Ovarian Cancer

Report
Ovarian Cancer: Standards of Care and New
Opportunities
Robert L. Coleman, M.D.
Professor & Vice Chair, Clinical Research
Department of Gynecologic Oncology
M.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
Progression
Diagnosis
Symptoms
Evaluation
? SLL
Chemotherapy #1
Death
Secondary
Surgery
Maintenance
Chemo #2
Chemo #3+
Supportive
Care
Staging
Progression-Free Survival
(12-28 mos)
Post Progression Survival
(12-38 mos)
Duration
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”
The Impact of Residual Tumor:
What Is Optimal Debulking?
% Progression-free Survival
100%
75%
HR
50%
0 mm
25%
(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
1-10 mm
> 10 mm
0%
0
12
24
36
48
60
72
84
96
108
120
132
144
Generated from 3 prospective
Phase III trials (OVAR 3,5, & 7)
N = 3126 pts
100%
% Overall Survival
75%
HR
0 mm
50%
25%
1-10 mm
24
36
48
60
72
84
96
108
120
132
2.70 (2.37; 3.07)
>10 mm vs. 1-10 mm:
1.34 (1.21; 1.49)
DuBois, Cancer (2009)115:1234
0%
12
1-10 mm vs. 0 mm:
log-rank: p < 0.0001
> 10 mm
0
(95%CI)
144
Primary Approach: What’s Best?
Progression-free survival
100
90
PDS:
12 mos
NACT: 12 mos
HR:
0.99 (0.87-1.13)
80
70
60
PFS
50
40
30
20
10
0
(years)
0
O N
320 360
100
320 357
90
1
2
3
4
5
6
7
8
Number of patients at risk :
168
60
39
26
177
60
36
20
17
13
7
3
2
1
Treatment
Upfront debulk
Neoadjuvant c
Overall survival
PDS: 29 months
IDS: 30 months
HR: 0.98 (0.85, 1.14)
80
70
60
OS
50
40
30
20
10
0
(years)
0
N Engl J Med (2010) 363:943
O N
259 361
251 357
2
4
Number of patients at risk :
183
68
191
56
6
8
16
11
2
1
10
Treatment
Upfront debulking surge
Neoadjuvant chemother
Neoadjuvant Chemotherapy in Ovarian Cancer
9/21/10
1/20/11
Primary Approach: What’s Best?
Progression-free survival
100
90
PDS:
12 mos
NACT: 12 mos
HR:
0.99 (0.87-1.13)
80
70
60
PFS
50
40
30
20
10
0
(years)
0
O N
320 360
100
320 357
90
1
2
3
4
5
6
7
8
Number of patients at risk :
168
60
39
26
177
60
36
20
17
13
7
3
2
1
Treatment
Upfront debulk
Neoadjuvant c
Overall survival
PDS: 29 months
IDS: 30 months
HR: 0.98 (0.85, 1.14)
80
70
60
OS
50
40
30
20
10
0
(years)
0
N Engl J Med (2010) 363:943
O N
259 361
251 357
2
4
Number of patients at risk :
183
68
191
56
6
8
16
11
2
1
10
Treatment
Upfront debulking surge
Neoadjuvant chemother
OV.21
CHORUS
Chemotherapy Or Upfront Surgery
Neoadjuvant Chemotherapy
X 3-4 courses
Randomized
IV-Arm
Pac/Carbo +
Pac (d8)
IP-Arm
Pac/Carbo (IP) +
Pac (IP, d8)
ICON-8
Pre-randomization
Strata for NACT or PDS
Randomized
Standard
Pac/Carbo
RCOG
Exp A
Exp B
DD-Pac/Carbo DD - Pac/DD-Carbo
Principle Approach: Iº Therapy
Chemotherapy
- - - Paclitaxel/Cisplatin
Cytoxan/Cisplatin
OS
GOG-172
GOG-158
GOG-111
PFS
Cisplatin 75 mg/m2
Cisplatin 75 mg/m2
Paclitaxel
Cytoxan 750mg/m
135 mg/m2 2
Paclitaxel 135 mg/m2
2 mg/m2
Day1:
IV Paclitaxel
135
Carboplatin
Cisplatin
75AUC
mg/m
7.5
2
2
Day
2: IP Cisplatin
100mg/m
Paclitaxel
135 mg/m
175
Day 8: IP Paclitaxel 60 mg/m2
McGuire New Engl J Med (1996) 334:1
Ozols, J Clin Oncol (2003) 21:3194
Armstrong New Engl J Med (2006) 354:34
