transforming treatment in ovarian cancer
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Your Input Is Very Important! Your Input Is Very Important!
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Chair’s Practice Patterns Research– Research data identifying common practices
– Understanding knowledge gaps and training needs
DISCLAIMERDISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this
activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this
activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USEDISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. University of California, Irvine School of Medicine (UCI-SOM) and Institute for Medical Education & Research (IMER), do not recommend the
use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of University of California, Irvine School of Medicine (UCI-
SOM) and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Disclosure of Conflicts of InterestDisclosure of Conflicts of InterestRobert F. Ozols, MDRobert F. Ozols, MD
Reported a financial interest/relationship or affiliation in the form of: Consultant, AstraZeneca Pharmaceuticals LP, Johnson & Johnson Pharmaceutical Research & Development, LLC.
Learning ObjectivesLearning ObjectivesUpon completion of this activity, participants Upon completion of this activity, participants
should be better able to:should be better able to: Outline evidence-based clinical decisions incorporating currently
approved standard chemotherapeutic and biologic treatments for ovarian cancer
Describe emerging clinical trial information that may facilitate individual treatment planning for ovarian cancer
Explain the rationale for and implications of the use of novel therapies in ovarian cancer
Discuss effective designs of treatment plans based upon individualized patient characteristics and other relevant clinical factors
Identify ways to counsel patients on the availability of clinical trial participation when warranted
Activity AgendaActivity Agenda Activity Overview (5 mins) Current Treatments in Ovarian Cancer (25 mins)
– Case study 1: Integrating personalized approaches into treatment planning and management for first-line therapy
• Updates on currently approved therapeutics
Emerging Treatments in Ovarian Cancer (25 mins)– Case study 2: Optimally managing recurrent ovarian cancer in relation
to platinum sensitivity/resistant disease• Novel therapies – Rationale for targets, relevant data, and impact on
therapeutic landscape
• Evidence-based updates and results from data presented at 2011 oncology meetings
Questions and Answers (5 mins)
Community and Academic Community and Academic Ground Rounds: Transforming Ground Rounds: Transforming Treatment in Ovarian CancerTreatment in Ovarian Cancer
Courtesy of Bradley J. Monk, MD, FACOG, FACS.
Newly Diagnosed Advanced Newly Diagnosed Advanced Ovarian CancerOvarian Cancer
Ovarian Carcinoma: Ovarian Carcinoma: Incidence and MortalityIncidence and Mortality
Incidence in US women– 21,990 cases in 2011
– Ninth most common cancer
– Second most common gynecologic cancer
– 1.4% lifetime risk of developing ovarian cancer
Mortality in US women– 15,460 deaths in 2011
– Fifth most common cause of cancer death
– Fourth leading cause of cancer deaths in women aged 40–59 yrs
– Most common cause of death due to gynecologic cancer
– 1.0% lifetime risk of dying of ovarian cancerUS = United States.ACS, 2011.
Stage Distribution and 5-yr Relative Stage Distribution and 5-yr Relative Survival by Stage at DiagnosisSurvival by Stage at Diagnosis
(2001–2007, all races)(2001–2007, all races)
LNs = lymph nodes.Howlader et al, 2011.
Results of Treatment: Results of Treatment: Advanced DiseaseAdvanced Disease
CR = complete response; PFS = progression-free survival.Gynecologic Oncology Group Database (courtesy of J. Tate Thigpen, MD).
Parameter Small Volume Large Volume
Response (%) 95 75
Clinical CR (%) 95 50
Pathologic CR (%) 50 25
PFS (mos) 25 18
Survival (mos) 50 36
10-yr Survival (%) 30–40 15–20
Results of Treatment: Results of Treatment: Advanced Disease (cont.)Advanced Disease (cont.)
Parameter (%) Small Volume Large Volume
1980: 10-yr survival 7 0
1990: 10-yr survival 20 10
2008: 10-yr survival 30–40 15–20
Gynecologic Oncology Group Database (courtesy of J. Tate Thigpen, MD).
First-Line Therapy First-Line Therapy Global Standard TreatmentGlobal Standard Treatment
IV Platinum + Taxane Chemotherapy(Carboplatin + Paclitaxel) x 6
IV = intravenous.Pfisterer & Ledermann, 2006.Courtesy of Bradley J. Monk, MD, FACOG, FACS.
