Robert L Coleman MD Professor amp Vice Chair Clinical Research Department of Gynecologic Oncology MD Anderson Cancer Center Ovarian Cancer Liner Notes Globally 7 th most incident and lethal cancer ID: 816464
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Slide1
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
Slide2Ovarian Cancer: Liner NotesGlobally 7
th most incident and lethal cancerNew cases: 225,000 annuallyDeaths: 140,000 annuallyBurden of disease is greater in developed countries
The
incidence increases with
age Almost 75% of cases present with advanced stage III / IV diseaseRisk of relapse of advanced stage disease is as high as 70%
CA Cancer, 2013
Slide3Ovarian Cancer: Natural History
Symptoms
Diagnosis
Chemotherapy #1
Staging
Evaluation
? SLL
Progression
Chemo #2
Chemo #3+
Supportive
Care
Death
Secondary
Surgery
Maintenance
Duration
Progression-Free Survival
(12-28 mos)
Post Progression Survival
(12-38 mos)
Slide4Slide5Surgical Management of Primary Ovarian Cancer
Theoretical: Reduced the volume of hypoxic, poorly perfused cellsHost immunocompetence is improved with lower tumor burdenRecruitment of residual cells into G1 potentiating the effects of cytotoxic therapyRemoval of chemoresistant clonesPractical:
“
Biology
vs Brawn”
Slide6% Progression-
free
Survival
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
% Overall Survival
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
PDS:
12
mos
NACT:
12
mos
HR
: 0.99
(0.87-1.13)
PDS: 29 months
IDS: 30 months
HR: 0.98 (0.85, 1.14)
PFS
OS
Slide8Neoadjuvant Chemotherapy in Ovarian Cancer
9/21
/10
1/20
/11
Slide9Primary Approach: What’s Best?
N Engl J Med (2010) 363:943
PDS:
12
mos
NACT:
12
mos
HR
: 0.99
(0.87-1.13)
PDS: 29 months
IDS: 30 months
HR: 0.98 (0.85, 1.14)
PFS
OS
Slide10CHORUS
Chemotherapy Or Upfront Surgery
RCOG
ICON-8
OV.21
Neoadjuvant
Chemotherapy
X 3-4 courses
Randomized
IV-Arm IP-Arm
Pac/
Carbo
+ Pac/
Carbo
(IP) +
Pac (d8) Pac (IP, d8)
Pre-randomization
Strata for
NACT
or PDS
Randomized
Standard
Pac/
Carbo
Exp A
DD-Pac/
Carbo
Exp B
DD - Pac/DD-
Carbo
Slide11Principle Approach: Iº Therapy
Chemotherapy
McGuire New
Engl
J Med (1996) 334:1
Ozols
, J
Clin
Oncol
(2003) 21:3194
Armstrong New
Engl
J Med (2006) 354:34
OS
Cytoxan
/Cisplatin
- - - Paclitaxel/Cisplatin
PFS
Slide12International Phase III Experience
CP
CPG
CP
PLD
CT
C
P
CG
C
P
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
≠ Better
Different ≠ Better
Slide13Moving The Bar: Primary TherapyDose-dense therapy
IP ChemotherapyBiologics: Anti-angiogenesis, PARPi, angiopoeitin inhibitors
Establishing a Front-Line Adjuvant Standard
Slide14Dose Dense: Weekly Therapy
Ovarian Epithelial, PP, FTFIGO Stage II-IV
Paclitaxel 180mg/m
2
Carboplatin AUC 6.0
q
21 days (6-9 cycles
)
Dose density: 60 mg/m
2
/wk
Paclitaxel 80mg/m
2
, 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, > 1cm
FIGO Stage: II vs. III vs. IV
Histology: clear cell/mucinous vs serous/others
R
Katsumata, Lancet 2009
Slide15JGOG 3016: Long-Term Follow-Up