International Phase III Experience
GOG0182-ICON5
SCOTROC
CP
CPG
CPPLD
CTCP
CGCP
864
864
862
861
861
PLD-C
Total
4312
No Significant Effect
538
CE
539
1077
635
647
1282
NSGO-EORTC-NCIC-GEICO
444
443
887
MITO
170
AGO-GINECO
AGO-GINECO-GERCORNSGO
NCIC-EORTC-GEICO OV16
156
326
More ≠ Better
Different ≠ Better
882
860
410
MITO-2
410
Regimen Total:
4353
1742
409
819
410
1724
1272
820
1426
861
539
1090 11265
Establishing a Front-Line Adjuvant Standard
Moving The Bar: Primary Therapy

Dose-dense therapy

IP Chemotherapy

Biologics: Anti-angiogenesis, PARPi,
angiopoeitin inhibitors
Dose Dense: Weekly Therapy
Ovarian Epithelial, PP, FT
FIGO Stage II-IV
Stratification;
Residual disease: <1cm, > 1cm
FIGO Stage: II vs. III vs. IV
Histology: clear cell/mucinous vs serous/others
Paclitaxel 180mg/m2
Carboplatin AUC 6.0
q 21 days (6-9 cycles)
Dose density: 60 mg/m2/wk
Katsumata, Lancet 2009
R
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%)
JGOG 3016: Long-Term Follow-Up
Katsumata N, ASCO Abstract 5003, 2012
iPocc JGOG Trial: Schema
Epithelial Ovarian Cancer
Stages II-IV
Including Bulky Tumor
RANDOMIZATION
Paclitaxel 80 mg/m2 IV Day 1,8,15
Carboplatin AUC 6 IV
Q21, 6-8 Cycles
Paclitaxel 80 mg/m2 IV Day 1,8,15
Carboplatin AUC 6 IP
Q21, 6-8 Cycles
Dose dense−TCiv
Dose dense−TCip
Primary Endpoint: PFS
Secondary Endpoint: OS, Toxicity, QOL
Accrual Goal: 746 pts / 511 events
Establishing a Front-Line Adjuvant Standard
GOG-0218 study schema
Carboplatin AUC 6
Previously untreated
epithelial ovarian, primary
peritoneal, or fallopian tube
cancer
• Stage III optimal
(macroscopic)
• Stage III
suboptimal
• Stage IV
n=1873
R
A
N
D
O
M
I
Z
E
Paclitaxel 175 mg/m2
Placebo
I
(CP + PLA →
PLA)
Carboplatin AUC 6
1:1:1
Paclitaxel 175 mg/m2
Bevacizumab
15 mg/kg
Placebo
Carboplatin AUC 6
Stratification variables:
• GOG performance status
• Stage/debulking status
Burger et al. N Engl J Med 2011;365:2473-83
Arm
Paclitaxel 175 mg/m2
Bevacizumab 15 mg/kg
Cytotoxic (6
cycles)
Maintenance
(16 cycles)
II
(CP + BEV
→ PLA)
III
(CP + BEV 
BEV)
15 months
Establishing a Front-Line Adjuvant Standard
Schema
1:1
Carboplatin AUC 5/6
Stratification variables:
Paclitaxel 175 mg/m2
• Stage & extent of debulking: I–III debulked
≤1cm vs stage
I–III debulked >1 cm vs stage IV and inoperable
stage III
Carboplatin AUC 5/6
• Timing of intended treatment start
≤4 vs >4 weeks after surgery
R
n=1528*
Paclitaxel 175 mg/m2
• GCIG group
Bevacizumab 7.5 mg/kg q3w
*Dec 2006 to Feb 2009
18 cycles
Academic-led, industry-supported trial to investigate use of bevacizumab and to
support licensing
Perrin, N Engl J Med 2011;365:2484-96
Anti-VEGF Targeting: Frontline
PFS
GOG 218
HR: 0.73
10.4 vs 13.9 mos
Median D: 3.5 mos
Burger, NEJM (2011) 365:2473
ICON7
HR: 0.87
17.4vs 19.8 mos
Median D: 2.4 mos
Perren, NEJM (2011) 365:2484
Anti-VEGF Targeting: Frontline
Overall Survival
GOG 218
ICON7
Burger, NEJM (2011) 365:2473
Perren, NEJM (2011) 365:2484
GOG-0218 and ICON7:
Restricted Means Estimate – Benefit During Exposure Only?