Surgery With Maximum Cytoreduction Effort
Basis for Current Standard: Basis for Current Standard: Systemic TherapySystemic Therapy
Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin – GOG Protocol 111
– EORTC-NCIC OV 10
Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy– AGO Trial
– GOG Protocol 158
GOG = Gynecologic Oncology Group; EORTC = European Organisation for Research and Treatment of Cancer; NCIC = National Cancer Institute of Canada; AGO = Arbeitsgemeinschaft Gynäkologische Onkologie.Ozols, 2008; Ozols et al, 2003; McGuire et al, 1996; Piccart et al, 2000; Du Bois et al, 2004.
Case Study 1Case Study 1Integrating Personalized Approaches Into Integrating Personalized Approaches Into Treatment Planning and Management for Treatment Planning and Management for
First-Line TherapyFirst-Line Therapy
Case Study 1Case Study 1
A 65-yr-old woman with diet controlled diabetes and a past history (18 mos ago) of an uncomplicated myocardial infarction presents to her PCP with a 1-mos history of increasing abdominal bloating and pain
Work-up reveals a 10-cm pelvic mass and extensive intra-abdominal ovarian cancer
PCP = primary care physician.
Based on Existing Evidence-Based Based on Existing Evidence-Based Data, What Options Might Be Data, What Options Might Be Considered at This Point? Considered at This Point?
1) Surgery + “standard” q3wk carboplatin + paclitaxel
2) Surgery + “standard” q3wk carboplatin + wkly paclitaxel
3) Neoadjuvant chemotherapy followed by surgery
4) Surgery + IP chemotherapy
5) Surgery + “standard” carboplatin + paclitaxel + bevacizumab
IP = intraperitoneal.
JGOG: Dose-Dense Wkly PaclitaxelJGOG: Dose-Dense Wkly Paclitaxel
EOC or PP Stage II–IV No prior therapy Stratified: Residual disease,
stage, and histology Primary end point: PFS Secondary end point: OS
Pac 180 mg/m2 Carb AUC = 6
Carb AUC = 6Pac 80 mg/m2/wk x 3
Accrual: 637 patients (ITT)
I
II
EOC = epithelial ovarian cancer; PP = primary peritoneal cancer; OS = overall survival; JGOG = Japanese Gynecologic Oncology Group; ITT = intent-to-treat; AUC = area under curve.Isonishi et al, 2008.
x 6–9
x 6–9
Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy
Improved PFS with dose-dense wkly paclitaxel
Isonishi et al, 2008.
JGOG: Dose-Dense Wkly Paclitaxel JGOG: Dose-Dense Wkly Paclitaxel (cont.)(cont.)
Justification for Neoadjuvant Justification for Neoadjuvant ChemotherapyChemotherapy
1. Extensive intra-abdominal ovarian cancer preventing, or increasing the risk for an unsuccessful “optimal” cytoreduction
2. Elderly patient or woman with significant comorbidity (eg, history of CHF) substantially increasing the risk associated with major abdominal surgery
CHF = congestive heart failure.Weinberg et al, 2010.
Ovarian, Tubal, or Peritoneal CancerFIGO Stage IIIC/IV (N = 670)
Primary End Point: OSSecondary End Points: PFS, QOL, AEs
Randomization
PDS NACT
3 x platinum-based CT
IDS if no PDIDS (not obligatory)
≥ 3 x platinum-based CT≥ 3 x platinum-based CT
3 x platinum-based CT
NACT = neoadjuvant chemotherapy; IDS = interval debulking surgery; PDS = primary debulking surgery; FIGO = International Federation of Gynaecology and Obstetrics; CT = chemotherapy; PD = progressive disease; QOL = quality of life; AEs = adverse events.Vergote et al, 2008, 2010.
NACT + IDS Vs. PDSNACT + IDS Vs. PDS
HR = hazard ratio.Vergote et al, 2010.
NACT + IDS Vs. PDS (cont.)NACT + IDS Vs. PDS (cont.)ITT AnalysisITT Analysis
NACT + IDS Vs. PDS (cont.)NACT + IDS Vs. PDS (cont.)Surgical Characteristics PDS
(n = 329)NACT IDS
(n = 339)Postoperative mortality (< 28 days)
2.5% 0.7%
Postoperative fever grade 3/4 8.1% 1.7%Fistula (bowel/GU) 1.2% / 0.3% 0.3% / 0.6%
Operative time (mins) 180 180
RBC transfusion 51% 53%
Hemorhage grade 3/4 7.4% 4.1%
Venous grade 3/4 2.6% 0%
GU = genitourinary; RBC = red blood cell.Vergote et al, 2008, 2010.
