

(n=1,520)

ICON 7: Progression-Free Survival

Control Experimental

Events, n (%) 130 (17) 111 (15)

Log-rank p=0.098

Hazard ratio (95% CI) 0.81 (0.63–1.04)

Sobrevida 1-ano, % 93 95

1.00

0.75

0.50

0.25

0

Pro

port

ion s

urv

ivin

g

Time (months)

0 3 6 9 12 15 18 21 24 27 30

ICON 7: Select Adverse Events

6.2

2.5 2.1 1.3 0.4

11.6

4.1

1.50.4 0

29.1

2.0

9.2

25.9

4.4 5.0

1.7 1.3

39.6

6.7

3.6

0.4 0

28.3

2.8

12.5

0

5

10

15

20

25

30

35

40

45Control (n=753)

Research (n=745)

ATE = arterial thromboembolism; CHF = congestive heart failure; RPLS = reversible posterior leucoencephalopathy syndrome; VTE = venous thromboembolism

Patients

(%

)

GOG 218 and ICON 7: Comparison of TrialsTrial GOG-0218 ICON7

Number of patients 1,800 1,520

Setting/design •Double-blinded, placebo-controlled

•First-line setting

•3-arm study:

Arm I: CT + placebo

Arm II: CT + Bevacizumab (5 cycles)

Arm III: CT + Bevacizumab (extended)

•Bevacizumab continued for 16 months

•Bevacizumab dose: 5mg/kg/week

•Rigid AUC for carboplatin

• Open-label

•First-line setting

• 2-arm study:

Arm A: carboplatin/paclitaxel (CT)

Arm B: CT + Bevacizumab

•Bevacizumab continued for 12 months

•Bevacizumab dose: 2.5mg/kg/week

•Flexibility in AUC for carboplatin

Patient population Post-cytoreductive surgery

Sub-optimally debulked stage III/IV

Macroscopic optimally debulked stage III

Post-cytoreductive surgery

I or IIa (grade 3 or clear-cell histology)

IIb–IV (all grades and histological types)

Target disease Epithelial ovarian, fallopian tube or primary

peritoneal cancer

Epithelial ovarian, fallopian tube or primary

peritoneal cancer

Stratification • PS (0–1 vs 2)

• Stage (III vs IV)

• FIGO stage

• ≤ vs>4 weeks after surgery

• GCIG group

Primary endpoint • Investigator-assessed PFS data

• Exploratory: IRC-assessed PFS data

• Investigator-assessed PFS data

P

R

I

M

A

R

Y

T

R

E

A

T

M

E

N

T

0 3 6 12 18 24

Refractory

Resistent

Sensitive

Highlysensitive

Months

70

60

50

40

30

20

10

0

12

33

59

< 6 months

12-18 months

> 18 months

Overall ResponseRate (%)

Intervalfrom prior platinumtreatment (months)

Platinum-

Sensitive

Platinum-

ResistantorRefrac

tory

Platinum-

basedTherapy

Platinum-sensitiveovariancancer

ΔT >6 m

RANDOMIZATION

CarboplatinAUC 5 a 6 EV

OR

Cisplatin75mg/m2 EV

q 21 days

CarboplatinAUC 5 EVOR

Cisplatin50mg/m2 EV+

Paclitaxel 175mg/m2 EVQ 21 days

Parmar MK, Lancet: 361, 2003

ICON-4/AGO-OVAR-2.2 Trial

Parmar MK, Lancet: 361, 2003

Overall Survival

ICON-4/AGO-OVAR-2.2 Trial

Pujades E etal, J ClinOncol, 2010

Inclusion Criteria:

• Platinum-sensitive (> 6 m)

• 1 or 2 prior platinum-based CT

• Measurable disease (image or CA125)

RANDOMIZATION

CarboplatinAUC 5 EV + Paclitaxel 175

mg/m2 IV 3

q21dx6 cycles

CarboplatinAUC 5 EV + DoxoLipossomal

30 mg/m2 IV 1 h

q 28 days x6 cycles*

*or until PD in patients with stable disease or response

CALYPSO: Scheme

Pujades E etal, J ClinOncol, 2010

CALYPSO: Progression-Free Survival

•Endpoints

– primary: PFS

– secondary: ORR, OS, response duration, safety

– exploratory: IRC, CA125 response, ascites

•Stratification: time to recurrence, cytoreductive surgery

Gemcitabine 1000mg/m2

days 1 and 8 q3w

CarboplatinAUC4 q3w

Gemcitabine 1000mg/m2

days 1 and 8 q3w

CarboplatinAUC4 q3w

Bevacizumab 15mg/kg

Placebo

EOC = epithelial ovarian; PP = primary peritoneal; FTC = fallopian tube carcinoma

PD

PD

Bev.