Katsumata N, ASCO Abstract 5003, 2012
Slide16iPocc JGOG Trial: Schema
Epithelial Ovarian CancerStages II-IV
Including Bulky Tumor
Paclitaxel 80 mg/m
2
IV
Day 1,8,15
Carboplatin AUC 6 IV
Q21, 6-8 Cycles
Paclitaxel 80 mg/m
2
IV
Day 1,8,15
Carboplatin AUC 6 IP
Q21, 6-8 Cycles
Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, QOL
Accrual Goal: 746 pts / 511 events
Dose dense
−TCip
Dose dense
−TCivRANDOMIZATION
Slide17GOG-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
RANDOM
I
Z E
1:1:1
15 months
Paclitaxel 175 mg/m
2
Carboplatin AUC 6
Placebo
I
Arm
Cytotoxic (6 cycles)
Maintenance
(16 cycles)
(CP + PLA → PLA)
Carboplatin AUC 6
Paclitaxel 175 mg/m
2
Placebo
Bevacizumab
15 mg/kg
II
(CP + BEV
→ PLA)
Bevacizumab 15 mg/kg
Carboplatin AUC 6
Paclitaxel 175 mg/m
2
III
(CP + BEV
BEV
)
Burger et al. N
Engl
J Med 2011;365:2473-83
Establishing a Front-Line Adjuvant Standard
Slide18Stratification 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/m
2
Carboplatin AUC 5/6
Carboplatin AUC 5/6
Paclitaxel 175 mg/m
2
18 cycles
R
n=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
Slide19Anti-VEGF Targeting: Frontline
PFS
Perren
, NEJM (2011) 365:2484
Burger, NEJM (2011) 365:2473
HR: 0.73
10.4
vs
13.9
mos
Median
D
: 3.5
mos
HR: 0.87
17.4vs 19.8
mos
Median
D
: 2.4
mos
GOG 218
ICON7
Slide20Anti-VEGF Targeting: Frontline
Overall
Survival
Perren
, NEJM (2011) 365:2484
Burger, NEJM (2011) 365:2473
GOG 218
ICON7
Slide210
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0
6
12
18
24
30
36
0
2
4
6
8
10
12
14
16
18
20
0
6
12
18
24
30
36
-15
-10
-5
0
5
10
15
20
25
30
0
6
12
18
24
30
36
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0
6
12
18
24
30
36
14
vs
17
3 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
Slide22GOG Ovarian Strategy: 262
262
Suboptimal
(> 1 cm Residual)
Neoadjuvant allowed
CT Perfusion Scan
IV Paclitaxel 80 mg/m
2
weekly
IV Carboplatin AUC 6
q
3 wk
IV Bevacizumab 15 mg/kg (optional)
IV Paclitaxel 175 mg/m
2
IV Carboplatin AUC 6
IV Bevacizumab 15 mg/kg (optional)
Bevacizumab
q
3 wk
(If chosen)
Maintenance to Progression
N: 702/625 (OPEN only for ACRIN Component
Primary endpoint: PFS
Slide23Phase III GOG 252 Schema
IV Paclitaxel 80 mg/m
2
days
1, 8,
15
IV Carboplatin AUC 6 day 1
Bevacizumab 15 mg/kg q3w
†
IV Paclitaxel 80 mg/m
2
days 1, 8, 15
IP Carboplatin AUC 6 day 1
Bevacizumab 15 mg/kg q3w
†
IV Paclitaxel 135 mg/m
2
day 1
IP Cisplatin 75 mg/m
2 day 2
IP Paclitaxel 60 mg/m2 day 8
Bevacizumab 15 mg/kg q3w
†
RANDOMIZATIONN = 1250
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; †B
egin cycle 2.
Bevacizumab 15 mg/kg q3w
Bevacizumab 15 mg/kg q3w
Slide24Other Pursuits in Front-Line TherapyVEGF TKI’sNintedanib (BIBF1120)PARPi
Veliparib (OVM1102)Angiopoeitin inhibitorsTRINOVA-3: Trebananib (AMG-386)
Slide25Bottom Line…Determine good candidates for surgeryPotential for better selection tools, e.g. LaparoscopyOptimal radical resection
Goal: R0Adjuvant therapyIP and dose dense are my favorite optionsGood place for clinical trial
Slide26Maintenance: The
Stakes are High!