Median PFS (mos)
HR Median OS (mos)
HR
IV IP IV IP
GOG 104 — — — 41 490.76
(p = .02)
GOG 114 22 280.78
(p = .01) 52 630.81
(p = .05)
GOG 172 18.3 23.80.80
(p = .05) 50 660.75
(p = .03)
Alberts et al, 1996; Markman et al, 2001; Armstrong et al, 2006.
Primary Therapy: IPPrimary Therapy: IP
GOG 172: Ovarian (Optimal III)GOG 172: Ovarian (Optimal III) EOC Optimal stage III No prior therapy Elective second-look
Open: 23-March-98Closed: 29-January-01Accrual: 415 patients (evaluable)
Pac 135 mg/m2 (24 hrs)Cis 75 mg/m2 Day 2
Pac 135 mg/m2 (24 hrs) IV Day 1Cis 100 mg/m2 IP Day 2Pac 60 mg/m2 IP Day 8
I
II
Armstrong et al, 2006.
GOG Protocol 172GOG Protocol 172
RR = response rate; CI = confidence interval.Adapted from Armstrong et al, 2006.
By Treatment GroupPr
opor
tion
Surv
iving
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months on Study0 12 24 36 48 60
Rx Group Alive Dead Total IV 93 117 210
Alive Dead Total
IP 117 88 205
IV median OS = 49.7 mos
IP median OS = 65.6 mos
RR of death = 0.75 (95% CI: 0.58, 0.97) p = .03
Rx Group Lost to Alive Dead TotalFollow-up
IV 5 78 127 210IP 11 93 101 205
GOG Protocol 172: ToxicityGOG Protocol 172: Toxicity
GradeIV
(N = 210; %)IP
(N = 201; %)
3/4 Leukopeniaa 64 76
3/4 Platelet 4 12
3/4 GIa 24 46
3/4 Renala 2 7
3/4 Neurologic eventa 9 19
3/4 Fatiguea 4 18
3/4 Infectiona 6 16
3/4 Metabolica 7 27
3/4 Paina 1 11
No difference in QOL at 12 mosap ≤ .05GI = gastrointestinal.Armstrong et al, 2006.
GOG 218: SchemaGOG 218: Schema
Front-Line EOC, PP, or FT
• Stage III optimal (macroscopic)
• Stage III suboptimal• Stage IV
N = 1,800 (planned)
Stratification variables – GOG PS – Stage/debulking status
1:1:1
15 mos
P 175 mg/m2
C AUC 6
Placebo
IArm
Cytotoxic(6 cycles)
Maintenance(16 cycles)
(CP)
C AUC 6
P 175 mg/m2
PlaceboBev 15 mg/kg
II(CP + Bev)
Bev 15 mg/kg
C AUC 6
P 175 mg/m2III
(CP + Bev Bev)
FT = fallopian tube; PS = performance status; C = carboplatin; P = paclitaxel.Burger et al, 2010.
GOG 218: Patient DispositionGOG 218: Patient Disposition
Characteristic
Arm ICP
(n = 625)
Arm IICP + Bev(n = 625)
Arm IIICP + Bev Bev
(n = 623)
Median (range) number Bev/placebo cycles 11 (0–22a) 12 (0–22a) 14 (0–21)
On treatment at time of analysis, n (%) 86 (14) 82 (13) 117 (19)
Completed regimen, n (%) 100 (16) 104 (17) 148 (24)
Discontinued study treatment, n (%)
Disease progression 299 (48) 264 (42) 164 (26)
AEs 69 (11) 86 (14) 94 (15)
Cycles 1–6 57 (9) 73 (12) 59 (9)
Cycle ≥ 7 12 (2) 13 (2) 35 (6)
Deaths 8 (1) 7 (1) 13 (2)
Patient refusal 44 (7) 55 (9) 50 (8)
Other 19 (3) 27 (4) 37 (6)
Percentages may not total 100% due to rounding or categorization
aOne patient in each group received Bev/placebo in Cycle 1.Burger et al, 2010.
AE (grade when limited), n (%)
Arm ICP
(n = 601)
Arm IICP + Bev(n = 607)
Arm IIICP + 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 AEsGOG 218: Select AEsOnset Between Cycle 2 and 30 Days After Date of Last TreatmentOnset Between Cycle 2 and 30 Days After Date of Last Treatment
aPerforation/fistula/necrosis/leak.b p < .05HTN = hypertension; CNS = central nervous system; RPLS = reversible posterior leukoencephalopathy syndrome.Burger et al, 2010.
