1) The document discusses platinum-based chemotherapy for ovarian cancer, which has a high response rate but most patients eventually relapse. 2) Two large randomized trials (GOG-0218 and ICON-7) found that adding bevacizumab to first-line platinum-based chemotherapy improved progression-free survival compared to chemotherapy alone in patients with advanced ovarian cancer. 3) For platinum-sensitive recurrent ovarian cancer, platinum-based chemotherapy regimens including carboplatin or cisplatin with paclitaxel are commonly used based on evidence from trials like ICON-4 that they provide a similar overall survival benefit.

1. Fernando Cotait Maluf
Chairof Medical OncologyDepartment
São José Hospital
São Paulo São Paulo Brazil

2. •Advancedstagesatdiagnosis (~75%)
•Highlychemotherapy-sensitive
• Complete clinicalresponse to platinum-based CT: 70-85%
•Stage III: 20-25% of complete remissionat 5y

3. • 81 studies
• 6885 patients
•StageIIIandIV
•Cytoreductivesurgeryfollowedbyplatinum-based CT
Bristowet al. J ClinOncol, 2002

4. • CT platinum-basedversus CT NON platinum-based1,2
• HR death: 0.88 [0.79 – 0.98]
•CT anthracyline-basedversus CT NON anthracyline-based3
•Absolutesurvivalbenefit: 5% ( p = 0.02)
•CisplatinversusCarboplatin1,2
• HR death: 1.02 [0.93 – 1.12]
•Platinum-dosenotassociatedwithsurvivalbenefit3
OvarianCancerMeta-Analysis Project (GynecolOncol, 2002) 1
AdvancedOvarianCancerTrialistsGroup (2002) 2
OvarianCancerMeta-Analysis Project (J ClinOncol, 1991) 3

5. •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

6. 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

7. GOG 172
Standard arm IV
D1 Paclitaxel IV 135mg/m2/24hs
D1 D2
D2 CisplatinIV 75mg/m2
IV IV
Experimental arm IV/IP D1 Paclitaxel EV 135mg/m2/24hs
D2 CisplatinIP100mg/m2
D1 D2 D8
D8 PaclitaxelIP60mg/m2
IVIP IP
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

8. 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

9. CarboplatinAUC 6 + Paclitaxel
R 180mg/m2
A
N
D
q 21 days x 6 cycles
AdvancedOvaria
O
nCancer M
I CarboplatinAUC 6 + Paclitaxel
(n = 637) Z
A 80mg/m2 d1,8,15
T
I q 21 days x 6 cycles
O
N
Katsumata N, Lancet: 374, 2009

10. Progression-freeSurvival Overall Survival
Katsumata N, Lancet: 374, 2009

11. PrimaryCitoreduc Platinun-CT
R
A tion x 6 cycles
N
D
AdvancedOv O
arianCancer M
I
(III/IV) Z
A
(n = 718) T
I Platinun-CT Platinun-CT
IntervalCytored
O
N x 3 cycles uction x 3 cycles
Vergote I, NEJM: 363 2010

12. OverallSurvival Overall Survivalvs Residual Disease
Vergote I, NEJM: 363 2010

13. Citoreduction CT CT
Citoreduction
Complete 20.4% 50.0%
resection
Vergote I, NEJM: 363 2010

14. Citoreduction CT
 CT Citoreductio
n
Pos-op Death 2.5% 0.7%
Hemorraghe G III/IV
Infection 7.1%
8.1% 4.1%
1.7%
DVT/PE 2.5% 0%
Vergote I, NEJM: 363 2010

15. GOG-0218: Scheme Arm
Carboplatin(C) AUC 6
Paclitaxel (P) 175 mg/m2
I
R
First-line : Epithelial A Placebo
OV, PP or F N
D 1:1:1 Carboplatin(C) AUC 6
• Stage III optimal
• Stage III suboptimal
O
M Paclitaxel (P) 175 mg/m2
II
• Stage IV
I
n=1800 (planned) Z
BEV 15 mg/kg Placebo
E
Carboplatin(C) AUC 6
Stratification III
• PS Paclitaxel (P) 175 mg/m2
• Stage/Citoreduction BEV 15 mg/kg
15 months