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
14 vs 17
3 months’ difference
Research Arm
0
6
20
18
16
14
12
10
8
6
4
Research Arm
2
0 0
6
12
18
GOG-0218
24
30
36
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
13.3 vs 16.5
3 months’ difference
Research Arm
0
6
12
18
24
30
ICON7 (III suboptimal and IV subgroup)
36
30
25
20
15
10
Research Arm
5
12
18
Time (months)
24
30
36
0
-5
-10
-15
0
6
12
Time (months)
18
24
30
36
GOG Ovarian Strategy: 262
Bevacizumab q 3 wk
(If chosen)
Maintenance to Progression
262
Suboptimal
(> 1 cm Residual)
Neoadjuvant allowed
CT Perfusion Scan
N: 702/625 (OPEN only for ACRIN Component
Primary endpoint: PFS
IV Paclitaxel 80 mg/m2 weekly
IV Carboplatin AUC 6 q 3 wk
IV Bevacizumab 15 mg/kg (optional)
IV Paclitaxel 175 mg/m2
IV Carboplatin AUC 6
IV Bevacizumab 15 mg/kg (optional)
Phase III GOG 252 Schema
RANDOMIZATION
N = 1250
Cycles 1-6*
Cycles 7-22*
IV Paclitaxel 80 mg/m2 days 1, 8, 15
IV Carboplatin AUC 6 day 1
Bevacizumab 15 mg/kg q3w†
Bevacizumab 15 mg/kg q3w
IV Paclitaxel 80 mg/m2 days 1, 8, 15
IP Carboplatin AUC 6 day 1
Bevacizumab 15 mg/kg q3w†
Bevacizumab 15 mg/kg q3w
IV Paclitaxel 135 mg/m2 day 1
IP Cisplatin 75 mg/m2 day 2
IP Paclitaxel 60 mg/m2 day 8
Bevacizumab 15 mg/kg q3w†
*Each cycle is 3 weeks; †Begin cycle 2.
Walker JL. Am Soc Clin Oncol Ed Book. 2009:308-312.
Bevacizumab 15 mg/kg q3w
N: 1554 (CLOSED)
Primary endpoint: PFS
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!
Progression
Diagnosis
Symptoms
Evaluation
? SLL
Chemotherapy #1
Maintenance
Death
Secondary
Surgery
Chemo #2
Chemo #3+
Staging
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
Supportive
Care
Maintenance Therapy Scorecard
Maintenance Beneficial?
Strategy
No
Prolonged 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
Yes
✓
Maintenance Trials: Ongoing
GOG-212
EOC, PP, FT cancer
Paclitaxel
Carboplatin
Paclitaxel
X 12 mos
CTI-2103
X 12 mos
No
Treatment
N = 1100 patients
Survival primary endpoints
QOL endpoints

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
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
Progression
Diagnosis
Symptoms
Evaluation
? SLL
Chemotherapy #1
Maintenance
Death
Secondary
Surgery
Chemo #2
Chemo #3+
Supportive
Care
Staging
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)
Treatment
Completion
6 mos
Platinum Resistant/Refractory
Platinum Sensitive
Non-Platinum Treatment
Platinum Retreatment
1000
100
900
90
800
80
700
70
600
60
500
50
400
40
300
30
200
20
100
10
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
9
24
35
52
62
Response (%)
Lauraine, Proc ASCO #829, 2002
Percentage
Days
Treatment-Free Interval and Survival
Summary of Phase III Single Agent Trials:
Resistant Ovarian Cancer
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
NS
resistant
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 trial
All 3rd line
PLD
Patupilone
802
16 vs 16
NS
55 vs 57
NS
RR: 8% vs 18%
(patupilone)
Summary of Phase III Combination Trials: PR
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)
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
R
A
N
D
O
M
I
Z
E
N = 361
Stratified
chemotherapy
PFI (< 3 vs 3-6 mo)
prior anti-angiogenesis
Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.
Non-Platinum Chemotherapy
Treat to progression
Non-Platinum Chemotherapy
+ Bevacizumab 15 mg/kg
Treat to progression
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
AURELIA: Patient Characteristics
Characteristic
CT (n = 182)
BEV + CT (n = 179)
61
62
Serous/adenocarcinoma at diagnosis
152 (84%)
156 (87%)
Histologic grade at diagnosis
1
2/3
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 PS
0
1-2
99 (54%)
80 (44%)
107 (60%)
70 (39%)
Measurable Disease
144 (79%)
143 (80%)
54 (30)
59 (34)
Median age, years
Ascites
Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.