GOG 218: Select AEs (cont.) GOG 218: Select AEs (cont.) Treatment PhaseTreatment Phase
Select AEs (n)(grade when limited)
Arm ICP
Arm IICP + Bev
Arm IIICP + Bev Bev
Patients (n) (n = 601) (n = 483) (n = 607) (n = 457) (n = 608) (n = 464)Cycles (n) 2,906 4,059 2,911 4,204 2,891 4,677
Treatment phasea Cytotoxic (Cycles 2–6)
Maintenance (Cycles ≥ 7)
Cytotoxic(Cycles 2–6)
Maintenance (Cycles ≥ 7)
Cytotoxic (Cycles 2–6)
Maintenance (Cycles ≥ 7)
GI eventsb (grade ≥ 2) 6 1 16 1 15 1
HTN (grade ≥ 3) 3 7 24 12 25 38
Proteinuria (grade ≥ 3) 2 2 4 0 0 10
Pain (grade ≥ 3) 28 23 42 31 46 37
Neutropenia (grade ≥ 4) 345 2 382 2 385 0
Febrile neutropenia 21 0 30 0 26 0
Venous thromboembolic event 26 9 27 5 27 14
Arterial thromboembolic event 4 1 1 3 3 1
CNS bleeding 0 0 0 0 0 2
Non-CNS bleeding (grade ≥ 3) 3 2 8 0 10 3
RPLS 0 0 1 0 0 1
aOnset within 30 days of last treatment.bPerforation/fistula/necrosis/leak.Burger et al, 2010.
CP (Arm I)
GOG 218: Investigator-Assessed GOG 218: Investigator-Assessed PFSPFS
+ Bev (Arm II)
+ Bev Bev maintenance (Arm III)
Pro
porti
on P
FS (%
)
Time (Mos Since Randomization)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 12 24 36
Arm I
CP (n = 625)
Patients with event (n; %) 423 (67.7)
Median PFS (mos) 10.3
Stratified analysis HR (95% CI)
One-sided p value (log rank)
Arm III
CP + Bev Bev(n = 623)
360 (57.8)
14.10.717
(0.625–0.824)< .0001a
Arm II
CP + Bev(n = 625)
418 (66.9)
11.20.908
(0.759–1.040).080a
a p = .0116Burger et al, 2010.
GOG 218: Subgroup Analyses of PFSGOG 218: Subgroup Analyses of PFSCP + Bev CP + Bev Bev (Arm III) Vs. CP (Arm I)Bev (Arm III) Vs. CP (Arm I)
HR
Experimental Arm (CP + Bev Bev;
Arm III) BetterControl Arm
(CP; Arm I) Better
Stage III optimal (n = 434) 0.618
Stage III suboptimal (n = 496) 0.763
Stage IV (n = 318) 0.698
PS 0 (n = 616) 0.710
PS 1/2 (n = 632) 0.690
Age < 60 yrs (n = 629) 0.680
Age 60–69 yrs (n = 409) 0.763
Age ≥ 70 yrs (n = 210) 0.678
Treatment HR
0.33 0.5 0.67 1.0 1.5 2.0 3.0
Burger et al, 2010.
GOG 218: OS Analysis GOG 218: OS Analysis At Time of Final PFS Analysis (January 2010)At Time of Final PFS Analysis (January 2010)
Arm ICP
(n = 625)
Arm IICP + Bev(n = 625)
Arm IIICP + Bev Bev
(n = 623)
Patients with events (n; %)
156
(25.0)
150
(24.0)
138
(22.2)
Median (mos) 39.3 38.7 39.7
HRa
(95% CI)
1.036(0.827–1.297)
0.915(0.727–1.152)
One-sided p value .361 .252
Pro
porti
on A
live
(%)
Time (Mos Since Randomization)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 12 24 36 48
aStratified analysis.
625/625/623 442/432/437 173/162/171 46/39/40No. at risk
Burger et al, 2010.
ICON7: Study DesignICON7: Study Design
Stratification variables – Stage/surgery– Time since surgery
– GCIG group
aMight vary based on GCIG group.