Symptoms
Diagnosis
Chemotherapy #1
Staging
Evaluation
? SLL
Progression
Chemo #2
Chemo #3+
Supportive
Care
Death
Secondary
Surgery
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
Slide27Maintenance Therapy Scorecard
Maintenance Beneficial?
Strategy
No
Yes
Prolonged
Initial
T
herapy
✓
Short
Duration / Non-Cross
R
esistant
C
hemotherapy
✓
High-Dose
C
hemotherapy
✓
Intraperitoneal
✓
Interferon-
✓
Anti-CA-125 Ab
✓
Biologic Agent (
MMPI, bevacizumab*)
✓
✓*
Paclitaxel (6 months)
✓
Paclitaxel (1 year)
✓#
Erlotinib
✓
Slide28Maintenance 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
TreatmentPaclitaxel
CarboplatinGOG-212
N = 1100 patientsSurvival primary endpointsQOL endpoints
28
Slide29Bottom Line…Experimental but evidence of PFS impact has been demonstratedI always have the conversation (longest of any counseling session) but it is only infrequently taken by the patient
Slide30Recurrent Therapy
: Ovarian Cancer
Symptoms
Diagnosis
Chemotherapy #1
Staging
Evaluation
? SLL
Progression
Chemo #2
Chemo #3+
Supportive
Care
Death
Maintenance
Secondary
Surgery
What we know
(Recurrence)
:
Nearly all patients will succumb to progression
Options are plentiful
Nothing a “homerun”
Slide31Treatment Free Interval: Traditional Model
Time
from last platinum exposure (TFI)
Treatment
Completion
6
mos
Platinum Resistant/Refractory
Platinum Sensitive
Non-Platinum Treatment
Platinum Retreatment
Slide32Treatment-Free Interval and Survival
Lauraine, Proc ASCO #829, 2002
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
Response (%)
9
24
35
52
62
Days
1000
900
800
700
600
500
400
300
200
100
Percentage
100
90
80
70
60
50
40
30
20
10
Slide33Control
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
5
6
vs
46
NS
All pts taxane
-naïve
Topotecan
Treosulfan
357
22
vs
12
0.001
56
vs
48
0.02
2
nd
– 3
rd
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 3
rd
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
Slide34Control
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%
Summary of Phase III Combination Trials: PR
Take home messages:
Many choices
No best cytotoxic agent
Combinations with non-targeted
cytotoxics
add morbidity only
Slide35Control
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
Slide36AURELIA: 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
C
hemotherapy
R
A
N
D
O
M
I
Z
E
Non-Platinum Chemotherapy + Bevacizumab 15
mg/kg
Chemotherapy Options
P
aclitaxel
80 mg/m
2
d 1,8,15, 22
q28
T
opotecan
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
Stratified
chemotherapy
PFI (< 3 vs 3-6 mo)prior anti-angiogenesis
Treat to progression
Treat to
progression
N
=
361
Pujade-Lauraine
E, et al.
J
Clin
Oncol
.
2012; Suppl. Abstract LBA5002.
Slide37AURELIA: Patient Characteristics
CharacteristicCT (n = 182) BEV + CT (n = 179)
Median
age, years
61
62
Serous/
adenocarcinoma at diagnosis
152 (84%)
156 (87%)
Histologic
g
rade at
diagnosis12/3
9 (5%)153 (84%)
10 (6%)147 (82%)Prior anti-angiogenic therapy
14 (8%)12 (7%)
2 prior chemotherapy regimens78 (43%)
72 (40%)PFI < 3 months
46 (25%)50 (28%)
ECOG PS01-299 (54%)80
(44%)107 (60%)70 (39%)
Measurable Disease144 (79%)
143 (80%)Ascites
54 (30)59 (34)
Pujade-Lauraine
E, et al. J Clin
Oncol
. 2012; Suppl. Abstract LBA5002.