AURELIA
Progression-Free Survival
CT
(n = 182)
Estimated Probability
1.0
Events, n (%)
0.8
166 (91%)
3.4
(2.2-3.7)
Median PFS, months
(95% CI)
HR (unadjusted)
0.6
135 (75%)
6.7
(5.7-7.9)
0.48
(95% CI)
Log-rnak P-value
(2-sided, unadjusted)
0.4
BEV + C T
(n = 179)
(0.38-0.60)
< 0.001
0.2
3.4
0.0
0
6.7
6
12
18
24
Time (months)
Number at risk
182
CT
BEV + CT
179
93
140
37
88
20
49
8
18
Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.
1
4
1
1
0
1
0
30
Subgroup analysis of PFS
Median PFS, months
No. of patients
CT
BEV + CT
HRa
361
3.4
6.7
0.48
<65
228
3.4
6.0
0.49
≥65
133
3.5
7.8
0.47
<3
96
2.1
5.4
0.53
3‒6
257
3.6
7.8
0.46
No (<1)
74
3.7
7.5
0.46
Yes (1‒<5)
126
3.3
7.5
0.50
Yes (≥5)
161
3.3
6.0
0.47
Yes
113
2.5
5.6
0.40
No
248
3.5
7.6
0.48
Paclitaxel
115
3.9
10.4
0.46
PLD
126
3.5
5.4
0.57
Topotecan
120
2.1
5.8
0.32
Subgroup
All patients
Age, years
PFI, monthsb
Measurable
disease, cm
Ascites
Chemotherapy
BEV + CT
better
0.2 0.3
aUnadjusted. bMissing
n=8
0.5
CT
better
1
2
3 4 5
Patients (%)
Summary of best overall response rates
50
45
40
35
30
25
20
15
10
5
0
CT
p<0.001a
30.9
12.6
Responders

aTwo-sided
(RECIST and/or CA-125)
(n=350)
BEV + CT
p<0.001a
p=0.001a
31.8
27.3
11.8
RECIST responders (n=287)
chi-square test with Schouten correction
11.6
CA-125 responders (n=297)
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 2013
Therapy 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
1.0
Survival probability
0.9
no residuals
median OS 45.2 mo
0.8
0.7
0.6
0.5
0.4
residuals > 10 mm
0.3
0.2
residuals 1-10 mm
0.1
0
0
12
24
Months from Randomization
36
48
Secondary Cytoreduction:
Multivariate Analysis Who Benefits?
Tay, Obstet Gynecol 99:1008, 2002
Secondary Cytoreductive Surgery
Goal of surgery: No gross residual disease
DFI
Multiple Sites:
Single Site
Carcinomatosis
No Carcinomatosis
6-12 mos Suggest SC
Offer SC
No SC
Suggest SC
Suggest SC
Offer SC
> 30 mos Suggest SC
Suggest SC
Suggest SC
12-30
mos
DFI = disease-free interval; mos = months; SC = secondary cytoreduction.
Chi DS, et al. Cancer. 2006;106(9):1933-1939.
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
N = 150/408 planned
Secondary
Cytoreduction
R
Chemo
No surgery
Regimens post-randomization
• Carboplatin/paclitaxel
• Carboplatin/gemcitabine
• Carboplatin/PLD
GOG-213
Recurrent Ovarian, PPT and FT Cancer
TFI ≥ 6 mos
Surgical Candidate?
Yes
No
Randomize
Randomize
Surgery
No Surgery
To Chemotherapy
Randomization
PI: Coleman
Carboplatin
Paclitaxel or
Gemcitabine
Carboplatin
Pac or Gem
Bevacizumab
Bevacizumab
SOC I
Shanghai Gynecologic Oncology Group
A randomized trial evaluating cytoreductive surgery
in patients with platinum-sensitive recurrent ovarian cancer
Platinum-sensitive, first relapse
recurrent cancer of the
ovaries, fallopian tubes, or
peritoneum
PFI > 6 mos
No 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
N=420
R
A
N
D
O
M
I
Z
E
Cytoreductive
surgery
Platinum-based
chemotherapy*
No surgery
Primary outcome: OS
Secondary outcome: PFS, QoL, Complications
Available at: http://www.clinicaltrials.gov/ct2/show/NCT01611766 Accessed March 04, 2013.