P 175 mg/m2
C AUC 6a
C AUC 6a
P 175 mg/m2
Arm A
Arm A
ArmArm BB
12 mos12 mos
Front-Line EOC, PP, or FT• Stage I/IIA (grade 3) • Stage IIB/C• Stage III• Stage IV
N = 1,520 (planned)
Bev 7.5 mg/kg
Primary end point: PFS
Secondary end points: OS, RR, QOL, safety, cost-effectiveness,translational
No IRC present
GCIG = Gynecologic Cancer Intergroup; IRC = independent review committee.Kristensen et al, 2011.
Key Differences Between Key Differences Between GOG 218 and ICON7GOG 218 and ICON7
Trial GOG 218 ICON7
Setting/Design
Double-blinded, placebo-controlled 3-arm study Bev for 15 mos Bev dose: 5 mg/kg/wk
Open-label 2-arm study Bev for 12 mos Bev dose: 2.5 mg/kg/wk
Patient Population
Stage III (suboptimal) Stage III (optimal, visual/palpable) Stage IV
Stage I or IIA (grade 3/clear cell histology)
Stages IIB–IV (all)
Additional End Point
OS analysis (formal testing at time of PFS) IRC
Defined final OS analysis (end 2012)
No IRC
Burger et al, 2010; Kristensen et al, 2011.
Stratification Variables Stage and extent of debulking:
I–III debulked ≤ 1 cm Stage I–III debulked > 1 cm Stage IV and inoperable stage III
Timing of intended treatment start≤ 4 vs. > 4 wks after surgery
GCIG group
ICON7 SchemaICON7 Schema
Academic-led, industry-supported trial to investigate use of Bev
and to support licensing
Paclitaxel 175 mg/m2
Carboplatin AUC 5/6
Carboplatin AUC 5/6
Paclitaxel 175 mg/m2
18 cycles
N = 1,528a
BEV 7.5 mg/kg q3wks
1:1
aDecember 2006 to February 2009.Kristensen et al, 2011.
R
ICON7 PFS: UpdatedICON7 PFS: Updated
17.419.8
ControlResearch
Kristensen et al, 2011.
PFS: “High Risk” Subgroup (Ad Hoc Analysis)PFS: “High Risk” Subgroup (Ad Hoc Analysis)
Number At RiskControl 234 205 98 36 14 2Research 231 213 159 56 10 1
1.00
0.75
0.50
0.25
0
Prop
ortio
n A
live
With
out P
rogr
essi
on (%
)
Time (mos) 0 3 6 9 12 15 18 21 24 27 30
Control(n = 234)
Research (n = 231)
Events, n (%) 173 (74) 158 (68)Median (mos) 10.5 15.9Log-rank test p < .001HR (95% CI) 0.68 (0.55–0.85)Restricted mean 13.3 16.5
10.5 15.9
ControlResearch
Kristensen et al, 2011.
High Risk: Stage IIIC Suboptimal/Stage IV
Interim Analysis of Overall Survival Interim Analysis of Overall Survival
Kristensen et al, 2011.
Case Study 2Case Study 2Optimally Managing Recurrent Optimally Managing Recurrent
Ovarian CancerOvarian Cancer
Case Study 2 Case Study 2
A 54-yr-old woman with ovarian cancer attains a clinically-defined CR to primary carboplatin/paclitaxel chemotherapy
10 mos following the completion of chemotherapy abdominal pain returns and a repeat CT scan reveals the presence of diffuse small IP masses
What are the current antineoplastic drug options and the direction of future research in this clinical setting?
Recurrence After First-Line Chemotherapy
PlatinumPlatinumSensitiveSensitive
> 6 Mos> 6 Mos
ChemotherapyChemotherapyDoubletDoublet
Platinum Platinum Refractory/ResistantRefractory/Resistant
< 6 Mos< 6 Mos
Non-PlatinumNon-PlatinumSingle AgentSingle Agent
The Traditional Treatment Paradigm The Traditional Treatment Paradigm
Ushijima, 2010.
Recurrent Ovarian Cancer:Recurrent Ovarian Cancer:Definition of Disease SensitivityDefinition of Disease Sensitivity
0 3 6 12 18 24
Refractory
PREVIOUS
TREATMENT
Resistant
Sensitive
Time to Recurrence (mos)
Highly Sensitive
Our Patient
Ushijima, 2010.