16. GOG-218: Progression-Free Survival
Arm I Arm II Arm III
1.0 CP CP + BEV CP + BEV  BEV
(n=625) (n=625) (n=623)
Proportion surviving progression free
0.9 423 418 360
Patients with event, n (%)
(67.7) (66.9) (57.8)
0.8 Median PFS, months 10.3 11.2 14.1
0.7 Stratified analysis HR 0.908 0.717
(95% CI) (0.759–1.040) (0.625–0.824)
0.6 One-sided p-value (log rank) 0.080a <0.0001a
0.5
0.4
0.3
0.2
CP (Arm I)
0.1 + BEV (Arm II)
+ BEV → BEV maintenance (Arm III)
0
0 12 24 36
Months since randomization

17. GOG-218: Select Adverse Events
Onset between cycle 2 and 30 days after date of last treatment
Arm I Arm II Arm III
CP CP + BEV CP + BEV  BEV
Adverse event (grade when limited), n (%)
(n=601) (n=607) (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)
RPLS = reversible posterior leukoencephalopathy syndrome
aPerforation/fistula/necrosis/leak
bp<0.05

18. ICON 7: Scheme
CarboplatinAUC6* q3w
Stage I or IIa (grade Paclitaxel 175mg/m2 q3w
3 or clear cell) or
stage IIb–IV EOC,
PP, FTC CarboplatinAUC6* q3w
(n=1,520) Paclitaxel 175mg/m2 q3w
Bevacizumab 7.5mg/kg q3w
• Open-label study 18 cycles
• Endpoints
– primary: PFS
– secondary: RR, OS, safety, QoL, cost effectiveness, translational
• Stratification
– FIGO stage/surgery; time since surgery; GCIG group

19. ICON 7: Progression-Free Survival
1.00
0.75
Proportion surviving
Control Experimental
0.50
Events, n (%) 130 (17) 111 (15)
Log-rank p=0.098
0.25 Hazard ratio (95% CI) 0.81 (0.63–1.04)
Sobrevida 1-ano, % 93 95
0
0 3 6 9 12 15 18 21 24 27 30
Time (months)

20. ICON 7: Select Adverse Events
45
39.6
Control (n=753)
40
Research (n=745)
35
29.1 28.3
30
Patients (%)
25.9
25
20
15 11.6 12.5
9.2
10 6.7
6.2
4.4 5.0 4.1
5 3.6 2.8
2.5 2.1 2.0
1.31.7 0.41.3 1.5
0.4 0.4 0 0
0
ATE = arterial thromboembolism; CHF = congestive heart failure; RPLS = reversible posterior
leucoencephalopathy syndrome; VTE = venous thromboembolism

21. GOG 218 and ICON 7: Comparison of Trials
Trial GOG-0218 ICON7
Number of patients 1,800 1,520
Setting/design •Double-blinded, placebo-controlled • Open-label
•First-line setting •First-line setting
•3-arm study: • 2-arm study:
Arm I: CT + placebo Arm A: carboplatin/paclitaxel (CT)
Arm II: CT + Bevacizumab (5 cycles) Arm B: CT + Bevacizumab
Arm III: CT + Bevacizumab (extended) •Bevacizumab continued for 12 months
•Bevacizumab continued for 16 months •Bevacizumab dose: 2.5mg/kg/week
•Bevacizumab dose: 5mg/kg/week •Flexibility in AUC for carboplatin
•Rigid AUC for carboplatin
Patient population Post-cytoreductive surgery Post-cytoreductive surgery
Sub-optimally debulked stage III/IV I or IIa (grade 3 or clear-cell histology)
Macroscopic optimally debulked stage III IIb–IV (all grades and histological types)
Target disease Epithelial ovarian, fallopian tube or primary Epithelial ovarian, fallopian tube or primary
peritoneal cancer peritoneal cancer
Stratification • PS (0–1 vs 2) • FIGO stage
• Stage (III vs IV) • ≤ vs>4 weeks after surgery
• GCIG group
Primary endpoint • Investigator-assessed PFS data • Investigator-assessed PFS data
• Exploratory: IRC-assessed PFS data