Outcomes in Recurrent Ovarian Cancer: PS
Trial
ICON 4
(n = 802)
AGO
(n = 366)
Treatment
RR (%)
PFS (mo)
C
54
9
C+P
66
12
C
31
5.8
GC
47
8.6
PLD
?
7.5
C + PLD
–
11.3
GC + PL
57
8.4
GC + BV
79
12.4
Take home messages:
OVA-301
•
(n = 417)
HR
0.76
P < 0.001
0.72
P = 0.003
OS (mo)
24
29
17.3
18
HR
0.82
P = 0.02
0.96
P = 0.73
24.1
0.73
PFS appears to be impacted from combination
therapy 0.83
P=0.017
P = 0.11
PLD + Trab
?
9.2
27.0
• No OS effect to date
CALYPSO
C+P
–survival 9.4
33.0
•
Post
progression
is
dramatically
increasing
0.82
0.99
(n = 976)
OCEANS
(n = 484)
*Data still maturing.
P = 0.005
0.48
P < 0.0001
30.7
35.2*
33.3
P = 0.94
1.03*
P = 0.84
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
Pericyte
Tumor Cell
Tumor
Endothelium
Microenvironment
Trebananib: Phase III Studies
TRINOVA-1 Phase III Trial
Recurrent ovarian,
FT, PP cancer
Weekly paclitaxel + Trebananib
R
Weekly paclitaxel + placebo
N = 900
Primary Objective: PFS
Secondary Objectives: OS, RR (RECIST and CA-125), Safety, pK, QOL
TRINOVA-2 Phase III Trial
Recurrent ovarian,
FT, PP cancer
ClinicalTrials.gov. NCT01204749.
Pegylated Liposomal Doxorubicin (PLD)
+ Trebananib
R
Pegylated Liposomal Doxorubicin (PLD)
+ placebo
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
BRCA +/+
BRCA +/1000x
BRCA -/-
Nature 2005
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 2009
Lancet 2010
3Kaye, ASCO 2011
4TCGA, 2011
5Gehlmon, Lancet 2011
6Konstantinopoulos, JCO 2010
2Audeh
Study 19: Maintenance Olaparib
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
•
•
•
•
Olaparib
400 mg po bid
Randomized 1:1
Treatment until
disease
progression
Placebo
po bid
Ledermann, N Engl J Med 2012
Study 19: Secondary Maintenance
Ledermann, N Engl J Med 2012
PARP Inhibitors in Clinical Trials
Agent
Administration
Phase
Comments
Oral
I, II, III
Single Agent and Combination, BRCA and non-BRCA, Platinumsensitive and resistant, Primary and Recurrent
AZD-2461
Oral
I
FIH, Solid Tumors
Veliparib
Oral
I, II
Single Agent and Combination, BRCA and non-BRCA, Platinumsensitive and resistant, Primary and Recurrent
Olaparib
(AZD-2281)
ABT-888
(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
Oral
I, II
Single Agent and Combination, BRCA and non-BRCA, Platinumsensitive and resistant
Oral
I, II
BRCA mutation carriers, Platinum Sensitive
AG014699
IV
II
Single Agent, BRCA, Platinum-sensitive and resistant
Iniparib
IV
II, III
Combination (Gem/Cis or Carbo), Platinum-sensitive and resistant
(MK4827)
Rucaparib
(CO-338)
(BSI-201)
Available at: http://www.clinicaltrials.gov.
2013:Phase III Studies in Ovarian Cancer*
Front-line added to chemotherapy then as Maintenance
1.
2.
3.
Bevacizumab (GOG 262 imaging biomarker study)
BIBF 1120 (OVAR 12) - closed
Trebananib (GOG 3001/TRINOVA-3)
Maintenance alone
1.
2.
3.
*Phase II studies of PARP inhibitors, and
Cabozantinib may lead to FDA approval
PLD = Pegylated Liposomal Doxorubicin
Polyglutamate paclitaxel (GOG 212)
Pazopanib (OVAR 16) - closed
CVAC (MUC-1)
Platinum-resistant recurrent ovarian cancer
1.
2.
3.
Karenitecin
Trebananib (with Paclitaxel/TRINOVA-1 [closed] or PLD/TRINOVA-2)
Vintafolide (with PLD)
Platinum-sensitive recurrent ovarian cancer
1.
2.
3.
4.
Bevacizumab (with chemotherapy - GOG 213)
Trebananib (with PLD or Paclitaxel)
Trabectedin with PLD (in 6 – 12 month group/INOVATYON)
Water soluble formulation of Paclitaxel
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!

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