Major Trials in Major Trials in Recurrent Ovarian CancerRecurrent Ovarian Cancer
Paclitaxel vs. topotecan Topotecan vs. PLD Platinum vs. platinum + paclitaxel Carboplatin vs. carboplatin + gemcitabine Carboplatin + paclitaxel vs. carboplatin + PLD PLD vs. PLD + trabectedin
PLD = pegylated liposomal doxorubicin.ten Bokkel Huinink et al, 1997, 2004; Gordon et al, 2004; Parmar et al, 2003; Pfisterer et al, 2006; Pujade-Lauraine et al, 2010; Monk et al, 2010.
FDA-Approved Drugs inFDA-Approved Drugs inOvarian CancerOvarian Cancer
1978
Cisp
latin
Carb
opla
tin
Altre
tam
ine
Pacli
taxe
lTo
pote
can
PLD
(acc
eler
ated
)Li
poso
mal
dox
orub
icin
(full)
Gem
citab
ine
(with
car
bopl
atin
)
2006
1989
1990
1992
1996
1999
2005
2009
Trab
ecte
din;
EU
only
(with
PLD
)
1964
Mel
phal
anDo
xoru
bicin
1974
NCCN, 2011; Shah et al, 2009.
Recurrence RegimensRecurrence RegimensNCCN Preferred AgentsNCCN Preferred Agents
aPlatinum-based combination therapy should be considered for platinum sensitive recurrences. NCCN = National Comprehensive Cancer Network.NCCN, 2011.
Phase III Study (Doublets): CALYPSOPhase III Study (Doublets): CALYPSO
RANDOMIZE
Relapse
Paclitaxel 175 mg/m2
Carboplatin AUC 5q3wks
PLD 30 mg/m2
Carboplatin AUC 5q4wks
Ovarian Cancer – First relapse– Platinum-sensitive
Pujade-Lauraine et al, 2010.
Opened: 4/2005Closed: 10/2007
N = 976
PFS: ITTPFS: ITTCD CP
Median PFS (mos) 11.3 9.4
HR (95% CI) 0.82 (0.72, 0.94)
Log-rank p (superiority) .005
p (non-inferiority) < .001
CD = carboplatin-PLD.Pujade-Lauraine et al, 2010.
Intermediate Sensitive: 6–12 mosIntermediate Sensitive: 6–12 mosCD CP
Median PFS (mos) 9.4 8.8
HR (95% CI) 0.73 (0.58, 0.90)
Log-rank p value (superiority) .004
p value (non-inferiority) < .001
Pujade-Lauraine et al, 2010.
Months from Randomization
PFS: Highly Platinum-Sensitive PFS: Highly Platinum-Sensitive (PFI > 24 mos)(PFI > 24 mos)
C-PLD C-P HR pPFS 12.0
mos12.3 mos
1.05 (0.79–1.40)
.73
RR 42% 38% .46
PFI = progression-free interval.Mahner et al, 2011.
CALPYSO: OS AnalysisCALPYSO: OS Analysis
Marth et al, 2011.
Bevacizumab: The First Active Bevacizumab: The First Active Targeted Agent in Ovarian CancerTargeted Agent in Ovarian Cancer
Case report of single-agent activity– Monk et al, 2005
Phase II of single-agent activity– Burger et al, 2007
Phase II of combination therapy– Garcia et al, 2008
Randomized phase III trial (GOG 218)– Burger et al, 2010
CG + PLA
OCEANS: Study SchemaOCEANS: Study Schema
CG for 6 (up to 10) cycles
Stratification VariablesPlatinum-free interval
(6–12 vs. > 12 mos)Cytoreductive surgery for
recurrent disease (yes vs. no)
Platinum-Sensitive ROCa Measurable disease ECOG 0/1 No prior chemotherapy for ROC No prior BEV
(N = 484)
aEOC, PP, or FT cancer.ROC = recurrent ovarian cancer; ECOG = Eastern Cooperative Oncology Group.Aghajanian et al, 2011.
Gemcitabine 1,000 mg/m2
Days 1, 8
Carboplatin AUC 4
PLA q3wks Until Progression
Carbopaltin AUC 4
BEV 15 mg/kg q3wks Until Progression
Gemcitabine 1,000 mg/m2
Days 1, 8CG + BEV
OCEANS: Patient CharacteristicsOCEANS: Patient CharacteristicsCharacteristic
CG + PLA (n = 242)
CG + BEV (n = 242)
Median age (yrs) (range)
61(28−86)
60(38–87)
Age ≥ 65 yrs (%) 38 35Race (%) White Other
928
9010
ECOG PS 0 (%) 76 75Histologic subtype (%) Serous Mucinous/clear cell Other
843 14
785
17Platinum-free interval (%) 6–12 mos > 12 mos
4258
4159
Cytoreductive surgery for recurrent disease (%) 10 12
Aghajanian et al, 2011.
