ovarian cancer: standards of care and new opportunities
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Ovarian Cancer: Standards of Care and New Opportunities
Robert L. Coleman, M.D.Professor & Vice Chair, Clinical Research
Department of Gynecologic OncologyM.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
Symptoms
Diagnosis
Chemotherapy #1
Staging
Evaluation? SLL
Progression
Chemo #2 Chemo #3+
SupportiveCare
Death
SecondarySurgery
Maintenance
Duration
Progression-Free Survival(12-28 mos)
Post Progression Survival(12-38 mos)
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”
0%
25%
50%
75%
100%
0 12 24 36 48 60 72 84 96 108 120 132 144
% P
rogr
essio
n-fr
ee S
urvi
val
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
0%
25%
50%
75%
100%
0 12 24 36 48 60 72 84 96 108 120 132 144
% O
vera
ll Su
rviv
al
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
(years)0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment320 360 168 60 39 26 17 7 2320 357 177 60 36 20 13 3 1
Upfront debulking surgeryNeoadjuvant chemotherapy
Progression-free survival
PDS: 12 mosNACT: 12 mosHR: 0.99 (0.87-1.13)
(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 2251 357 191 56 11 1
Upfront debulking surgeryNeoadjuvant chemotherapy
Overall survival
PDS: 29 monthsIDS: 30 monthsHR: 0.98 (0.85, 1.14)
PFS
OS
Neoadjuvant Chemotherapy in Ovarian Cancer
9/21/10 1/20/11
Primary Approach: What’s Best?
N Engl J Med (2010) 363:943
(years)0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment320 360 168 60 39 26 17 7 2320 357 177 60 36 20 13 3 1
Upfront debulking surgeryNeoadjuvant chemotherapy
Progression-free survival
PDS: 12 mosNACT: 12 mosHR: 0.99 (0.87-1.13)
(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 2251 357 191 56 11 1
Upfront debulking surgeryNeoadjuvant chemotherapy
Overall survival
PDS: 29 monthsIDS: 30 monthsHR: 0.98 (0.85, 1.14)
PFS
OS
CHORUSChemotherapy Or Upfront Surgery
RCOG
ICON-8
OV.21Neoadjuvant Chemotherapy
X 3-4 courses
Randomized
IV-Arm IP-ArmPac/Carbo + Pac/Carbo (IP) +
Pac (d8) Pac (IP, d8)
Pre-randomization Strata for NACT or PDS
Randomized
StandardPac/Carbo
Exp ADD-Pac/Carbo
Exp BDD - Pac/DD-Carbo
Principle Approach: Iº Therapy
Chemotherapy
GOG-111
Cisplatin 75 mg/m2
Cytoxan 750mg/m2 Cisplatin 75 mg/m2
Paclitaxel 135 mg/m2
GOG-158
Cisplatin 75 mg/m2
Paclitaxel 135 mg/m2 Carboplatin AUC 7.5Paclitaxel 175 mg/m2
GOG-172
Cisplatin 75 mg/m2
Paclitaxel 135 mg/m2
Day1: IV Paclitaxel 135 mg/m2 Day 2: IP Cisplatin 100mg/m2
Day 8: IP Paclitaxel 60 mg/m2
McGuire New Engl J Med (1996) 334:1Ozols, J Clin Oncol (2003) 21:3194Armstrong New Engl J Med (2006) 354:34
OS
Cytoxan/Cisplatin
- - - Paclitaxel/Cisplatin
PFS
International Phase III Experience
CP CPG CPPLD CTCP CGCP 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 ≠ BetterDifferent ≠ Better
Moving The Bar: Primary Therapy
Dose-dense therapy
IP Chemotherapy