15mg/kg

Pretreated

platinum-sensitive,

EOC, PP or FTC

(n=480)

Placebo

OCEANS: Scheme

OCEANS: Patients Characteristics

CharacteristicCG + PL

(n=242)

CG + BV

(n=242)

Median age, years

(range)

61

(28−86)

60

(38–87)

Age ≥65 years, % 38 35

Race, %

White

Other

92

8

90

10

ECOG PS 0, % 76 75

Histologic subtype, %

Serous

Mucinous/clear cell

Other

84

3

14

78

5

17

Platinum-free interval, %

6–12 months

>12 months

42

58

41

59

Cytoreductive surgery for recurrent disease, % 10 12

OCEANS: Progression-free SurvivalCG + PL

(n=242)

CG + BV

(n=242)

Events, n (%) 148 (61) 119 (49)

Median PFS,

months (95% CI)

8.6

(8.3–10.2)

12.3

(10.7–14.6)

Stratified analysis

HR (95% CI)

Log-rank p-value

0.451

(0.351–0.580)

<0.0001

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n p

rog

ress

ion

fre

e

0 6 12 18 24 30

242 168 31 8 3 0CG + PL242 195 73 22 7 0CG + BV

MonthsNo. at risk

OCEANS: Progression-free Survival vs Subgroups

Median PFS

(months)

Baseline risk factorNo. of

patientsCG + PL

(n=242)

CG + BV

(n=242) HR (95% CI)

CG + BV

better

CG + PL

better

All patients 484 8.4 12.4 0.49 (0.40–0.61)

Platinum-free interval,

months6–12 202 8.0 11.9 0.41 (0.29–0.58)

>12 282 9.7 12.4 0.55 (0.41–0.73)

Cytoreductive surgery

for recurrent diseaseYes 54 7.5 16.7 0.50 (0.24–1.01)

No 430 8.4 12.3 0.49 (0.39–0.62)

Age, years <65 306 8.5 12.5 0.47 (0.36–0.62)

≥65 178 8.4 12.3 0.50 (0.34–0.72)

Baseline ECOG PS 0 367 8.6 12.5 0.47 (0.36–0.60)

1 116 8.3 10.6 0.61 (0.39–0.95)

HR0.2 0.5 1 2 5

OCEANS: Response Rate

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

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)

Median PFS

(months)

Baseline risk factorNo. of

patientsCG + PL

(n=242)

CG + BV

(n=242) HR (95% CI)

CG + BV

better

CG + PL

better

All patients 484 8.4 12.4 0.49 (0.40–0.61)

Platinum-free interval,

months6–12 202 8.0 11.9 0.41 (0.29–0.58)

>12 282 9.7 12.4 0.55 (0.41–0.73)

Cytoreductive surgery

for recurrent diseaseYes 54 7.5 16.7 0.50 (0.24–1.01)

No 430 8.4 12.3 0.49 (0.39–0.62)

Age, years <65 306 8.5 12.5 0.47 (0.36–0.62)

≥65 178 8.4 12.3 0.50 (0.34–0.72)

Baseline ECOG PS 0 367 8.6 12.5 0.47 (0.36–0.60)

1 116 8.3 10.6 0.61 (0.39–0.95)

HR0.2 0.5 1 2 5

Median PFS

(months)

Baseline risk factorNo. of

patientsCG + PL

(n=242)

CG + BV

(n=242) HR (95% CI)

CG + BV

better

CG + PL

better

All patients 484 8.4 12.4 0.49 (0.40–0.61)

Platinum-free interval,

months6–12 202 8.0 11.9 0.41 (0.29–0.58)

>12 282 9.7 12.4 0.55 (0.41–0.73)

Cytoreductive surgery

for recurrent diseaseYes 54 7.5 16.7 0.50 (0.24–1.01)

No 430 8.4 12.3 0.49 (0.39–0.62)

Age, years <65 306 8.5 12.5 0.47 (0.36–0.62)

≥65 178 8.4 12.3 0.50 (0.34–0.72)

Baseline ECOG PS 0 367 8.6 12.5 0.47 (0.36–0.60)

1 116 8.3 10.6 0.61 (0.39–0.95)

HR0.2 0.5 1 2 5

Platinum-

Sensitive

Platinum-

ResistantorRefrac

tory

Retrospectiveanalysis: 111 pts

Recurrence< 3m orØ Response

Median OS 6

months

SV <4months 32%

SV <12months 73%Markmanet al. GynecolOncol, 2004

LiposomalDoxorrubicin

Gemcitabine

Paclitaxel (weekly)

Docetaxel

Topotecan

Etoposide (oral)

Vinorelbine

Ifosfamide

AURELIA/MO22224: Scheme

Physician’s choice:

Bevacizumab

15mg/kg q3w or

SOC

•Endpoints

– primary: PFS

– secondary endpoints: ORR (RECIST and/or CA125), biological progression-free interval, OS, QoL, safety

•FPI: October 2009 (recruitment: 24 months)EOC = epithelial ovarian; PP = primary peritoneal; FTC = fallopian tube carcinoma; PLD = pegylated liposomal doxorubicin;

SOC = standard of care

Bevacizumab 10mg/kg q2w or

15mg/kg q3w+

chemotherapy (physician’s

choice, as in control arm)

SOC

Progression

Progression

Chemotherapy alone

(physician’s choice):

paclitaxel 80mg/m2qw or

topotecan4mg/m2 days 1, 8 and 15

q4w or 1.25mg/kg days 1–5 q3wor

PLD 40mg/m2 q4w

EOC, PP or FTC

that relapsed

within <6 months

after platinum-

based

chemotherapy

(n=300)

PARP inhibitors

Randomized Phase II trial: (Ledermann et al, ASCO , 2011)

N = 265

CTOlaparibvs Placebo

PFS: 8.4 vs 4.8 months (p< 0.00001)

Phase II trial: (Penson et al, ASCO , 2011)

N = 41

Carboplatin + Gemcitabine + Iniparib

OR: 70%

Convidados

Internacionais