242 177 45 11 3 0CG + PL
OCEANS: Primary Analysis of PFSOCEANS: Primary Analysis of PFSCG + PLA(n = 242)
CG + BEV(n = 242)
Events, n (%) 187 (77) 151 (62)Median PFS (mos) (95% CI)
8.4(8.3–9.7)
12.4(11.4–12.7)
Stratified analysis HR (95% CI)Log-rank p value
0.484 (0.388–0.605)
< .0001
Time (mos)Number At Risk
242 203 92 33 11 0CG + BV
1.0
0.8
0.6
0.4
0.2
0
Prop
ortio
n PF
S (%
)
0 6 12 18 24 30
ORRGC: 57.4%GC+B: 78.5% p < .0001
Aghajanian et al, 2011.
Median PFS (mos)
Baseline risk factor No. of patients CG + PLA
(n = 242)CG + BEV (n = 242) HR (95% CI)
CG + BEV
betterCG + PLA
betterAll patients 484 8.4 12.4 0.49 (0.40–
0.61)Platinum-free interval (mos)
6–12 202 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 disease
Yes 54 7.5 16.7 0.50 (0.24–1.01)
No 430 8.4 12.3 0.49 (0.39–0.62)
Age (yrs) < 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)
OCEANS: PFS Subgroup AnalysesOCEANS: PFS Subgroup Analyses
HR0.2 0.5 1 2 5
Aghajanian et al, 2011.
OCEANS: Interim OSOCEANS: Interim OS1.0
0.8
0.6
0.4
0.2
0
Prop
ortio
n A
live
(%)
0Time (mos)
6 12 30 36 42
Number At Risk
18 24
242 235 195 26 8 0CG + PL 131 77242 238 200 42 8 0CG + BV 146 82
CG + PLA(n = 242)
CG + BEV(n = 242)
Events, n (%) 78 (32) 63 (26)Median OS (mos) (95% CI)
29.9(26.4–NE)
35.5(30.0–NE)
Stratified analysis HR (95% CI)Log-rank p value
0.751(0.537–1.052)
.094a
ap value does not cross pre-specified boundary of .001NE = not estimable.Aghajanian et al, 2011.
OCEANS: AEs of Special InterestOCEANS: AEs of Special Interest Patients (%)
CG + PLA(n = 233)
CG + BEV(n = 247)
ATE, all grades 1 3VTE, grade ≥ 3 3 4CNS bleeding, all grades < 1 1Non-CNS bleeding, grades ≥ 3 1 6CHF, grades ≥ 3 1 1Neutropenia, grade ≥ 3 56 58Febrile neutropenia, grade ≥ 3 2 2HTN, grade ≥ 3 < 1 17Fistula/abscess, all grades < 1 2GI perforation, all grades 0 0a
Proteinuria, grade ≥ 3 1 9RPLS, all grade 0 1Wound-healing complication, grades ≥ 3 0 1
aTwo GI perforations occurred 69 days after last BEV dose.ATE = arterial thromboembolic event; VTE = venous thromboembolic event. Aghajanian et al, 2011.
OCEANS: Preliminary ConclusionsOCEANS: Preliminary Conclusions
BEV + carboplatin + gemcitabine followed by BEV until progression provides a clinically meaningful benefit over chemotherapy alone in ROC– Improved PFS: HR 0.484 (p < .0001);
median 8.4 → 12.4 mos
– Improved ORR and duration of response
– OS data not yet mature
Safety data consistent with BEV profile– No GI perforations and no new safety signal
Aghajanian et al, 2011.
Novel Therapies andNovel Therapies and Future Directions Future Directions
PARP InhibitorsPARP InhibitorsSuggested Mechanism of ActionSuggested Mechanism of Action
PARP1
PARP1
PARP1
CELL DEATHCELL SURVIVAL
BRCA1BRCA2
Replication fork collapse
Double strand DNA break
Disables DNA
base-excision repair
Inhibition of PARP1
Base-excision repair of DNA damage
PARP1 Upregulation
Chemotherapy inflicts DNA damage via adducts and
DNA cross-linking
PARP Inhibitor
PARP = poly (ADP-ribose) polymerase; DNA = deoxyribonucleic acid. O’Shaughnessy et al, 2009.