Slide38AURELIA Progression-Free Survival
1.0
0.8
0.6
0.4
0.2
0.0
6
12
T
ime (months)
Estimated Probability
18
30
24
182
93
37
8
1
1
0
0
20
179
140
88
18
4
1
1
49
0
BEV + CT
C
T
Number at risk
Events, n (%)
Median PFS, months
(95% CI)
166 (91%)
3.4
(2.2-3.7)
135 (75%)
C
T
(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.
Slide39Subgroup analysis of PFS
aUnadjusted. bMissing n=8
Subgroup
No. of patients
Median PFS, months
HR
a
BEV + CT
better
CT
better
CT
BEV + CT
All patients
361
3.4
6.7
0.48
Age, years
<65
≥65
228
133
3.4
3.5
6.0
7.8
0.49
0.47
PFI,
months
b
<3
3‒6
96
257
2.1
3.6
5.4
7.8
0.53
0.46
Measurable disease, cm
No (<1)
Yes (1‒<5)
Yes (≥5)
74
126
161
3.7
3.3
3.3
7.5
7.5
6.0
0.46
0.50
0.47
Ascites
Yes
No
113
248
2.5
3.5
5.6
7.6
0.40
0.48
Chemotherapy
Paclitaxel
PLD
Topotecan
115
126
120
3.9
3.5
2.1
10.4
5.4
5.8
0.46
0.57
0.32
0.2 0.3 0.5 1 2 3 4 5
Slide40Summary of best overall response rates
aTwo-sided chi-square test with Schouten correction
p=0.001
a
p<0.001
a
p<0.001
a
Patients (%)
Slide41AURELIA: ConclusionsNo 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
CAVEATSNot placebo-controlled
Pretreatment characteristics: 80% measurable, 30% ascites, 8% prior AA therapyEach arm is equivalent to RP2
Slide42Bottom Line…For platinum-resistant disease, I like:Weekly paclitaxel ± bevacizumabPLD
Gemcitabine + cisplatin (q 2 wk infusion)Try HARD to get onto clinical trialLots of options with interesting new agents
Slide43NCCN 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
Slide44DESKTOP-I: Surgical Endpoint of Surgery at Relapse
no residualsmedian OS 45.2 mo
residuals > 10 mm
residuals 1-10 mm
Survival probability
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
Slide45Secondary Cytoreduction: Multivariate Analysis Who Benefits?
Tay
,
Obstet
Gynecol
99:1008, 2002
Slide46Secondary 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
>
6No
prior
recurrence
chemotherapy
Complete
resection
seems feasible and positive
AGO score:PS
ECOG 0No
ascites > 500 mlPrior 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
Slide48PI: Coleman
Recurrent Ovarian, PPT and FT Cancer
TFI ≥ 6
mos
Yes
No
Randomize
Surgery
No Surgery
Carboplatin
Paclitaxel or
Gemcitabine
Carboplatin
Pac or Gem
Bevacizumab
Bevacizumab
GOG-213
To Chemotherapy
Randomization
Randomize
Surgical Candidate?
Slide49A randomized trial evaluating cytoreductive surgery
in patients with platinum-sensitive recurrent ovarian cancer
R
A
N
D
OM
I
Z
E
Cytoreductive
surgery
Platinum-based
chemotherapy*
Primary outcome: OS
Secondary 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=420
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
Slide50Outcomes 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
= 0.02
C + P
66
12
29
AGO
(n = 366)
C
31
5.8
0.72
P
= 0.003
17.3
0.96
P
= 0.73
GC
47
8.6
18
OVA-301
(n = 417)
PLD
?
7.5
0.73
P
=0.017
24.1
0.83
P
= 0.11
PLD +
Trab
?