22. P
R
I 0 3 6 12 18 24
M
A Refractory Months
R
Y
T
Resistent
R
E
Sensitive
A
T
M
E Highlysensitive
N
T

23. < 6 months
12-18 months
70 > 18 months
59
60
Overall Response 50
33
Rate (%) 40
30
20 12
10
0
Intervalfrom prior platinumtreatment (months)

24. Platinum- Platinum-
Sensitive ResistantorRefrac
tory
Platinum-
basedTherapy

25. ICON-4/AGO-OVAR-2.2 Trial
CarboplatinAUC 5 a 6 EV
R OR
A
N Cisplatin75mg/m2 EV
D q 21 days
Platinum- O
sensitiveovariancancer M
ΔT >6 m I CarboplatinAUC 5 EV
Z OR
A Cisplatin50mg/m2 EV
T +
I Paclitaxel 175mg/m2 EV
O Q 21 days
N
Parmar MK, Lancet: 361, 2003

26. ICON-4/AGO-OVAR-2.2 Trial
Overall Survival
Parmar MK, Lancet: 361, 2003

27. CALYPSO: Scheme
R
A
Inclusion Criteria: N CarboplatinAUC 5 EV + Paclitaxel 175
D mg/m2 IV 3
• Platinum-sensitive (> 6 O
m) M q21dx6 cycles
• 1 or 2 prior platinum- I
based CT Z
• Measurable disease A
(image or CA125) T CarboplatinAUC 5 EV + DoxoLipossomal
I 30 mg/m2 IV 1 h
O
N q 28 days x6 cycles*
*or until PD in patients with stable disease or response
Pujades E etal, J ClinOncol, 2010

28. CALYPSO: Progression-Free Survival
Pujades E etal, J ClinOncol, 2010

29. OCEANS: Scheme
CarboplatinAUC4 q3w
Gemcitabine 1000mg/m2 Placebo PD
days 1 and 8 q3w
Pretreated Placebo
platinum-sensitive,
EOC, PP or FTC
(n=480)
CarboplatinAUC4 q3w
Gemcitabine 1000mg/m2 Bev.
PD
days 1 and 8 q3w 15mg/kg
•Endpoints Bevacizumab 15mg/kg
– primary: PFS
– secondary: ORR, OS, response duration, safety
– exploratory: IRC, CA125 response, ascites
•Stratification: time to recurrence, cytoreductive surgery
EOC = epithelial ovarian; PP = primary peritoneal; FTC = fallopian tube carcinoma

30. OCEANS: Patients Characteristics
CG + PL CG + BV
Characteristic (n=242) (n=242)
Median age, years 61 60
(range) (28−86) (38–87)
Age ≥65 years, % 38 35
Race, %
White 92 90
Other 8 10
ECOG PS 0, % 76 75
Histologic subtype, %
Serous 84 78
Mucinous/clear cell 3 5
Other 14 17
Platinum-free interval, %
6–12 months 42 41
>12 months 58 59
Cytoreductive surgery for recurrent disease, % 10 12

31. OCEANS: Progression-free Survival
CG + PL CG + BV
(n=242) (n=242)
Events, n (%) 148 (61) 119 (49)
1.0
Median PFS, 8.6 12.3
Proportion progression free
months (95% CI) (8.3–10.2) (10.7–14.6)
0.8 Stratified analysis 0.451
HR (95% CI) (0.351–0.580)
Log-rank p-value <0.0001
0.6
0.4
0.2
0
0 6 12 18 24 30
No. at risk Months
CG + PL 242 168 31 8 3 0
CG + BV 242 195 73 22 7 0