Phase II Study of Olaparib of Patients With Phase II Study of Olaparib of Patients With BRCA1 BRCA1 or or BRCA2BRCA2 Mutation Mutation
Two dosages tested in sequential cohorts of patients with recurrent, measurable disease
Primary end point: RR
AEs: Nausea, fatigue, anemiaBRCA = breast cancer gene; BID = twice daily; ORR = overall response rate.Audeh et al, 2010.
400 mg BIDn = 33ORR = 33%
100 mg BIDn = 24ORR = 13%
Study 19: Aim and DesignStudy 19: Aim and Design To assess the efficacy of olaparib (OLA) as a maintenance
treatment in patients with platinum-sensitive high grade serous ovarian cancer
Randomized, double-blind, placebo-controlled phase II study Multinational study; 82 sites in 16 countries
OLA 400 mg po BID
Randomized 1:1
PLApo BID
Patient EligibilityPlatinum-sensitive high grade serous ovarian cancer 2 previous platinum regimens Last chemotherapy: Platinum-based with a
maintained responseStable CA125 at trial entryRandomization stratification factors
– Time to PD on penultimate platinum therapy– Objective response to last platinum therapy – Ethnic descent
Treatment until PD
po = oral; PD = progressive disease.Ledermann et al, 2011.
Patient CharacteristicsPatient CharacteristicsOlaparib
400 mg bid(n = 136)
Placebo(n = 129)
Median age, yrs (range) 58 (21–89) 59 (33–84)
Ethnicity, n (%)Jewish descent 20 (15) 17 (13)
ECOG status, n0 / 1 / 2 / unknown 110 / 23 / 1 / 2 95 / 30 / 2 / 2
BRCA mutation status, n (%)a
BRCA1BRCA2BRCA1 and BRCA2Known negativeUnknown
25 (18)6 (4)
018 (13)87 (64)
20 (16)7 (5)1 (1)
20 (16)81 (63)
aBRCA mutation status was not a requirement.Ledermann et al, 2011.
Progression-Free SurvivalProgression-Free Survival
0
Time from randomization (mos)
136 104 51 23 6 0 0129 72 23 7 1 0 0
At risk (n)OlaparibPlacebo
0.6
0.8
0.9
0
0.1
0.2
0.3
0.4
0.5
0.7
1.0
3 6 9 12 15 18
No. of events: Total patients (%)
Median PFS (mos)
Olaparib60:136 (44.1)
8.4
Placebo93:129 (72.1)
4.8
HR 0.35 (95% CI, 0.25–0.49)p < .00001
Olaparib 400 mg bidPlacebo
Randomized TreatmentProp
ortio
n of
PFS
(%)
Ledermann et al, 2011.
Preplanned Subgroup Analysis of PFSPreplanned Subgroup Analysis of PFS
Global interaction test showed no evidence of inconsistency across the subgroups (p = .282)
HR (OLA: PLA) and 95% CI0.0 0.2 0.4 0.6 0.8 1.00.1 0.3 0.5 0.7 0.9
OverallBRCA mutationBRCA status known
Age < 50Age ≤ 50 to < 65Age ≥ 65Race, whiteNon-Jewish descentCR at baselinePR at baselineTTP penultimate platinum regimen 6–12 mosTTP penultimate platinum regimen > 12 mos
BRCA unknown
Favors OLA
Size of circle is proportional to number of events; grey band represents 95% CI in overall population
PR = partial response; TTP = time to progression.Ledermann et al, 2011.
Pharmacogenomics
Molecular Biology
Companion Diagnostics
Bioinformatics Translational Genomics
Pharmacometabonomics
Personalized Medicine
Confluence of Multiple AdvancesConfluence of Multiple Advances
Targets
AngiogenesisVEGF/VEGFR
MoAb
EGFR
FR
Repackaging Traditional Agents
PARP
mTOR/Akt/PI3K
VEGF/R = vascular endothelial growth factor/receptor; EGFR = epidermal growth factor receptor; ER = estrogen receptor; PDGFR = platelet-derived growth factor receptor; MoAb = monoclonal antibody; mTOR = mammalian target of rapamycin; PI3K = phosphatidylinositol 3-kinase; FR = folate receptor; PKC = protein kinase C; HSP90 = heat shock protein-90.Banerjee et al, 2009.
ER
CA125
Src
PDGFR HSP90PKC
Future Strategies in Ovarian CancerFuture Strategies in Ovarian Cancer
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