9.2
27.0
CALYPSO
(n = 976)
C + P
–
9.4
0.82
P
= 0.005
33.0
0.99
P
= 0.94
C + PLD
–
11.3
30.7
OCEANS
(
n = 484)
GC + PL
57
8.4
0.48
P
< 0.0001
35.2
*
1.03
*
P
= 0.84
GC + 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
Slide51Bottom 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 situationPlatinum-based doubletsPLD, Gemcitabine and Paclitaxel with carboplatinIf I give gemcitabine doublet I give with bevacizumabLots of new trials coming online here as well
Slide52Ovarian Cancer: Novel Targets
Matei, Expert Opin Investig
Drugs (2007) 16:1227
Slide53Developmental Therapeutics: Targets
Pericyte
Tumor Endothelium
Tumor
Cell
Microenvironment
Slide54Trebananib: Phase III Studies
Weekly paclitaxel +
Trebananib
ClinicalTrials.gov. NCT01204749.
Weekly paclitaxel + placebo
R
Recurrent
ovarian,
FT, PP cancer
R
Pegylated Liposomal Doxorubicin (PLD) +
Trebananib
Pegylated Liposomal Doxorubicin (PLD) + placebo
N = 900
Primary Objective: PFS
Secondary 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
Slide55EC145 Phase III Randomized Study Design in Patients with Platinum Resistant Ovarian Cancer
Blinded Randomized study comparing EC145 + PLD vs. PLD alonePlatinum Resistant patients~600 Patients randomized 2:1Study objectives:Compare PFS between armsIndependent radiology reviewOS in EC20 ++ patients
Slide56PARP Inhibitors in the Clinic
Nature 2005
BRCA
+/+
BRCA
-/-
BRCA
+/-
1000x
Slide57Olaparib Development: Lessons Learned
1Phase I MTD 400 mg BIDExpansion Phase (N=39 BRCA+) = responsesPlatinum-sensitive > resistantPhase II
(BRCA+)
Dose effect (100 mg BID
vs 400 mg BID)2PARPi is best measured by PK (AUC
ss)2
Is as active as PLD (RP2)
3
Phase II
(BRCA-
wt
)
HRD exists as somatic event (30%)4RR seen in BRCA-
wt, high grade serous5Genomic signature may identify these patients6
1Fong, NEJM 20092Audeh Lancet 2010
3Kaye, ASCO 20114TCGA, 2011
5Gehlmon, Lancet 20116
Konstantinopoulos, JCO 2010
Slide58Study 19: Maintenance Olaparib
Olaparib
400 mg po bid
Randomized 1:1
Placebo
po 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
Slide59Study 19: Secondary Maintenance
Ledermann, N Engl
J Med
2012
Slide60PARP Inhibitors in Clinical Trials
Agent
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
Veliparib
ABT-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.
Slide612013:Phase III Studies in Ovarian Cancer*
Front-line added to chemotherapy then as MaintenanceBevacizumab (GOG 262 imaging biomarker study)BIBF 1120 (OVAR 12) - closed
Trebananib (GOG 3001/TRINOVA-3)
Maintenance
alone
Polyglutamate paclitaxel (GOG 212)Pazopanib (OVAR 16) - closed
CVAC (MUC-1)
Platinum
-resistant
recurrent ovarian cancer
Karenitecin
Trebananib (
with Paclitaxel/TRINOVA-1 [closed] or PLD/TRINOVA-2)
Vintafolide (with PLD)Platinum-sensitive recurrent ovarian cancer
Bevacizumab (with chemotherapy - GOG 213)Trebananib (
with PLD or Paclitaxel)Trabectedin with PLD (in 6 – 12 month group/INOVATYON)
Water soluble formulation of Paclitaxel
*Phase II studies of PARP inhibitors,
and
Cabozantinib
may lead to FDA approvalPLD =
Pegylated Liposomal Doxorubicin
Slide62Take Home MessagesOvarian cancer is a heterogeneous disease
Molecular sub-classification can describe dependency on different driving/survival mechanisms in otherwise morphologically similar tumorsConsistent patterns of chromosomal change suggests interdependency within individual tumorsTarget discovery has led to a flood of clinical trial developmentMost promising: angiogenesis, PI3K, HRD, EMTLagging are strategic solutions for induced and adaptive responses to treatment and study designs
Need for new composite endpoints (FDA discussions underway)
Slide63Thanks!