32. OCEANS: Progression-free Survival vs Subgroups
Median PFS
(months)
No. of CG + PL CG + BV CG + BV CG + PL
Baseline risk factor
patients (n=242) (n=242) HR (95% CI) better better
All patients 484 8.4 12.4 0.49 (0.40–0.61)
Platinum-free interval, 6–12 202 8.0 11.9 0.41 (0.29–0.58)
months
>12 282 9.7 12.4 0.55 (0.41–0.73)
Cytoreductive surgery Yes 54 7.5 16.7 0.50 (0.24–1.01)
for recurrent disease
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)
0.2 0.5 1 2 5
HR

33. OCEANS: Response Rate
Difference: 21.1%
%
p<0.0001
100
78.5 Duration of response CG + PL CG + BV
80
(n=139) (n=190)
60 57.4 PR = 61
Median, months 7.4 10.4
40 PR = 48 HR (95% CI) 0.534
(0.408–0.698)
20 p<0.0001a
CR = 9 CR = 17 aCompared for descriptive purposes only
0
CG + PL CG + BV
(n=242) (n=242)

34. Median PFS
(months)
No. of CG + PL CG + BV CG + BV CG + PL
Baseline risk factor
patients (n=242) (n=242) HR (95% CI) better better
All patients 484 8.4 12.4 0.49 (0.40–0.61)
Platinum-free interval, 6–12 202 8.0 11.9 0.41 (0.29–0.58)
months
>12 282 9.7 12.4 0.55 (0.41–0.73)
Cytoreductive surgery Yes 54 7.5 16.7 0.50 (0.24–1.01)
for recurrent disease
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)
0.2 0.5 1 2 5
HR

35. Median PFS
(months)
No. of CG + PL CG + BV CG + BV CG + PL
Baseline risk factor
patients (n=242) (n=242) HR (95% CI) better better
All patients 484 8.4 12.4 0.49 (0.40–0.61)
Platinum-free interval, 6–12 202 8.0 11.9 0.41 (0.29–0.58)
months
>12 282 9.7 12.4 0.55 (0.41–0.73)
Cytoreductive surgery Yes 54 7.5 16.7 0.50 (0.24–1.01)
for recurrent disease
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)
0.2 0.5 1 2 5
HR

36. Platinum- Platinum-
Sensitive ResistantorRefrac
tory
Median OS 6 Retrospectiveanalysis: 111 pts
months Recurrence< 3m orØ Response
SV <4months 32%
SV <12months 73%
Markmanet al. GynecolOncol, 2004

37.  LiposomalDoxorrubicin
 Gemcitabine
 Paclitaxel (weekly)
 Docetaxel
 Topotecan
 Etoposide (oral)
 Vinorelbine
 Ifosfamide

38. AURELIA/MO22224: Scheme Progression
Chemotherapy alone
(physician’s choice): Physician’s choice:
paclitaxel 80mg/m2qw or Bevacizumab
EOC, PP or FTC topotecan4mg/m2 days 1, 8 and 15 15mg/kg q3w or
that relapsed q4w or 1.25mg/kg days 1–5 q3wor SOC
PLD 40mg/m2 q4w
within <6 months
after platinum-
based
chemotherapy Bevacizumab 10mg/kg q2w or
(n=300) 15mg/kg q3w+
SOC
chemotherapy (physician’s
choice, as in control arm)
•Endpoints Progression
– primary: PFS
– secondary endpoints: ORR (RECIST and/or CA125), biological progression-free interval, OS, QoL,
safety
•FPI: = epithelial of care PP =(recruitment: 24 months)
EOC October 2009 primary peritoneal; FTC = fallopian tube carcinoma; PLD = pegylated liposomal doxorubicin;
SOC = standard
ovarian;

42.  PARP inhibitors
 Randomized Phase II trial: (Ledermann et al, ASCO , 2011)
 N = 265
 CT Olaparibvs 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%

44. Convidados
Internacionais