Biologics: Anti-angiogenesis, PARPi, angiopoeitin inhibitors
Establishing a Front-Line Adjuvant Standard
Dose Dense: Weekly Therapy
Ovarian Epithelial, PP, FTFIGO Stage II-IV
Paclitaxel 180mg/m2
Carboplatin AUC 6.0 q 21 days (6-9 cycles)
Dose density: 60 mg/m2/wk
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%)
Stratification; Residual disease: <1cm, > 1cmFIGO Stage : II vs. III vs. IVHistology : clear cell/mucinous vs serous/others
R
Katsumata, Lancet 2009
JGOG 3016: Long-Term Follow-Up
Katsumata N, ASCO Abstract 5003, 2012
iPocc JGOG Trial: SchemaEpithelial Ovarian Cancer
Stages II-IVIncluding Bulky Tumor
Paclitaxel 80 mg/m2 IV Day 1,8,15Carboplatin AUC 6 IV
Q21, 6-8 Cycles
Paclitaxel 80 mg/m2 IV Day 1,8,15Carboplatin AUC 6 IP
Q21, 6-8 Cycles
Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, QOLAccrual Goal: 746 pts / 511 events
Dose dense−TCipDose dense−TCiv
RANDOMIZATION
GOG-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
RANDOMI
Z E
1:1:1
15 months
Paclitaxel 175 mg/m2
Carboplatin AUC 6
Placebo
IArm
Cytotoxic (6 cycles)
Maintenance(16 cycles)
(CP + PLA → PLA)
Carboplatin AUC 6
Paclitaxel 175 mg/m2
PlaceboBevacizumab15 mg/kg
II(CP + BEV→ PLA)
Bevacizumab 15 mg/kg
Carboplatin AUC 6
Paclitaxel 175 mg/m2 III(CP + BEV
BEV)
Burger et al. N Engl J Med 2011;365:2473-83
Establishing a Front-Line Adjuvant Standard
Stratification 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/m2
Carboplatin AUC 5/6
Carboplatin AUC 5/6
Paclitaxel 175 mg/m2
18 cycles
Rn=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
Anti-VEGF Targeting: FrontlinePFS
Perren, NEJM (2011) 365:2484Burger, NEJM (2011) 365:2473
HR: 0.7310.4 vs 13.9 mosMedian D: 3.5 mos
HR: 0.8717.4vs 19.8 mosMedian D: 2.4 mos
GOG 218 ICON7
Anti-VEGF Targeting: FrontlineOverall Survival
Perren, NEJM (2011) 365:2484Burger, NEJM (2011) 365:2473
GOG 218 ICON7
00.10.20.30.40.50.60.70.80.91.0
0 6 12 18 24 30 36
02468
101214161820
0 6 12 18 24 30 36
-15
-10
-5
0
5
10
15
20
25
30
0 6 12 18 24 30 36
0.00.10.20.30.40.50.60.70.80.91.0
0 6 12 18 24 30 36
14 vs 173 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
GOG Ovarian Strategy: 262
262Suboptimal
(> 1 cm Residual)Neoadjuvant allowed
CT Perfusion Scan
IV Paclitaxel 80 mg/m2 weeklyIV Carboplatin AUC 6 q 3 wkIV Bevacizumab 15 mg/kg (optional)
IV Paclitaxel 175 mg/m2
IV Carboplatin AUC 6IV Bevacizumab 15 mg/kg (optional)
Bevacizumab q 3 wk(If chosen)
Maintenance to Progression
N: 702/625 (OPEN only for ACRIN ComponentPrimary endpoint: PFS
Phase III GOG 252 Schema
IV Paclitaxel 80 mg/m2 days 1, 8, 15IV Carboplatin AUC 6 day 1
Bevacizumab 15 mg/kg q3w†
IV Paclitaxel 80 mg/m2 days 1, 8, 15IP Carboplatin AUC 6 day 1
Bevacizumab 15 mg/kg q3w†
IV Paclitaxel 135 mg/m2 day 1 IP Cisplatin 75 mg/m2 day 2IP Paclitaxel 60 mg/m2 day 8Bevacizumab 15 mg/kg q3w†
RAN
DOM
IZAT
ION
N =
125
0
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; †Begin cycle 2.
Bevacizumab 15 mg/kg q3w
Bevacizumab 15 mg/kg q3w
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!
Symptoms
Diagnosis
Chemotherapy #1
Staging
Evaluation? SLL
Progression
Chemo #2 Chemo #3+
SupportiveCare
Death
SecondarySurgery
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
Maintenance Therapy ScorecardMaintenance Beneficial?
Strategy No YesProlonged 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 ✓
Maintenance 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 Treatment
PaclitaxelCarboplatin
GOG-212
N = 1100 patientsSurvival primary endpoints
QOL endpoints 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
Symptoms
Diagnosis
Chemotherapy #1
Staging
Evaluation? SLL
Progression
Chemo #2 Chemo #3+
SupportiveCare
Death
Maintenance
SecondarySurgery
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)
TreatmentCompletion 6 mos
Platinum Resistant/Refractory Platinum Sensitive
Non-Platinum Treatment Platinum Retreatment
Treatment-Free Interval and Survival
Lauraine, Proc ASCO #829, 2002
0-3 Prog 0-3 Non PD 3-12 mos 12-18 mos 18+ mosPFS (days) 90 176 174 275 339OS (days) 217 375 375 657 957Response (%) 9 24 35 52 62
Day
s1000
900
800
700
600
500
400
300
200
100
Percentage
100
90
80
70
60
50
40
30
20
10
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 NSresistant
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 trialAll 3rd 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
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)
Summary of Phase III Combination Trials: PR
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
Non-Platinum Chemotherapy
RANDOMIZE Non-Platinum Chemotherapy
+ Bevacizumab 15 mg/kg
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
Stratifiedchemotherapy
PFI (< 3 vs 3-6 mo)prior anti-angiogenesis
Treat to progression
Treat to progressionN = 361
Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.
AURELIA: Patient CharacteristicsCharacteristic CT (n = 182) BEV + CT (n = 179)
Median age, years 61 62
Serous/adenocarcinoma at diagnosis 152 (84%) 156 (87%)Histologic grade at diagnosis12/3
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 PS01-2
99 (54%)80 (44%)
107 (60%)70 (39%)
Measurable Disease 144 (79%) 143 (80%)Ascites 54 (30) 59 (34)
Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.
AURELIA Progression-Free Survival
1.0
0.8
0.6
0.4
0.2
0.06 12
Time (months)
Est
imat
ed P
roba
bilit
y
18 3024
182 93 37 8 1 1 0 020179 140 88 18 4 1 149
0
BEV + CTCTNumber at risk
Events, n (%)Median PFS, months(95% CI)
166 (91%)3.4
(2.2-3.7)
135 (75%)
CT(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.
Subgroup analysis of PFS
aUnadjusted. bMissing n=8
Subgroup No. of patients
Median PFS, months
HRaBEV + CT
betterCT
better CT BEV + CT
All patients 361 3.4 6.7 0.48
Age, years <65 ≥65
228133
3.43.5
6.07.8
0.490.47
PFI, monthsb <33‒6
96257
2.13.6
5.47.8
0.530.46
Measurable disease, cm
No (<1)Yes (1‒<5)
Yes (≥5)
74126161
3.73.33.3
7.57.56.0
0.460.500.47
Ascites YesNo
113248
2.53.5
5.67.6
0.400.48
Chemotherapy PaclitaxelPLD
Topotecan
115126120
3.93.52.1
10.45.45.8
0.460.570.32
0.2 0.3 0.5 1 2 3 4 5
Summary of best overall response rates
Responders (RECIST and/or CA-125) (n=350)
RECIST responders (n=287) CA-125 responders (n=297)05
101520253035404550
12.6 11.8 11.6
30.927.3
31.8
CT BEV + CT
aTwo-sided chi-square test with Schouten correction
p=0.001ap<0.001a p<0.001a
Patie
nts (
%)
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 2013Therapy 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
no residualsmedian OS 45.2 mo
residuals > 10 mm
residuals 1-10 mm
Surv
ival
pro
babi
lity
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
Secondary Cytoreduction: Multivariate Analysis Who Benefits?
Tay, Obstet Gynecol 99:1008, 2002
Secondary 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 > 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
Secondary Cytoreduction
Chemo
Regimens post-randomization• Carboplatin/paclitaxel• Carboplatin/gemcitabine• Carboplatin/PLD
No surgery
R
N = 150/408 planned
PI: Coleman
Recurrent Ovarian, PPT and FT CancerTFI ≥ 6 mos
Yes No
Randomize
Surgery No Surgery CarboplatinPaclitaxel or Gemcitabine
CarboplatinPac or Gem
Bevacizumab
Bevacizumab
GOG-213
To Chemotherapy Randomization
Randomize
Surgical Candidate?
A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer
RANDOMIZE
Cytoreductivesurgery
Platinum-basedchemotherapy*
Primary outcome: OSSecondary 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=420Platinum-sensitive, first relapserecurrent cancer of the
ovaries, fallopian tubes, orperitoneum
PFI > 6 mosNo 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
Outcomes 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 = 0.02C + P 66 12 29
AGO(n = 366) C 31 5.8 0.72
P = 0.003
17.3 0.96P = 0.73GC 47 8.6 18
OVA-301(n = 417)
PLD ? 7.5 0.73P=0.017
24.1 0.83P = 0.11PLD + Trab ? 9.2 27.0
CALYPSO (n = 976) C + P – 9.4 0.82
P = 0.005
33.0 0.99P = 0.94C + PLD – 11.3 30.7
OCEANS (n = 484)
GC + PL 57 8.4 0.48 P < 0.0001
35.2* 1.03*
P = 0.84GC + 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
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
PericyteTumor
Endothelium
Tumor Cell
Microenvironment
Trebananib: Phase III Studies
Weekly paclitaxel + Trebananib
ClinicalTrials.gov. NCT01204749.
Weekly paclitaxel + placebo
RRecurrent ovarian,FT, PP cancer
R
Pegylated Liposomal Doxorubicin (PLD) + Trebananib
Pegylated Liposomal Doxorubicin (PLD) + placebo
N = 900Primary Objective: PFSSecondary 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
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
Nature 2005
BRCA +/+
BRCA -/-
BRCA +/-
1000x
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 20092Audeh Lancet 20103Kaye, ASCO 20114TCGA, 20115Gehlmon, Lancet 20116Konstantinopoulos, JCO 2010
Study 19: Maintenance Olaparib
Olaparib 400 mg po bid
Randomized 1:1
Placebopo 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
Study 19: Secondary Maintenance
Ledermann, N Engl J Med 2012
PARP Inhibitors in Clinical TrialsAgent 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
VeliparibABT-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.
2013:Phase III Studies in Ovarian Cancer*Front-line added to chemotherapy then as Maintenance
1. Bevacizumab (GOG 262 imaging biomarker study)2. BIBF 1120 (OVAR 12) - closed3. Trebananib (GOG 3001/TRINOVA-3)
Maintenance alone4. Polyglutamate paclitaxel (GOG 212)5. Pazopanib (OVAR 16) - closed6. CVAC (MUC-1)
Platinum-resistant recurrent ovarian cancer 7. Karenitecin8. Trebananib (with Paclitaxel/TRINOVA-1 [closed] or PLD/TRINOVA-2)9. Vintafolide (with PLD)
Platinum-sensitive recurrent ovarian cancer10. Bevacizumab (with chemotherapy - GOG 213)11. Trebananib (with PLD or Paclitaxel)12. Trabectedin with PLD (in 6 – 12 month group/INOVATYON)13. Water soluble formulation of Paclitaxel
*Phase II studies of PARP inhibitors, and Cabozantinib may lead to FDA approval
PLD = Pegylated Liposomal Doxorubicin
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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